Monday, May 27, 2013
Peptide
Adrenocorticotropic hormone
Adrenocorticotropic hormone (ACTH) or corticotropin, is a hormone produced by the anterior pituitary gland in response to biological stress by effecting the increased production and release of corticosteroids(a)
1. Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome inhibition and transmissible enteritis
Stress alters brain-gut interactions and could exacerbate intestinal disorders, including irritable bowel syndrome. Alterations in the intestinal microbiota have been associated with irritable bowel syndrome.
In the study to mice that were not exposed to stress were co-housed with mice subjected to WAS to determine the effects of WAS-induced dysbiosis, measured by sequencing bacterial 16S ribosomal RNA. We also assessed the effects of a peroxisome proliferator-activated receptor-γ agonist and probiotics, found that mice expose to stress inhibits NLRP6 and alters the composition of the gut microbiota, leading to intestinal inflammation. These findings might explain the benefits of probiotics for patients with stress-associated gastrointestinal disorders(1).
2. Corticotropin-releasing hormone in depression and post-traumatic stress disorder
Corticotropin-releasing hormone (CRH) has been implicated in the regulation of a wide range of behaviors including arousal, motor function, feeding, and reproduction. According to the study by the Cincinnati VAMC, Psychiatry Service, overall, the data suggest that melancholic depression is characterized by hyperactive central CRH systems with overactivity of the pituitary-adrenal (HPA) axis. On the other hand, atypical depression is characterized by hypoactive central CRH systems and accompanying underactivity of the hypothalamic-pituitary-adrenal axis. Furthermore, the neuroendocrinology of PTSD appears to be unique, in that patients have hyperactive central CRH systems with underactivity of the pituitary-adrenal axis(2).
3. Early-life stress-induced anxiety-related behavior in adult mice
Early-life stress may lead to persistent changes in central corticotropin-releasing hormone (CRH) and the CRH receptor 1 (CRHR1) system that modulates anxiety-related behavior. In the study used conditional forebrain CRHR1 knockout (CRHR1-CKO) mice and examined the potential role of forebrain CRHR1 in the anxiogenic effects of early-life stress, indicated that as adults, wild-type mice that received unstable maternal care during the first postnatal week showed reduced body weight gain and increased anxiety levels in the open field test, which were prevented in stressed CRHR1-CKO mice. In the light-dark box test, control CRHR1-CKO mice were less anxious, but early-life stress increased anxiety levels in both wild-type and CRHR1-CKO mice. In the elevated plus maze test, early-life stress had only subtle effects on anxiety-related behavior. Moreover, early-life stress did not alter the basal home cage activity and gene expression levels of key hypothalamic-pituitary-adrenal axis regulators in adult wild-type and CRHR1-CKO mice, but enhanced neuroendocrine reactivity to acute immobilization stress in CRHR1-CKO mice(3).
4. Stress and Visceral Pain: Focusing on Irritable Bowel Syndrome
Irritable bowel syndrome (IBS) is characterized by chronic recurrent abdominal pain or abdominal discomfort associated with bowel dysfunction. According to the study by the Tohoku University Graduate School of Medicine Sendai, it is also thought to be a disorder of the brain-gut link associated with an exaggerated response to stress. Corticotropin-releasing hormone (CRH), a major mediator of the stress response in the brain-gut axis, is an obvious candidate in the pathophysiology of IBS. Indeed, administration of CRH has been shown to aggravate the visceral sensorimotor response in IBS patients and the administration of peptidergic CRH antagonists seems to alleviate IBS pathophysiology. Serotonin (5-HT) is another likely candidate associated with brain-gut function in IBS since 5-HT3 antagonists, 5-HT4 agonists, and antidepressants were demonstrated to regulate 5-HT neurotransmission in IBS patients. Autonomic nervous system function, the neuroimmune axis, and the brain-gut-microbiota axis show specific profiles in IBS patients(4).
5. Role of corticotropin-releasing hormone in irritable bowel syndrome and intestinal inflammation
Corticotropin-releasing hormone (CRH) is a major mediator of stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with exaggerated response to stress. The study by Tohoku University Graduate School of Medicine, first showed that peripheral administration of CRH aggravated visceral sensorimotor function as well as adrenocorticotropic hormone (ACTH) response in IBS patients and administered alpha-helical CRH (alphahCRH), a non-selective CRH receptor antagonist among IBS patients. Electrical stimulation of the rectum induced significantly higher motility indices of the colon in IBS patients than in the controls. This response was significantly suppressed in IBS patients but not in the controls after administration of alphahCRH. Administration of alphahCRH induced a significant increase in the barostat bag volume of the controls but not in that of IBS patients. alphahCRH significantly reduced the ordinate scale of abdominal pain and anxiety evoked by electrical stimulation in IBS patients. Plasma ACTH and serum cortisol were generally not suppressed by alphahCRH. Last, administration of CRH1-receptor (CRH-R1) specific antagonist blocked colorectal distention-induced sensitization of the visceral perception in rats. Moreover, pretreatment with CRH-R1 antagonist blocked colorectal distention-induced anxiety, which was measured with elevated plus-maze, in rats. Evidence supporting the concept that peripheral CRH and CRH-R1 play important roles in brain-gut sensitization is increasing(5).
6. Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with IBS.
Corticotropin releasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with an exaggerated response to stress. In the study of ten normal healthy subjects and 10 IBS patients, diagnosed according to the Rome II criteria, the tone of the descending colon and intraluminal pressure of the sigmoid colon were measured at baseline, during rectal electrical stimulation (ES), and at recovery after administration of saline and visceral perception after colonic distension or rectal ES was evaluated as threshold values on an ordinate scale. The same measurements were repeated after administration of alphahCRH (10 micro g/kg), found that peripheral administration of alphahCRH improves gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation, without affecting the hypothalamo-pituitary-adrenal axis in IBS patients(6).
7. Impact of corticotropin-releasing hormone on gastrointestinal motility and adrenocorticotropic hormone in normal controls and patients with IBS
Corticotropin-releasing hormone (CRH) plays a key role in modulating intestinal motility in stressed animals. In the study to evaluate the effect of CRH on intestinal motility in humans and to determine whether patients with irritable bowel syndrome (IBS) have an exaggerated response to CRH, showed that
CRH induced motility of the descending colon in both groups (p < 0.001) and induced greater motility indexes in IBS patients than in controls (p < 0.05). CRH produced duodenal phase III motor activity in 80% of the subjects and duodenal dysmotility in 40% of IBS patients. Abdominal symptoms evoked by CRH in IBS patients lasted significantly longer than those in controls (p < 0.05). CRH induced significant increases in plasma ACTH levels in both groups (p < 0.001) and produced significantly higher plasma ACTH levels in IBS patients than in controls (p < 0.001)(7).
8. Placental Corticotropin-Releasing Hormone Mediates the Association Between Prenatal Social Support and Postpartum Depression
In the study to test whether prenatal social support predicted depressive symptoms at 8 weeks postpartum in a multiethnic sample of 210 women and whether the stress hormone placental corticotropin-releasing hormone (pCRH), measured at 19, 29, and 37 weeks' gestation, mediated this relationship, found that prenatal family support predicted significantly fewer depressive symptoms postpartum and more gradual increases in pCRH from 29 to 37 weeks' gestation. Furthermore, steeper increases in pCRH during this same period predicted more depressive symptoms postpartum. Finally, these changes in pCRH in late pregnancy mediated the relationship between prenatal family support and postpartum depressive symptoms. These results suggest that social and biological risk factors for postpartum depressive symptoms are intertwined and move us closer to an integrated biopsychosocial understanding of postpartum depression(8).
9. Maternal corticotropin-releasing hormone levels in the early third trimester predict length of gestation in human pregnancy
Corticotropin releasing hormone, a hypothalamic neuropeptide, plays a major role in regulating pituitary-adrenal function and the physiologic response to stress. In the study of a sample of 63 women with singleton intrauterine pregnancies, maternal plasma samples was collected between 28 and 30 weeks' gestation and corticotropin-releasing hormone concentrations were determined by radioimmunoassay and each pregnancy was dated on the basis of last menstrual period and early ultrasonography. Parity, antepartum risk conditions, presence or absence of spontaneous labor, and birth outcomes were abstracted from the medical record, found that maternal corticotropin-releasing hormone levels between 28 and 30 weeks' gestation significantly and negatively predicted gestational length (P < .01) after adjustment for antepartum risk. Moreover, subjects who were delivered preterm had significantly higher corticotropin-releasing hormone levels in the early third trimester (P < .01) than did those who were delivered at term. In deliveries preceded by spontaneous onset of labor, maternal third-trimester corticotropin-releasing hormone levels significantly and independently predicted earlier onset of labor (P < .01) and preterm labor (P < .05), whereas in deliveries effected by induction of labor or cesarean delivery, maternal corticotropin-releasing hormone levels were a marker of antepartum risk but not a statistically independent predictor of gestational length(9).
10. Predicting risk of preterm delivery by second-trimester measurement of maternal plasma corticotropin-releasing hormone and alpha-fetoprotein concentrations
In the study to to evaluate the ability of these biochemical tests and a clinical risk factor score to prospectively discriminate pregnancies at high risk for preterm delivery with a sample of eight hundred sixty women were studied prospectively from the early second trimester until delivery found that the combination of measurement of maternal plasma corticotropin-releasing hormone and alpha-fetoprotein concentrations in the second trimester with risk factor scoring provides a more accurate indicator of the risk of preterm delivery than does risk factor scoring alone. This method of risk assessment may therefore be of use in targeting prevention strategies(10).
11. Central deficiency of corticotropin-releasing hormone receptor type 1 (CRH-R1) abolishes effects of CRH on NREM but not on REM sleep in mice
Corticotropin-releasing hormone (CRH) is the major activator of the hypothalamic-pituitary-adrenocortical (HPA) system and orchestrates the neuroendocrine, autonomous as well as behavioral responses to stress. In the study to investigate in CNS-specific CRH receptor type 1 deficient mice whether centrally administered CRH could induce its sleep-wake modulatory effects without peripheral induction of HPA activity, found that CRH has a major impact on wake and NREMS regulation which is predominantly mediated through central CRH-R1. Peripheral actions of CRH, i.e., elevated HPA activity, may interfere with its central effects on REMS but not on NREMS suppression(11).
12. Deficiency of corticotropin-releasing hormone type-2 receptor alters sleep responses to bacterial lipopolysaccharide in mice
In the study to investigate whether CRH-R2 interferes with sleep responses to immune challeng and to examine effects of bacterial lipopolysaccharide (LPS) on sleep in CRH-R2 deficient (KO) mice. CRH-R2 KO mice and control littermates (CL) were implanted with electrodes for recording electroencephalogram (EEG) and electromyogram, indicated that after recovery, LPS was applied by intraperitoneal injection at doses of 0.1, 1.0, or 10 μg at dark onset. In response to LPS injection NREMS of both genotypes was enhanced in a dose-dependent manner. However, CRH-R2 KO mice showed a larger increase, in particular after 10 μg of LPS compared to CL mice. During postinjection, reduced delta power for NREMS was detected in both genotypes after each dose, but the highest dose evoked a marked elevation of EEG activity in a limited frequency band (4 Hz). However, the EEG power of lower frequencies (1-2 Hz) increased more in CRH-R2 KO than in CL mice(12).
13. Corticotropin-releasing hormone exerts direct effects on neuronal progenitor cells: implications for neuroprotection
In the study to investiage the involvement process of corticotrophin-releasing hormone (CRH) or factor as the major mediator of adaptive response to stressors, found that CRH could reverse the damaging effects of glucocorticoid on neural stem/progenitor cells (NS/PCs), while its genetic deficiency results in compromised proliferation and enhanced apoptosis during neurogenesis. Analyses in fetal and adult mouse brain revealed significant expression of CRH receptors in proliferating neuronal progenitors. Furthermore, by using primary cultures of NS/PCs, we characterized the molecular mechanisms and identified CRH receptor-1 as the receptor mediating the neuroprotective effects of CRH. Finally, we demonstrate the expression of CRH receptors in human fetal brain from early gestational age, in areas of active neuronal proliferation. These observations raise the intriguing possibility for CRH-mediated pharmacological applications in diseases characterized by altered neuronal homeostasis, including depression, dementia, neurodegenerative diseases, brain traumas and obesity(13).
14. Nesfatin-1, corticotropin-releasing hormone, thyrotropin-releasing hormone, and neuronal histamine interact in the hypothalamus to regulate feeding behavior
In the study to investigate whether the anorectic effect of nesfatin-1, α-fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), a CRH antagonist, or anti-TRH antibody affects the anorectic effect of nesfatin-1, whether nesfatin-1 increases CRH and TRH contents and histamine turnover in the hypothalamus, and whether histamine increases nesfatin-1 content in the hypothalamus. We also investigated whether nesfatin-1 decreases food intake in mice with targeted disruption of the histamine H1 receptor (H1KO mice) and if the H1 receptor (H1-R) co-localizes in nesfatin-1 neurons. Nesfatin-1-suppressed feeding was partially attenuated in rats administered with FMH, a CRH antagonist, or anti-TRH antibody, and in H1KO mice, showed that Nesfatin-1 increased CRH and TRH levels and histamine turnover, whereas histamine increased nesfatin-1 in the hypothalamus. Immunohistochemical analysis revealed H1-R expression on nesfatin-1 neurons in the paraventricular nucleus of the hypothalamus. These results indicate that CRH, TRH, and hypothalamic neuronal histamine mediate the suppressive effects of nesfatin-1 on feeding behavior(14).
15.. Corticotropin-releasing hormone deficiency is associated with reduced local inflammation in a mouse model of experimental colitis
CRH, the hypothalamic component of the hypothalamic-pituitary adrenal axis, attenuates inflammation through stimulation of glucocorticoid release, whereas peripherally expressed CRH acts as a proinflammatory mediator. AQccording to the study by Division of Endocrinology, Children's Hospital, Boston, despite low glucocorticoid levels, CRH-deficient mice develop substantially reduced local inflammatory responses. These effects were shown by histological scoring of tissue damage and neutrophil infiltration. At the same time, CRH deficiency was found to be associated with higher serum leptin and IL-6 levels along with sustained anorexia and weight loss, although central CRH has been reported to be a strong appetite suppressor. Taken together, our results support an important proinflammatory role for CRH during mouse experimental colitis and possibly in inflammatory bowel disease in humans. Moreover, the results suggest that CRH is involved in homeostatic pathways that link inflammation and metabolism(15).
16. Cell-type specific deletion of GABA(A)α1 in corticotropin-releasing factor-containing neurons enhances anxiety and disrupts fear extinction
Corticotropin-releasing factor (CRF) is critical for the endocrine, autonomic, and behavioral responses to stressors, and it has been shown to modulate fear and anxiety. In the study used a unique CRF-Cre driver transgenic mouse line to remove floxed GABA(A)α1 subunits specifically from CRF neurons [CRF-GABA(A)α1 KO] resulted in mice with decreased GABA(A)α1 expression only in CRF neurons and increased CRF mRNA within the amygdala, bed nucleus of the stria terminalis (BNST) and paraventricular nucleus of the hypothalamus, showed that normal locomotor and pain responses and no difference in depressive-like behavior or Pavlovian fear conditioning. However, CRF-GABA(A)α1 KO increased anxiety-like behavior and impaired extinction of conditioned fear, coincident with an increase in plasma corticosterone concentration. These behavioral impairments were rescued with systemic or BNST infusion of the CRF antagonist R121919. Infusion of Zolpidem, a GABA(A)α1-preferring benzodiazepine-site agonist, into the BNST of the CRF-GABA(A)α1 KO was ineffective at decreasing anxiety. Electrophysiological findings suggest a disruption in inhibitory current may play a role in these changes(16).
17. A novel role of peripheral corticotropin-releasing hormone (CRH) on dermal fibroblasts
In the study to to assess the effects of endogenous CRH in the biology of mouse and human skin fibroblasts, the primary cell type involved in wound healing, showed that expression of CRH and its receptors in primary fibroblasts, and we demonstrate the functionality of fibroblast CRH receptors by induction of cAMP. Fibroblasts genetically deficient in Crh (Crh-/-) had higher proliferation and migration rates and compromised production of IL-6 and TGF-β1 compared to the wildtype (Crh+/+) cells. Human primary cultures of foreskin fibroblasts exposed to the CRF(1) antagonist antalarmin recapitulated the findings in the Crh-/- cells, exhibiting altered proliferative and migratory behavior and suppressed production of IL-6(17).
18. Isolated adrenocorticotropic hormone deficiency presenting with hypercalcemia in a patient on long-term hemodialysis
There is a report of a report on a 44-year-old female hemodialysis (HD) patient who presented with hypercalcemia secondary to isolated adrenocorticotropic hormone (ACTH) deficiency. She had been suffering from nausea and abdominal pain caused by recurrent esophageal ulcer. Blood calcium (Ca) adjusted for serum albumin concentration was increased to 14.9 mg/dL (3.72 mmol/L) concurrently with fever and hypotension. Serum intact parathyroid hormone (PTH)-related peptide was not elevated, but serum intact PTH and 1,25-(OH)2 vitamin D3 were decreased to 31 pg/mL (ng/L) and 8.1 pg/mL (2.6 pmol/L), respectively. This case suggested that secondary adrenal insufficiency caused by isolated ACTH deficiency could be an occult cause of severe hypercalcemia in HD subjects(18).
19. May primary empty sella turcica be a cause of isolated ACTH deficiency
Isolated ACTH deficiency is an uncommon cause of secondary adrenocortical insufficiency and accompaniment with primary empty sella has been reported in several case. There is a report of a case of isolated ACTH deficiency associated with empty sella. A sixty-two year old woman was admitted to our endocrine clinic with complaints of weakness, fatigue, weight loss, nausea, vomiting, and lack of appetite for about one month. Physical examination indicated orthostatic hypotension and epigastric tenderness. Although cranial and abdominal computerized tomography images were evaluated as normal, cranial magnetic resonance imaging of the pituitary gland revealed 'primary empty sella turcica'. Replacement therapy with methylprednisolon resulted in the improvement of hypoglycemia, hyponatremia and clinical symptoms. Based on these results, the patient was diagnosed as isolated ACTH deficiency and was scheduled for follow up by our outpatient clinic(19).
20. The cause of syndrome of inappropriate ADH secretion" (SIADH)
According to the centre hospitalier régional universitaire de Lille, the causes of SIADH are classic: neoplastic (notably small-cell lung cancer), iatrogenic (particularly psychoactive drugs, chemotherapy), lung and cerebral. Some causes have been recently described: familial hyponatraemia via X-linked recessive disease caused by an activating mutation of the vasopressin 2 receptor; and corticotropin insufficiency related to drug interference between some inhaled glucocorticoids and cytochrome p450 inhibitors, such as the antiretroviral drugs and itraconazole, etc. SIADH in marathon runners exposes them to a risk of hypotonic encephalopathy with fatal cerebral oedema. SIADH treatment is based on water restriction and demeclocycline. V2 receptor antagonists are still not marketed in France. These aquaretics seem effective clinically and biologically, without demonstrated improvement to date of mortality in eu- and hypervolaemic hyponatraemia. Obviously treatment of a corticotropic deficit, even subtle, should not be overlooked, as well as the introduction of fludrocortisone in isolated hypoaldosteronism and discontinuation of iatrogenic drugs(20).
21. Severe Hypoglycemia due to Isolated ACTH Deficiency in Children
Isolated ACTH deficiency causes life-threatening severe hypoglycemia. There is a report of a patient had undetectable plasma ACTH repeatedly and cortisol 0 mcg/dl before and after ACTH 1-24 stimulation. There was no evidence of other pituitary hormone deficiency. Glucocorticoid replacement therapy resulted in resolution of all symptoms and normalization of blood glucose. Previously published data on isolated ACTH deficiency in children is summarized. Review of the literature showed that the prevalence of this condition could be underestimated in the neonatal period and in Prader-Willi syndrome. Isolated ACTH deficiency occurs in older children as well as in neonates(21).
22. ACTH deficiency suspected as depression with severe appetite loss
There is a report of a patient showed severe appetite loss and vomiting in May of the year X. His business had started to experience difficulty two months earlier. A medical workup of the digestive system and a brain MRI revealed no abnormality. Subsequently, the patient was referred for a psychiatric examination with suspected depression in August. Psychiatric pharmacotherapy improved his appetite only temporarily, and he was admitted as a psychiatric inpatient. A more thorough evaluation led to a diagnosis of isolated ACTH deficiency on the basis of abnormally low levels of ACTH and cortisol. The patient's symptoms improved with hydrocortisone supplementation. CASE II: A factory worker in his late fifties started to experience appetite loss, nausea/ vomiting, and decreased energy in May of the year Y, without any apparent cause. Medical evaluations by a family physician, a digestive system specialist, and a neurologist, including a brain CT, were unremarkable. Depression was suspected and the patient was referred to the authors' psychiatric clinic in July of the same year. Upon examination, the patient presented with depressive symptoms such as a depressed mood, decreased energy, middle insomnia, and loss of interest. Blood tests and a hormonal workup revealed abnormally low ACTH and cortisol levels. The patient was admitted as an inpatient of the endocrinology department, and a diagnosis of isolated ACTH deficiency was made. Hydrocortisone supplementation improved his symptoms. In both cases, anti-pituitary antibody was negative and there were no findings of an empty sella or swelling of the pituitary gland. Therefore, isolated ACTH deficiency was a more likely diagnosis than lymphocytic adenohypophysitis. It is important to diagnose this condition as early as possible since it is treatable with hydrocortisone supplementation with a favorable prognosis. Screening for ACTH and cortisol levels should be considered when symptoms of suspected depression include severe general fatigue and appetite loss with vomiting(22).
23. Elderly case of isolated ACTH deficiency presenting with depression and digestive symptoms
There is a report of a 76-year-old man first referred to his local hospital at the beginning of August 2005 with nausea and vomiting, and admitted on August 15 with progressive fatigue of unknown etiology. Gastrointestinal examination was performed, but no obvious abnormalities were detected in the upper or lower digestive tract. Hematology tests also revealed no abnormalities, except for slight eosinophilia. He developed depression and was given an antidepressant agent. After suffering from hyponatremia and disorientation, he was subsequently admitted to our hospital on August 28. At that time, serum adrenocorticotropic hormone (ACTH) and cortisol levels were low, while both the ACTH and corticotrophin-releasing hormone (CRH) stress tests showed no response. Other stress tests revealed normal responses, so he was given a diagnosis isolated ACTH deficiency and received corticosteroid therapy(23).
24. May hydrocortisone cause adrenocorticotropic hormone (ACTH) deficiency
There is a report of a case of ACTH deficiency. A 75-year-old man complained of anoxia, nausea and vomiting. Three years ago, he had an attack of loss of consciousness. On admission, his serum sodium level was down to 119.6 mEq.l-1. Plasma osmolality was low and urinary osmolality was high without edema, and he was diagnosed as having SIADH. After CRH test, rapid ACTH test and continuous ACTH test, he was diagnosed as having ACTH deficiency, and he was treated with steroids. One year later, he received urethrotomy due to urethrostenosis under spinal anesthesia with no trouble. In the next year, he was scheduled for sigmoidectomy due to sigmoid colon cancer under general anesthesia combined with epidural anesthesia. In the morning of his operation, he took hydrocortisone 10 mg per os. During operation, hydrocortisone 300 mg was given intravenously divided for three times. Plasma ACTH and aldosterone levels were below normal ranges, but serum cortisol was above the normal range. His operation was finished without troubles. Regarding this case, we discussed steroid therapy during anesthesia and operation(24).
25. Testicular adrenal rest "tumor" or Leydig cell tumor
There is a report of a case of mass-forming TART and we discuss the clinical, radiological, and morphological features as well as the major differential diagnosis of this rare lesion. Testicular adrenal rest tumors (TARTs) are an important complication of CAH, which probably develop from ectopic remnants of intra-testicular adrenal tissue stimulated by Adrenocorticotropic hormone (ACTH) hypersecretion. These lesions are typically located within the rete testis and are bilateral, synchronous, nodular and multiple. TART usually, but not always, responses to suppressive medical therapy. TART leads to testicular structural damage, spermatogenesis disorders, infertility and most importantly, mass-forming lesions that could be mistaken for Leydig cell tumor (LCT). The later has a significantly different behavior with up to 10% of being malignant. Nowadays, due to advances in diagnosing and treating CAH, mass-forming TART is rarely encountered(25).
26. Isolated ACTH deficiency: a heterogeneous disorder
Isolated adrenocorticotropin (ACTH) deficiency is a rare cause of secondary adrenocortical insufficiency. The clinical manifestations of isolated ACTH deficiency are variable, nonspecific and similar to those seen in adrenocortical insufficiency of any cause. The diagnosis of isolated ACTH deficiency due to intrinsic pituitary disease is made unequivocally when all the following criteria are met: 1) low basal urinary 17-hydroxycorticosteroid (17-OHCS) levels with or without low basal plasma cortisol, 2) low or normal basal plasma ACTH, 3) stimulation of cortisol, 17-OHCS or both during prolonged ACTH administration, 4) lack of 17-OHCS elevation in response to metyrapone and 5) normal secretory indices of other pituitary hormones. Isolated ACTH deficiency secondary to suprapituitary (e.g., hypothalamic) dysfunction is also based upon the above criteria, but, in addition, is associated with stimulation of cortisol and ACTH secretion following vasopressin administration(26).
27. Isolated ACTH deficiency
Isolated ACTH is a rare cause of secondary adrenocortical insufficiency. The diagnosis is made by the demonstration of low cortisol production with low plasma ACTH, absent adrenal responses to stimulation for pituitary or hypothalamus with intact adrenal response to exogenous ACTH, and normal secretory indices of other pituitary hormones. We conclude that the diagnosis of this condition may be difficult due to the varied clinical presentation and etiologies, according to the study by the University of Alcalá de Henares(27).
28. Chronic adrenal failure secondary to an isolated deficiency of ACTH
Chronic adrenal failure due to hypothalamic-hypophyseal disorders is rarely encountered. This can be due to hormonal deficiencies generally related to the presence of a brain tumor or an infiltrating process and sometimes to an isolated deficiency of ACTH. There is a report of two patients with adrenal failure with low basal cortisol levels and a poor response to short cortisol stimulation test with ACTH. Long cortisol stimulation test with ACTH was normal and ACTH was not stimulated with corticotropin releasing factor. However, other specific dynamic pituitary hormonal tests were normal. The uncommon clinical presentation of the disease, such as severe hypoglycemic crisis and fever of unknown origin (FUO), is underscored(28).
29. Thyroid dysfunction in isolated adrenocorticotropic hormone (ACTH) deficiency
There is a report of a 56-year-old woman, developed somnolence and hypoglycemia due to isolated ACTH deficiency. She also had the features of hypothyroidism, namely mounding phenomenon, muscle rigidity, increased plasma myogenic enzymes and cold intolerance. Both free T3 and free T4 were decreased, and basal as well as TRH-stimulated TSH levels were abnormally high. Plasma thyroglobulin was increased and no anti-thyroid antibodies were detected. All thyroid related physical and biochemical abnormalities disappeared after hydrocortisone replacement. A review of the literature on 103 cases disclosed that more than half the cases with isolated ACTH deficiency had a high plasma level of TSH, basal and/or TRH-induced, while the antithyroid antibodies were reported to be positive in only 13 cases. In more than 70% of such cases, the abnormality in the pituitary-thyroid axis was transient and was reversed by glucocorticoid replacement. Our case and cases in the literature indicate that the interference of thyroid hormone synthesis and/or secretion by glucocorticoid deficiency per se is the major cause of thyroid dysfunction rather than associated autoimmune thyroid disease(29).
30. Musculoskeletal symptoms and neurological investigations in adrenocortical insufficiency
There is a report of a case of a 61-year-old man with isolated adrenocorticotropic hormone deficiency who presented with musculoskeletal symptoms, including flexion contractures. We performed three neurological investigations: nerve conduction studies, electromyography, and muscle biopsy analysis. From the literature review, we found that (a) analysis of muscle biopsy is the most sensitive technique, followed by electromyography and then nerve conduction studies; and (b) the longer the duration of the musculoskeletal symptoms, the greater the incidence of abnormal findings with all three techniques(30).
31. Behçet disease with isolated ACTH deficiency
There is report of a case of a patient with longstanding Behçet disease, with neurological symptoms predominantly, who became hospitalized for adrenal insufficiency, caused by isolated deficiency of corticotropin (DAACTH). DAACTH is a typical characteristic of hypophysitis, reported in association with many autoimmune diseases. Nevertheless, hypothalamic-pituitary injury in Behçet disease is exceptional. We review the literature and possible mechanisms of this association until now not reported(31).
32. Isolated ACTH deficiency and primary thyroid insufficiency in an atopic patient: hypophysitis
There is a report of 6 years after surgery for epidermoid lung cancer, a 58-year-old man presented with atopic dermatitis and a high level of IgE, primary hypothyroidism of autoimmune origin, slight hyperprolactinemia and adrenal insufficiency of pituitary origin. ACTH levels were low and unresponsive to CRH. There was no deficiency of the other pituitary hormones and the MRI of the pituitary was normal. The other instances of autoimmune thyroiditis associated with ACTH deficiency are reviewed. The etiology of the deficiency is discussed in the context of a possible hypophysitis(32).
33. Isolated ACTH deficiency associated with Hashimoto disease
Isolated ACTH deficiency is a rare cause of secondary adrenocortical insufficiency. The diagnosis is made by the demonstration of low cortisol production with low plasma ACTH, absent adrenal responses to stimulation for pituitary or hypothalamus with intact adrenal response to exogenous ACTH, and normal secretory indices of other pituitary hormones. Although the pathogenesis of isolated ACTH deficiency is uncertain in most cases, autoimmune process is intimately involved as suggested by the histological evidence of lymphocytic hypophysitis and frequent observation of circulating antipituitary antibodies. In isolated ACTH deficiency, there have been occasional associations with Hashimoto disease which is characterized by the presence of a autoimmune mechanism, according to the study by the Osaka City University Medical School(33).
34. Isolated adrenocorticotropin deficiency and flexion contractures syndrome
There is a report of a 73-year-old man with isolated adrenocorticotropic hormone deficiency and "flexion contractures" syndrome along with a review of the relevant literature. The patient initially presented anorexia, vomiting, arthralgias, malaise, and weight loss, which progressively deteriorated during the subsequent 6 months. He was admitted to the hospital with fever, confusion, severe cachexia, sinus tachycardia, low blood pressure, hyponatremia, and inability to stand or walk due to severe flexion contractures of the lower extremities (from hips to knees). The flexion contractures were not resolved by physiotherapy or diazepam administration. Due to his life-threatening condition the patient was empirically submitted to glucocorticoid replacement therapy and a remarkable relief from all the above symptoms was observed. A subsequent thorough endocrine investigation suggested the diagnosis of isolated ACTH deficiency (IAD) of unknown pathogenetic mechanism(34).
35. Flexion contractures of the legs as the initial manifestation of adrenocortical insufficiency
There is a report of a 51-year-old woman presented with flexion contractures of the legs. Physical examination showed decreased passive movements of the bilateral hip and knee joints without muscle spasms or neurological abnormalities. Laboratory evaluation showed no response of ACTH or plasma cortisol to stimulation with CRH or insulin. Diagnosis of isolated adrenocorticotropic hormone deficiency was made. The patient was started on prednisolone 5 mg daily, and flexion contractures of the legs rapidly disappeared. Although the musculoskeletal manifestation of this patient is similar to that of stiff-person syndrome, flexion contracture of the legs associated with adrenocortical insufficiency seems to be a separate disease entity from stiff-person syndrome(35).
36. Mental deterioration and hypertension: uncommon manifestation of corticotropin insufficiency and functional carboxymethyl oxidase block
There is a report of a a new case of muscle contractures associated with adrenocortical deficiency. Outstanding features were the diffusion of the contractures, rhabdomyolysis and an encephalopathy which disappeared with hormonal therapy. Endocrinological investigations revealed a functional carboxymethyl oxidase type II defect which could, in part, explain our patient's neuromuscular symptoms(36).
37. Acquired corticotropin insufficiency in adults
There is a report of two new cases of isolated corticotropin deficiency, associated with TSH deficiency in one of the two patient. The diagnostic was made difficult because the symptoms were mainly psychiatric. Low plasmatic cortisol and ACTH level were found, with low T3, T4 and TSH in the second patient. The TSH did not respond to the stimulation by TRH. The cerebral tomodensitometry and magnetic resonance imaging focused on the sella turcica were normal, eliminated a tumor and showed an empty sella turcica. The patients have to be followed-up because an isolated deficiency may further complete to panhypopituitarism(37).
38. Dementia with contractures' as presenting signs of secondary adrenocortical insufficiency
There is a report of a 61-year-old man with progressive mental deterioration and flexion contractures of abdominal muscles and legs as initial signs of hypopituitarism. Five years after onset of symptoms, an endocrinologically non-functioning pituitary adenoma was demonstrated. Thyroid replacement therapy had no effect, but administration of hydrocortisone was followed by rapid recovery. The opportunity to treat such cases of curable dementia is easily missed(38).
39. Isolated acquired ACTH deficiency and primary hypothyroidism
Idiopathic isolated ACTH deficiency, congenital or acquired, is rare. It may be found in association with primary hypothyroidism. There is a report of four cases of acquired idiopathic isolated ACTH deficiency illustrating its importance and variable presentation. All cases had a structurally normal pituitary gland and persistently normal residual pituitary function. Three cases had co-existing primary hypothyroidism. We discuss the protean presentation of this rare but important condition, its treatment, associations, and possible aetiologies(39).
40. Early-onset severe obesity with ACTH deficiency and red hair in a boy
There is a report of a patient of 2.8 years old male who is extremely obese and severe hyperphagic from birth. He had seizures attacks and apnea from the second week of his life. He has red hair and serum cortisol and ACTH levels are very low. We examined our patient as a hypocortisolism due to ACTH deficiency and central hypothyrodism. After the corticosteroid replacement therapy hair color changed to brown. We performed molecular genetic analysis at the Institue for Experimental Pediatric Endocrinology laboratory in Berlin, Germany by Krude H. and found compound heterozygous mutations. As a result the case is diagnosed as POMC deficiency(40).
Sources
(a) http://en.wikipedia.org/wiki/Adrenocorticotropic_hormone
(1) http://www.ncbi.nlm.nih.gov/pubmed/23470617
(2) http://www.ncbi.nlm.nih.gov/pubmed/11337099
(3) http://www.ncbi.nlm.nih.gov/pubmed/22672268
(4) http://www.ncbi.nlm.nih.gov/pubmed/24021863
(5) http://www.ncbi.nlm.nih.gov/pubmed/17238026
(6) http://www.ncbi.nlm.nih.gov/pubmed/15194643
(7) http://www.ncbi.nlm.nih.gov/pubmed/9691924
(8) http://www.ncbi.nlm.nih.gov/pubmed/23997996
(9) http://www.ncbi.nlm.nih.gov/pubmed/9790402
(10) http://www.ncbi.nlm.nih.gov/pubmed/10411821
(11) http://www.ncbi.nlm.nih.gov/pubmed/20394311
(12) http://www.ncbi.nlm.nih.gov/pubmed/21704697
(13) http://www.ncbi.nlm.nih.gov/pubmed/23380766
(14) http://www.ncbi.nlm.nih.gov/pubmed/23106615
(15) http://www.ncbi.nlm.nih.gov/pubmed/18403481
(16) http://www.ncbi.nlm.nih.gov/pubmed/22992651
(17) http://www.ncbi.nlm.nih.gov/pubmed/21765902
(18) http://www.ncbi.nlm.nih.gov/pubmed/12900850
(19) http://www.ncbi.nlm.nih.gov/pubmed/18063931
(20) http://www.ncbi.nlm.nih.gov/pubmed/22119069
(21) http://www.ncbi.nlm.nih.gov/pubmed/21760815
(22) http://www.ncbi.nlm.nih.gov/pubmed/21226246
(23) http://www.ncbi.nlm.nih.gov/pubmed/17337864
(24) http://www.ncbi.nlm.nih.gov/pubmed/12134656
(25) http://www.ncbi.nlm.nih.gov/pubmed/23984262
(26) http://www.ncbi.nlm.nih.gov/pubmed/6276646
(27) http://www.ncbi.nlm.nih.gov/pubmed/9568810
(28) http://www.ncbi.nlm.nih.gov/pubmed/2547231
(29) http://www.ncbi.nlm.nih.gov/pubmed/7920902
(30) http://www.ncbi.nlm.nih.gov/pubmed/21116065
(31) http://www.ncbi.nlm.nih.gov/pubmed/20096211
(32) http://www.ncbi.nlm.nih.gov/pubmed/8209203
(33) http://www.ncbi.nlm.nih.gov/pubmed/8254946
(34) http://www.ncbi.nlm.nih.gov/pubmed/19121993
(35) http://www.ncbi.nlm.nih.gov/pubmed/12924497
(36) http://www.ncbi.nlm.nih.gov/pubmed/8059160
(37) http://www.ncbi.nlm.nih.gov/pubmed/8191076
(38) http://www.ncbi.nlm.nih.gov/pubmed/3709003
(39) http://www.ncbi.nlm.nih.gov/pubmed/19110973
(40) http://www.ncbi.nlm.nih.gov/pubmed/23431750
Wednesday, February 20, 2013
Hormone Prostaglandins, Leukotrienes
Eicosanoid
II. Prostaglandins
Prostaglandins, are a group of lipid mediators, found and isolated from human semen in the 1930s by Ulf von Euler of Sweden, responsible for inflammation features, such as swelling, pain, stiffness, redness and warmth. The hormones are produced by almost all nucleated cells and synthesized in the cell from the essential fatty acids (EFAs), include prostacyclin I2 (PGI2), prostaglandin E2 (PGE2), and prostaglandin F2α (PGF2α)
1. Prostaglandins and other lipid mediators in Alzheimer's disease
In the central nervous system (CNS), prostaglandin (PG) and other bioactive lipids regulate vital aspects of neural membrane biology, including protein-lipid interactions, trans-membrane and trans-synaptic signaling. According to the study by Louisiana State University Health Sciences Center, showed that biochemical mechanisms of PLA2 overactivation and its pathophysiological consequences on CNS structure and function have been extensively studied using animal models and brain cells in culture triggered with PLA2 inducers, PGs, cytokines, and related lipid mediators. Moreover, the expression of both COX-2 and PLA2 appears to be strongly activated during Alzheimer's disease (AD), indicating the importance of inflammatory gene pathways as a response to brain injury. How brain PLA2 and brain PGs are early and key players in acute neural trauma and in brain-cell damage associated with chronic neurodegenerative diseases such as AD.(1).
2. Prostaglandins in labor and delivery
Prostaglandins are produced by almost every tissue in the body and serve as important messengers or effectors in a wide variety of functions. The pivotal role of prostaglandins in contraction of the smooth muscle of the uterus and the biophysical changes associated with cervical ripening, however, point to a major problem with their clinical use. According to the study of the role of prostaglandins in labor and delivery by University of South Florida College of Medicine, found that unlike oxytocin which requires an induction of receptors that does not usually occur until the later part of pregnancy, prostaglandins receptors always are present in myometrial tissue. This allows for the use of prostaglandins in usual doses throughout pregnancy. Although both F and E series prostaglandins result in uterine contractions, E series prostaglandins are relatively more uteroselective and are clearly superior to F series prostaglandins in producing cervical ripening. Modification of the naturally occurring prostaglandins by blocking the sites that are affected during their usual rapid metabolism, results in products with much longer durations of action, efficacy at much lower concentrations, and a potential for significant savings in cost(2).
3. Prostaglandins and inflammation
Prostaglandins are lipid autacoids derived from arachidonic acid. They both sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. They are generated from arachidonate by the action of cyclooxygenase isoenzymes, and their biosynthesis is blocked by nonsteroidal antiinflammatory drugs, including those selective for inhibition of cyclooxygenase-2. Despite the clinical efficacy of nonsteroidal antiinflammatory drugs, prostaglandins may function in both the promotion and resolution of inflammation, according to the study by University of Pennsylvania(3).
4. Brain prostaglandins that promote neuroinflammation
Phospholipase A(2)(PLA(2)) enzymes are considered the primary source of arachidonic acid for cyclooxygenase (COX)-mediated biosynthesis of prostaglandins. According to the study in MAGL-disrupted animals, showed that a distinct pathway exists in brain, where monoacylglycerol lipase (MAGL) hydrolyzes the endocannabinoid 2-arachidonoylglycerol to generate a major arachidonate precursor pool for neuroinflammatory prostaglandins(4).
5. Prostaglandins and human glioma cells
In many types of cancer, prostaglandin E2 (PGE2) is associated with tumour related processes including proliferation, migration, angiogenesis and apoptosis. In the study on the proliferative, migratory, and apoptotic effects of PGE1, PGE2 and Ibuprofen (IBP) observed in the T98G human glioma cell line in vitro, found that treatments which alter PGE1 and PGE2 metabolism influence the proliferative and apoptotic indices of T98G glioma cells. The migratory capacity of the cells was also significantly affected by the change in prostaglandin metabolism. Modifying PG metabolism remains an interesting target for future studies in gliomas(5).
6. Prostaglandins in cancer cell adhesion, migration, and invasion
Prostaglandins exert a profound influence over the adhesive, migratory, and invasive behavior of cells during the development and progression of cancer. According to the study by the University of Texas MD Anderson Cancer Center, cyclooxygenase-2 (COX-2) and microsomal prostaglandin E(2) synthase-1 (mPGES-1) are upregulated in inflammation and cancer. This results in the production of prostaglandin E(2) (PGE(2)), which binds to and activates G-protein-coupled prostaglandin E(1-4) receptors (EP(1-4)). Selectively targeting the COX-2/mPGES-1/PGE(2)/EP(1-4) axis of the prostaglandin pathway can reduce the adhesion, migration, invasion, and angiogenesis. Combining the use of COX-2/mPGES-1/PGE(2)/EP(1-4) axis-targeted molecules with those targeting cell surface adhesion receptors or their downstream signaling molecules may enhance cancer therapy(6).
7. Prostaglandin E2 promotes lung cancer cell migration
Many human cancers express elevated levels of cyclooxygenase-2 (COX-2), an enzyme responsible for the biosynthesis of prostaglandins. Available clinical data establish the protective effect of COX-2 inhibition on human cancer progression. According to the study by Medical College of Georgia, showed that the COX-2 product prostaglandin E(2) (PGE(2)) acts on cognate receptor EP4 to promote the migration of A549 lung cancer cells. Treatment with PGE(2) enhances tyrosine kinase c-Src activation, and blockade of c-Src activity represses the PGE(2)-mediated lung cancer cell migration. PGE(2) affects target cells by activating four receptors named EP1 to EP4. Use of EP subtype-selective ligand agonists suggested that EP4 mediates prostaglandin-induced A549 lung cancer cell migration, and this conclusion was confirmed using a short hairpin RNA approach to specifically knock down EP4 expression(7).
8. Prostaglandins and hepatocellular carcinoma cells
Prostaglandin E2 has been implicated in cell growth and metastasis in many types of cancers. According to the study by Nanjing Medical University, showed that PGE2 treatment significantly increased the cell adhesion, migration, and invasion in hepatocellular carcinoma (HCC) cells. In addition, the effects of PGE2 were found to be associated with focal adhesion kinase (FAK). PGE2 treatment increased the phosphorylation and synthesis of FAK in a dose-dependent manner. RNA interference targeting FAK suppressed PGE2-mediated cell adhesion and migration. Furthermore, the downstream proteins of FAK, paxillin and Erk2, were also activated by PGE2. PGE2 treatment increased the phosphorylation and synthesis of paxillin in a dose-dependent manner. PGE2 treatment also induced the phosphorylation of Erk2(8).
9. Caspase-3 and prostaglandins in cancer regrowth
Chemo- and radio-therapeutic regimens frequently kill cancer cells by inducing apoptosis, a cell-death subroutine that involves the activation of a particular class of proteases called caspases. According to the study of Caspase-3 and prostaglandins signal for tumor regrowth in cancer therapy,. indicated in a recent issue of Nature Medicine, Huang et al. (2011) show that caspase activation in dying tumor cells causes the release of soluble lipid messengers, notably prostaglandin E(2), that stimulate tumor cell proliferation(9).
10. Physiological regulation of prostaglandins in the kidney
Cyclooxygenase-derived prostanoids exert complex and diverse functions within the kidney. The biological effect of each prostanoid is controlled at multiple levels, including (a) enzymatic reactions catalyzed sequentially by cyclooxygenase and prostanoid synthase for the synthesis of bioactive prostanoid and (b) the interaction with its receptors that mediate its functions. Cyclooxygenase-derived prostanoids act in an autocrine or a paracrine fashion and can serve as physiological buffers, protecting the kidney from excessive functional changes during physiological stress. According to the study by Vanderbilt University, and Veterans Affair Medical Center, alhrough these actions, prostanoids play important roles in maintaining renal function, body fluid homeostasis, and blood pressure. Renal cortical COX2-derived prostanoids, particularly PGI2 and PGE2, play critical roles in maintaining blood pressure and renal function in volume-contracted states. Renal medullary COX2-derived prostanoids appear to have an antihypertensive effect in individuals challenged with a high-salt diet. Loss of EP2 or IP receptor is associated with salt-sensitive hypertension. COX2 also plays a role in maintaining renal medullary interstitial cell viability in the hypertonic environment of the medulla. Cyclooxygenase-derived prostanoids also are involved in certain pathological processes. The cortical COX2-derived PGI2 participates in the pathogenesis of renal vascular hypertension through stimulating renal renin synthesis and release. COX-derived prostanoids also appear to be involved in the pathogenesis of diabetic nephropathy(10).
11. Prostaglandins and the kidney
In the review of a summary and assessment of research involving renal prostaglandins (Arachidonic acid released from phospholipids is converted by prostaglandin cyclo-oxygenase in the kidney to PGF2, PGF2alpha, PGD2, and, possibly, to PGI2 and thromboxane A2. Production of PGE2 and PGF2alpha is predominately but not exclusively in the medulla, whereas degradative enzymes are present in both cortex and medulla. Prostaglandins enter the tubular lumen by facilitated transport and are partially reabsorbed from the urine in the distal nephron. Urine prostaglandins probably reflect renal synthesis. PGE2 and endoperoxides stimulate and PGF2alpha and indomethacin inhibit renal renin synthesis. In response to ischemia, vasoconstriction, or angiotensin II the kidney increases prostaglandin synthesis to modulate renal vascular resistance), found that in conscious animals or man no role has been established for prostaglandins in the maintenance of basal renal blood flow or renal sodium excretion. PGE influences renal water excretion by inhibiting the action vasopressin. Despite conflicting data there is evidence that renal prostaglandins are involved either primarily or secondarily in many types of hypertension. Inhibitors of prostaglandin cyclooxygenase have been used with success in Bartter's syndrome. Conflicting results in many areas of investigation may be resolved by the use of more accurate and reliable assays, careful handling of samples, and the use of urine to further investigate renal prostaglandin synthesis(11).
12. Prostaglandins in regulating the contraction and relaxation of smooth muscle tissue
According to the Nelson, Randy F. (2005). "An introduction to behavioral endocrinology (3rd ed.). Sunderland, Mass: Sinauer Associates", hormone prostaglandins play an important role in numbers of physiological effects, including the function of regulating the contraction and relaxation of smooth muscle tissue, by ligating a sub-family of cell surface seven-transmembrane receptors, G-protein-coupled receptors.
13. Prostaglandins and platelet aggregation
Prostaglandins which are derivatives of arachidonic acid including prostaglandin, endoperoxides, thromboxane A2, prostaglandin E2, prostaglandin D2 and prostacyclin. may induce or inhibit platelet aggregation and constrict ro dilate blood vessels. According to the study by Dr. Smith JB., it exacerbates ischaemic damage because of a selective increase in vascular resistance due to coronary vasospasm and platelet aggregation which acts to decrease myocardial blood flow. The stable prostaglandins PGD2 and PGE2 are also of interest as both are formed during platelet aggregation. Like PGI2, PGD2 inhibits platelet aggregation(13).
14. Prostaglandin I2 (PGI2) and disaggregation of platelets
In the study to examine the synergistic platelet disaggregating effects among the products of endothelial cells using urokinase, prostaglandin I2 (PGI2), and sodium nitroprusside (SNP) (which is the chemical substitute as nitric oxide(NO)-donor) for endothelium-derived relaxing factor (EDRF), showed that platelet disaggregation rate was increased in a dose-dependent manner and decreased in a time-dependent manner, and the combined use of two or three agents had synergistic effects on platelet disaggregation. Furthermore, flow cytometric analysis showed decreases in the binding of fibrinogen to activated platelets by the addition of PGI2 or SNP. . In addition our data revealed that PGI2 and SNP can act synergistically with fibrinolytic agents. These findings suggest a potential strategy for improving the efficacy of thrombolytic therapy by a combination of these products or their substitutes(14).
15. Platelet prostaglandin H synthase-1 (PGHS-1) deficiency and Bleeding disorder
Defective platelet prostaglandin H synthase (PGHS) activity has been recognized as a cause of bleeding disorders. In the study of a tatal of three female patients aged 37, 48 and 55 who presented with a mild bleeding disorder due to platelet dysfunction, showed that human platelet PGHS-1 deficiency is due to two types of enzyme defects: type 1 defect is manifested by an undetectable PGHS-1 protein in platelets whereas the type 2 defect is manifested by a normal quantity of PGHS-1 protein which has an impaired catalytic activity(15).
16. Prostaglandins E2 and labor
In the study to determine safety of induction of labor with vaginal Prostaglandins (E2) in Grand Multipara., showed that in a total of 50% cases were induced for past dates, the ceasarean rate was high in the induction group (19.5%) compared to the control (12.5%) OR 1.69 RR 1.37(95% CI-1.07-1.75) difference was statistically significant. Adverse neonatal outcome was found to be similar in both groups. Special Care Baby Unit (SCBU) admissions were 19 in the induction group and 21 in the control group, which was not statistically significant. No severe maternal complications were observed such as infection or uterine rupture(16).
17. Hormone Prostaglandins sensitize spinal neurons to pain
A number of prostaglandins (PGs) sensitize dorsal root ganglion (DRG) neurons and contribute to inflammatory hyperalgesia by signaling through specific G protein-coupled receptors (GPCRs). According to the study by the Washington University Pain Center, suggested that 15d-PGJ2 induces activation followed by persistent inhibition of TRPA1 channels in DRG sensory neurons in vitro and in vivo. Moreover, we demonstrate novel evidence that 15d-PGJ2 is analgesic in mouse models of pain via a TRPA1-dependent mechanism. Collectively, our studies support that TRPA1 agonists may be useful as pain therapeutics(17).
18. Hormone Prostaglandins and Intraocular pressure (IOP)
Intraocular pressure (IOP) reduction is currently the only therapeutic approach demonstrated to preserve visual function in patients with glaucoma. According to the study by Universit Joseph Fourier (UJF), Grenoble, in the study to review of published studies evaluating the efficacy and tolerability of the IOP-lowering unfixed and fixed combination therapies with PGAs, indicated that
α(2)-adrenergic agonists-PGA and carbonic anhydrase inhibitor-PGA combinations seem to be at least as effective at reducing IOP as the β-blocker-PGA combinations. As for the fixed combinations, the review shows that the three PGA-timolol fixed combinations are more effective than their component medications used separately as monotherapy and are better tolerated than the three respective prostaglandins(18).
19. prostaglandins and inflammatory mediation
Overproduction of prostaglandins has been considered in mediation of inflammation and carcinogenic process. In the study to search for anti-inflammatory and chemopreventive agents from natural products, bioassay-guided fractionation led to the isolation of curdione from the rhizome of Curcuma zedoaria with the inhibitory effect on the production of prostaglandin E2 in lipopolysaccharide (LPS)-stimulated mouse macrophage RAW 264.7 cells in a concentration-dependent manner (IC50 = 1.1 microM). Mechanistic studies suggest that the suppression of cyclooxygenase-2 (COX-2) mRNA expression is, at least in part, involved in this inhibitory activity of curdione, according to the study by the Ewha Womans University, Seoul.(19).
20. Prostaglandin E2 and tooth movement
In the study to to investigate the occurrence of orthodontic root resorption in connection with local injection of prostaglandin E2 (PGE2) consisting 25 male Wistar rats, in the duration of experiments was 3 days, 7 days, and 10 days, showed that the maxillary first molars on both sides were each moved mesially by means of a coil spring. On the right side 0.1 ml of PGE2 0.1 micrograms/microliters was injected in the gingiva on the buccal side of the upper first molar on days 0, 3, 5, and 7. On the left side no injection of PGE2 was performed. In three animals in the 7-day group the vehicle (Waymouth medium) was injected. There was no significant difference in root resorption between the experimentally moved teeth with and without local injection of PGE2, but a trend towards more root resorption was registered on the teeth where such injections had been performed(20).
21. Prostaglandin E2 (PGE2) and orthodontic tooth movement and bone metabolism
In the study to to investigate and compare the in vivo effects of prostaglandin E2 (PGE2) administered by different methods on orthodontic tooth movement and bone metabolism macroscopically, histopatologically, and biochemically, showed that Tooth movement was observed in the experimental and positive control groups, but the intraligamentous PGE2 group had the highest values of all analyzed parameters, including serum calcium and phosphorus levels and osteoclastic and osteoblastic populations (p < 0.001)(21).
22. Prostaglandin E2 and voltage-dependent calcium channels
According to the study by the University of Occupational and Environmental Health, in the study of The effects of PGE2 on voltage-dependent Ca2+ channel currents in dissociated rat melanotrophs by the whole-cell configuration of the patch-clamp technique, indicated that PGE2 inhibits P/Q- and L-type Ca2+ channels of rat melanotrophs via EP1 and EP3 receptors, which are coupled to pertussis toxin-sensitive G proteins, and produces both voltage-sensitive and -insensitive inhibition of Ca2+ channels(22).
23. Prostaglandins in pregnancy and parturition
Prostaglandin (PG) production by intrauterine tissues plays a key part in the control of pregnancy and parturition. In the study to to investigate the role of placenta-derived CRH and CRH-related peptides in the regulation of PG synthesis and metabolism, showed that CRH and CRH-related peptides act on CRH-R1 and CRH-R2 to exert different effects on PG biosynthetic enzymes cPLA2 and COX-2 and thereby modulate output of PGs from placenta, which would be important for controlling pregnancy and parturition(23).
24. Prostaglandins in regulation of PPARγ function in adipocytes
Adipocytes and fat cells play critical roles in the regulation of energy homeostasis. Adipogenesis (adipocyte differentiation) is regulated via a complex process including coordinated changes in hormone sensitivity and gene expression. According to the study by the Osaka University of Pharmaceutical Sciences, Prostaglandins (PGs), which are lipid mediators, are associated with the regulation of PPARγ function in adipocytes. Prostacyclin promotes the differentiation of adipocyte-precursor cells to adipose cells via activation of the expression of C/EBPβ and δ. These proteins are important transcription factors in the activation of the early phase of adipogenesis, and they activate the expression of PPARγ, which event precedes the maturation of adipocytes. PGE(2) and PGF(2α) strongly suppress the early phase of adipocyte differentiation by enhancing their own production via receptor-mediated elevation of the expression of cycloxygenase-2, and they also suppress the function of PPARγ(24).
25. Prostaglandins in prevulatory phase
In the study to to evaluate the effect of luteinizing hormone (LH), steroids, prostaglandins (PGs) and peptides on the oviductal contraction and secretion of PGs and endothelin (ET-1) in cows, showed that the preovulatory LH surge, together with increasing E(2) levels from the Graafian follicle and a basal P(4) from regressing corpora lutea (CL), stimulates maximum oviductal production of PG and ET-1, resulting in oviductal contraction for a rapid transport of gametes. OT released from the newly-formed CL may block these mechanisms, and slow contractions for transport of the embryo to the uterus(25).
26. Prostaglandins hormone regulation
The optimal oviductal environment, including contractile activity for gamete transport, fertilization and early embryonic development, is mediated by physiological and anatomical changes in the oviduct during the estrous cycle. In the study by the University of Peradeniya, indicated that the preovulatory LH surge, together with locally re-circulated high levels of E2 from the Graafian follicle and basal P4 from regressing corpus luteum (CL), induces the maximum stimulatory effect on oviductal PGE2, PGF2 alpha and ET-1 production during the periovulatory period. Consequently, the elevated local ET-1 concentration during periovulatory period may induce the high contractile activity of the oviduct and, at the same time, the stimulation of PG production. Thus, ET-1 may act as a local amplifier for oviductal PG production stimulated by LH and ovarian steroids(26).
27. Prostaglandin D2 and Oral cancer
Prostaglandins are secreted by oral carcinomas and may be involved in eosinophil infiltration. In the study to determine the factors contributing to eosinophil migration and potential anti-neoplastic effects on oral squamous carcinoma (OSC), eosinophil degranulation was evaluated by measuring release of eosinophil peroxidase (EPO), showed that growth inhibition of the OSC cell line, SCC-9, during co-culture with human eosinophils, in vitro, which correlated with EPO activity that possesses growth inhibitory activity. The PGD2 synthase inhibitor, HQL-79, abrogated migration towards SCC-9. Our data suggest that OSC-derived PGD2 may play an important role via CRTH2 (the PGD2 receptor on eosinophils) in eosinophil recruitment and subsequent anti-tumor activity through the action of eosinophil cationic proteins(27).
28. Prostaglandins in T cells activation
In the study to investigate the role of PGE(2), which binds to the E-prostanoid family of G protein-coupled receptors through four subtypes of receptors called EP 1-4, in the regulation of CD46 expression and function, showed that addition of PGE(2) strongly downregulates CD46 expression in activated T cells. Moreover, PGE(2) differentially affects T cell activation, cytokine production, and phenotype depending on the activation signals received by the T cells. This was correlated with a distinct pattern of the PGE(2) receptors expressed, with EP4 being preferentially induced by CD46 activation. Indeed, addition of an EP4 antagonist could reverse the effects observed on cytokine production after CD46 costimulation. These data demonstrate a novel role of the PGE(2)-EP4 axis in CD46 functions, which might at least partly explain the diverse roles of PGE(2) in T cell functions(28).
29. Prostaglandins and lymphangiogenesis
One of the hallmarks of inflammation is lymphangiogesis that drains the interstitial fluids. During chronic inflammation, angiogenesis is induced by a variety of inflammatory mediators, such as prostaglandins (PGs). According to the study by the Kitasato University School of Medicine, suggested that COX-2 and prostaglandin E2-EP3/EP4 signaling contributes to lymphangiogenesis in proliferative inflammation, possibly via induction of VEGF-C and VEGF-D, and may become a therapeutic target for controlling lymphangiogenesis(29).
30. Prostaglandin E2 and colorectal carcinoma cells
Chronic use of nonsteroidal anti-inflammatory drugs results in a significant reduction of risk and mortality from colorectal cancer in humans. They are known to inhibit cyclooxygenase activity. The cyclooxygenase enzymes catalyze a key reaction in the conversion of arachidonic acid to prostaglandins, such as prostaglandin E(2) (PGE(2)). In the study to demonstrate that PGE(2) treatment of LS-174 human colorectal carcinoma cells leads to increased motility and changes in cell shape by Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, indicated that
PGE(2) treatment results in an activation of phosphatidylinositol 3-kinase/protein kinase B pathway that is required for the PGE(2)-induced changes in carcinoma cell motility and colony morphology. PGE(2) might enhance the invasive potential of colorectal carcinoma cells via activation of major intracellular signal transduction pathways not previously reported to be regulated by prostaglandins(30).
31. Prostaglandin E(2) and fever
Systemic inflammation is accompanied by changes in body temperature, either fever or hypothermia. Rat and mouse have become the predominant animal models, and new species-specific tools (recombinant antibodies and other proteins) and genetic manipulations have been applied to study fever and hypothermia. According to the study by the St. Joseph's Hospital and Medical Center, an indispensable role of PGE2 in the febrile response to LPS has been demonstrated in studies with targeted disruption of genes encoding either PGE2-synthesizing enzymes or PGE2 receptors. The PGE2-synthesizing enzymes include numerous phospholipases (PL) A2, cyclooxygenases (COX)-1 and 2, and several newly discovered terminal PGE synthases (PGES). It has been realized that the "physiological," low-scale production of PGE2 and the accelerated synthesis of PGE2 in inflammation are catalyzed by different sets of these enzymes. The "inflammatory" set includes several isoforms of PLA2 and inducible isoforms of COX (COX-2) and microsomal (m) PGES (mPGES-1). The PGE2 receptors are multiple; one of them, EP3 is likely to be a primary "fever receptor." The effector pathways of fever start from EP3-bearing preoptic neurons. These neurons have been found to project to the raphe pallidus, where premotor sympathetic neurons driving thermogenesis in the brown fat and skin vaso-constriction are located(31).
32. Prostaglandins and the Inhibition of acid secretion
In the study to evaluate the inhibition of acid secretion in isolated canine parietal cells by prostaglandins, indcated that PGE2 was the most potent inhibitor of acid secretion, with a 50% inhibition of maximal acid secretion (ID50) at 7.5 X 10(-8) M. PGI2 and PGF2 alpha also inhibited acid secretion, but at higher concentrations. The ID50 for PGI2 and PGF2 alpha was 10(-5) M. PGD2 was inactive at inhibiting acid secretion and suggested that both endogenous and exogenous PGs inhibit acid secretion directly at the parietal cells and that PGE2 is most likely the PG produced locally to modulate parietal cell acid secretion.(32).
33. Synthetic prostaglandins and abortion
In general, termination of second trimester pregnancy is associated with three to five times higher morbidity and mortality risks than termination during the first trimester. According to the study by Bygdeman M. the procedures mainly used are extra- or intra-amniotic administration of solutions such as hypertonic saline, ethacridine lactate, PGF2 alpha and PGE2. In comparison with these procedures, the use of prostaglandin analogues may offer important advantages, the most important one being the possibility of using non-invasive routes of administration. Pretreatment with prostaglandin analogues also reduces the risk of both operative and postoperative complications. The prostaglandins also offer a possibility as a non-surgical procedure for termination of very early pregnancy. Both vaginal and intramuscular administration of the latest generation of PG analogues have been shown in several studies to be equally as effective as vacuum aspiration if the treatment is restricted to the first three weeks following the first missed menstrual period. Gastrointestinal side-effects are still a problem although of significantly less importance than if natural prostaglandins are used(33).
34. Synthetic prostaglandins in prevention of closure of patent ductus arteriosu
Patent ductus arteriosus is a congenital disorder in the heart, with symptoms of increased work of breathing and poor weight gain in the first uear of the new born. According to the study by Rudolph AM, Heymann MA., prostaglandin administered by aortic infusion prevents ductus closure when this is desirable--as in term infants with pulmonary atresia or critical pulmonic stenosis--raising arterial oxygen tension to levels compatible with life. On the other hand, in prematures with persistent patency of the ductus, administering indomethacin inhibits prostaglandin sysnthesis, inducing closure, and can obviate surgery(34).
35. Synthetic prostaglandins and gastric ulcer
In the study to examine the role of macrophage colony-stimulating factor (M-CSF)-dependent macrophages in the healing of gastric ulcers in mice with male M-CSF-deficient (op/op) and M-CSF-expressing heterozygote (+/?) mice were used. Gastric ulcers were induced by thermal cauterization under ether anesthesia, and healing was observed for 14 days after ulceration, found that M-CSF-dependent macrophages play an important role in the healing of gastric ulcers, and that this action may be associated with angiogenesis promoted by upregulation of COX-2/PGE(2) production(35).
36. Synthetic prostaglandins and Raynaud's phenomenon
Raynaud's phenomenon is episodic vasospasm of the peripheral vessels, causing pallor followed by cyanosis and redness with pain and sometimes paraesthesia, and, rarely, ulceration of the fingers and toes. Raynaud's phenomenon can be primary (idiopathic) or secondary to several different conditions and causes.According to the study by Ariane Herrick, Intravenous iloprost (a prostaglandin) reduces the frequency and severity of attacks compared with placebo in people with Raynaud's phenomenon secondary to systemic sclerosis(36).
37. Synthetic prostaglandins and pulmonary hypertension
Iloprost (a prostaglandin) has been used to test acute pulmonary vasoreactivity in idiopathic pulmonary arterial hypertension (PAH). In the study to investigate the acute hemodynamic and oxygenation responses and tolerability to 20 µg aerosolized Iloprost in Chinese patients with pulmonary hypertension, found that Inhalation of 20 µg Iloprost showed potent and selective pulmonary hemodynamic effects and was well tolerated in the Chinese pulmonary hypertension patients. Patients with idiopathic PAH and less severe pulmonary hypertension responded more favorably to inhalation of Iloprost(37).
38. Synthetic prostaglandins and glaucoma
In the study to compare the ocular hypotensive effect of tafluprost with prostaglandin analogues (PGAs) in glaucoma patients, found that the comparison between latanoprost and tafluprost and travoprost and tafluprost did not show any statistically significant difference in mean daily IOP and at each time point. The comparison between bimatoprost and tafluprost showed a statistically significant difference in mean daily IOP (P < 0.05) and at each time point (P < 0.05). After 3 months of switching tafluprost showed an overall IOP lowering effect similar to others PGAs. When each PGA was compared with tafluprost, bimatoprost showed to provide a statistically significant additional IOP lowering effect(38).
39. Synthetic prostaglandin and erectile dysfunction
The global burden of erectile dysfunction (ED) is increasing. It is estimated that 8-19% of men in Europe have ED and that by 2025 the prevalence of ED worldwide will reach 322 million. According to the study by the University of Montpellier I, it has a fast onset of effect and a good safety profile, with no occurrences of priapism, fibrosis (as seen with intracavernosal injection) or the typical systemic effects observed with oral ED pharmacological treatments. Intraurethral alprostadil has been associated with high patient preference, acceptance rates and quality of life versus intracavernosal injection due to its ease of administration. Evidence has shown that combination treatment with sildenafil may be a possible efficient alternative when single oral or local treatment has failed. Intraurethral alprostadil can be administered in all patients irrespective of ED origin and should be the first option in patients with ED for whom therapy with PDE5 inhibitors has failed or is contraindicated(39).
40. Synthetic prostaglandin and alopecia areata of eyelashes and eyebrows
Latanoprost is an analogue of prostaglandin F(2alpha) which is used to treat glaucoma. Increases in eyelash number, thickness, and pigmentation have been reported as latanoprost side effects. In the study to evaluate if topical use of this drug can be used as a treatment of alopecia areata of eyebrows and eyelashes or not of a total of 26 patients with symmetrical eyelash and eyebrow alopecia areata were treated over 4 months with topical latanoprost for one side and the other side was not treated with any drug, showed that only one of the latanoprost-treated cases showed partial hair regrowth on the treated side. The relationship between hair regrowth and latanoprost application was not statistically significant (P = 1) by Fisher test. Based on the results, topical latanoprost has no efficacy in the treatment of alopecia areata. More studies with a larger sample size, longer study duration, and higher concentration of medication are suggested(40).
Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/12432919
(2) http://www.ncbi.nlm.nih.gov/pubmed/8665768
(3) http://www.ncbi.nlm.nih.gov/pubmed/21508345
(4) http://www.ncbi.nlm.nih.gov/pubmed/22021672
(5) http://www.ncbi.nlm.nih.gov/pubmed/23231886
(6) http://www.ncbi.nlm.nih.gov/pubmed/22505934
(7) http://www.ncbi.nlm.nih.gov/pubmed/20353998
(8) http://www.ncbi.nlm.nih.gov/pubmed/19082453
(9) http://www.researchgate.net/publication/51685919_Caspase-3_and_prostaglandins_signal_for_tumor_regrowth_in_cancer_therapy
(10) http://www.ncbi.nlm.nih.gov/pubmed/17988207
(11) http://www.ncbi.nlm.nih.gov/pubmed/333946
(13) http://www.ncbi.nlm.nih.gov/pubmed/7034481
(14) http://www.ncbi.nlm.nih.gov/pubmed/10839560
(15) http://www.ncbi.nlm.nih.gov/pubmed/8562397
(16) http://www.ncbi.nlm.nih.gov/pubmed/22224182
(17) http://www.ncbi.nlm.nih.gov/pubmed/23013719
(18) http://www.ncbi.nlm.nih.gov/pubmed/22686588
(19) http://www.ncbi.nlm.nih.gov/pubmed/18038902
(20) http://www.ncbi.nlm.nih.gov/pubmed/1717297
(21) http://www.ncbi.nlm.nih.gov/pubmed/23112942
(22) http://www.ncbi.nlm.nih.gov/pubmed/9832416
(23) http://www.ncbi.nlm.nih.gov/pubmed/18325997
(24) http://www.ncbi.nlm.nih.gov/pubmed/23319937
(25) http://www.ncbi.nlm.nih.gov/pubmed/11139776
(26) http://www.ncbi.nlm.nih.gov/pubmed/10735120
(27) http://www.ncbi.nlm.nih.gov/pubmed/23369060
(28) http://www.ncbi.nlm.nih.gov/pubmed/22544928
(29) http://www.ncbi.nlm.nih.gov/pubmed/21311040
(30) http://www.ncbi.nlm.nih.gov/pubmed/11278548
(31) http://www.ncbi.nlm.nih.gov/pubmed/15970487
(32) http://www.ncbi.nlm.nih.gov/pubmed/6799643
(33) http://www.ncbi.nlm.nih.gov/pubmed/6391777
(34) http://www.ncbi.nlm.nih.gov/pubmed/557025
(35) http://www.ncbi.nlm.nih.gov/pubmed/22100845
(36) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907943/
(37) http://www.ncbi.nlm.nih.gov/pubmed/22932074
(38) http://www.ncbi.nlm.nih.gov/pubmed/22606063
(39) http://www.ncbi.nlm.nih.gov/pubmed/23170913
(40) http://www.ncbi.nlm.nih.gov/pubmed/19620039
III. Leukotrienes
According to the study of Prostaglandins and leukotrienes as inflammatory mediators by John A Salmon and Gerald A Higgs(a), Leukotrienes is produced in leukocytes as a result of oxidative metabolism of arachidonic acid by the enzyme arachidonate 5-lipoxygenase, belonging to the family of eicosanoid inflammatory mediators(a). Its production is usually accompanied by the production of histamine and prostaglandins.
1. Leukotrienes in immunopathogenesis of rheumatoid arthritis
Leukotrienes are a family of paracrine agents derived from oxidative metabolism of arachidonic acid. According to the study by the Tehran University of Medical Sciences, Leukotrienes (often leukotriene B4) as potent chemotactic agents can provoke most signs and symptoms in rheumatoid arthritis by initiating, coordinating, sustaining, and amplifying the inflammatory response, through recruitment of leukocytes. A number of studies have reported that pharmacological modulation in this field can significantly attenuate clinical manifestations associated with different inflammatory pathologies(1).
2. Leukotrienes and inflammatory and allergic response
According to the study to Department of Medical Biochemistry and Biophysics, Karolinska Institutet,
Leukotrienes are recognized as important signal molecules in a variety of inflammatory and allergic conditions affecting the skin, joints, gastrointestinal and respiratory systems typified by local pain, tissue edema, hyperemia and functional losses. In the tissues, immunocompetent cells accumulate at the site of injury which contribute to tissue damage and perpetuation of the disease process. Leukotrienes can elicit most, if not all, of these signs and symptoms. Thus, leukotriene B4 is one of the most powerful chemotactic agents known to date and participates in the recruitment of leukocytes. The cysteinyl leukotrienes, on the other hand, contract smooth muscles, particularly in the peripheral airways and microcirculation of that function leading to the formation of drugs which block the formation and action of leukotrienes introduced as novel antiasthmatic medications.(2).
3. Leukotrienes in asthma and allergic rhinitis
Leukotrienes have been shown to mediate diverse features of allergic conditions including inflammatory cell chemotaxis/activation and smooth muscle contraction. Cysteinyl leukotrienes (LTC(4), LTD(4) and, LTE(4)) and the dihydroxy leukotriene LTB(4) generated by a series of enzymes/proteins constituting the LT synthetic pathway or 5-lipoxygenase (5-LO) pathway to mediate the interaction of multiple receptors. Leukotriene receptor antagonists (LTRA) and LT synthesis inhibitors (LTSI) have shown clinical efficacy in asthma and more recently in allergic rhinitis. Despite growing knowledge of leukotriene biology, the molecular regulation of these inflammatory mediators remains to be fully understood. Genes encoding enzymes of the 5-LO pathway (i.e. ALOX5, LTC4S and LTA4H) and encoding for LT receptors (CYSLTR1/2 and LTB4R1/2) provide excellent candidates for disease susceptibility and severity(3).
4. Treatment heterogeneity in asthma with leukotriene modifiers
Despite advances in treatment, asthma continues to be a significant health and economic burden. According to the study by the Centers for Clinical Pediatric Pharmacology & Pharmacogenetics, Jacksonville, two classes of LT modifiers are 5-lipoxygenase (ALOX5) inhibitors (zileuton) and leukotriene receptor antagonists (LTRAs) [montelukast, pranlukast, and zarfirlukast]. LT modifiers can be used as alternatives to low-dose inhaled corticosteroids (ICS) in mild persistent asthma, as add-on therapy to low- to medium-dose ICS in moderate persistent asthma, and as add-on to high-dose ICS and a long-acting ss2 agonist in severe persistent asthma. Studies have reported that genetic variation in ALOX5, LTA4H, LTC4S, and ABCC1 influences response to LT modifiers. Plasma concentrations of LTRAs vary considerably among patients(4).
5. Leukotrienes and Fibroblasts
Fibroblasts are implicated in sub-epithelial fibrosis in remodeled asthmatic airways and contribute to airway inflammation by releasing cytokines and other mediators. In the study to investigate the expression of leukotriene biosynthetic enzymes and receptors in primary fibroblasts from the bronchi of normal and asthmatic adult subjects using RT-PCR, Western blotting, immunocytochemistry and flow cytometry, indicated that human bronchial fibroblasts may not only respond to exogenous leukotrienes but also generate leukotrienes implicated in narrowing, inflammation and remodeling of the asthmatic airway(5).
6. Leukotriene and skin inflammation
Scratching triggers skin flares in atopic dermatitis. According to the study by the Boston Children's Hospital, in mice, tape stripping of mouse skin cause neutrophil influx was largely dependent on the generation of leukotriene B4 (LTB4) by neutrophils and their expression of the LTB4 receptor BLT1. Allergic skin inflammation in response to epicutaneous (EC) application of ovalbumin to tape-stripped skin was severely impaired in Ltb4r1(-/-) mice and required expression of BLT1 on both T cells and non-T cells. Cotransfer of wild-type (WT) neutrophils, but not neutrophils deficient in BLT1 or the LTB4-synthesizing enzyme LTA4H, restored the ability of WT CD4(+) effector T cells to transfer allergic skin inflammation to Ltb4r1(-/-) recipients(6).
7. Leukotriene and local effects
In the study to assess the local effects of intracutaneous injections into humans of 1-3 nmol of five products of arachidonic acid metabolism, leukotrienes (LT) C4, D4, E4, and B4 from the 5-lipoxygenase pathways and prostaglandin (PG) D2 from the cyclooxygenase pathway, clinically and histologically, showed that The dermal vascular sites affected by LTD4 and PGD2 included capillaries, superficial and deep venules, and arterioles. LTB4 elicited a transient wheal and flare, followed in 3-4 hr by induration that was characterized by a dermal infiltrate comprised predominantly of neutrophils. The combination of LTB4 and PGD2 elicited tenderness and increased induration associated with a more intense neutrophil infiltration(7).
8. The functions of The leukotrienes
Leukotrienes (LTs) are metabolites of arachidonic acid formed by a 5-lipoxygenase and generated during immunological challenge or by reactions which involve changes in calcium levels. According to the study by the, Leukotriene B4 (LTB4), a dihydroxy metabolite, has been shown to exert marked chemotactic effect in many different animal species. LTB4 probably plays a role in inflammatory responses, and has been detected in several pathologic conditions. Reaction of LTA4, another lipoxygenase metabolite of arachidonic acid, with glutathione yields peptidolipid leukotrienes, LTC4, LTD4, and LTE4; these are components of slow reacting substance (SRS and SRS-A). The peptidolipid leukotrienes are potent bronchoconstrictors and enhance mucus production in the lungs. Furthermore, they constrict coronary arteries and have a negative inotropic effect. They probably play an important role in asthma and anaphylaxis. LTB4 and the peptidolipid leukotrienes may be important in several other organs, too, e.g., the skin and the eye. They may exert effects on a variety of smooth muscles and have neuronal and immunological effects(8).
9. Acetylsalicylic acid (aspirin) in regulation of LTB4 and LTC4
In the sttudy to to investigate the effect of the non-steroidal anti-inflammatory agent, acetylsalicylic acid (ASA) at different concentrations on the release rates of the pro-inflammatory mediators, leukotriene B4 (LTB4) and leukotriene C4 (LTC4), indicated that ASA treatment at 3 different concentrations (15, 75 and 150 microg/ml), the release rates of LTB4 and LTC4 were increased from melanocytes of the normal individuals (13%, 7.5% and 30%; 7.2%, 51.4% and 60.7%, p<0.001). However, in patients with active vitiligo, the release rate of LTB4 from melanocytes was decreased (2.9%, 14.4% and 7.4%, p<0.05), whereas that of LTC4 was increased (3.9%, 93.8% and 101.4%, p<0.001)(9).
10. Leukotrienes in rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory disorder of joints for which there is no strict cure. According to the study by the Tehran University of Medical Sciences, Leukotrienes (often leukotriene B4) as potent chemotactic agents can provoke most signs and symptoms in rheumatoid arthritis by initiating, coordinating, sustaining, and amplifying the inflammatory response, through recruitment of leukocytes. A number of studies have reported that pharmacological modulation in this field can significantly attenuate clinical manifestations associated with different inflammatory pathologies(10).
11. Bradykinin, prostaglandins and leukotrienes and Osteoarthritis
Osteoarthritis (OA) of the knee and hip is among the most frequent and debilitating arthritic conditions. According to the study by the McMaster University Faculty of Health Sciences, despite the central involvement of hyaline cartilage in OA pathogenesis, the source of pain likely stems from the richly innervated synovium, subchondral bone and periosteum components of the joint. Tissue damage during joint degeneration generates nociceptive stimuli. The presence of inflammatory mediators, including bradykinin, prostaglandins and leukotrienes, lowers the threshold of the Aδ and C pain fibres, resulting in a heightened response to painful stimuli. it is important to base and centre the management of OA patients on the severity of patient-important outcomes, rather than purely an assessment of damage to the joint. The joint damage, as interpreted from radiographs, is not necessarily representative of the symptoms experienced(11).
12. Leukotriene B4 receptors BLT1 and BLT2 in inflammatory arthritis
Lipid mediators derived from arachidonic acid through the cyclooxygenase and lipoxygenase pathways are known to be important mediators of inflammation. According to the study by the
James Graham Brown Cancer Center, Louisville, in the study of study of developed mice deficient in BLT2 by targeted disruption, indicated that the BLT2(-/-) mice developed normally, and analysis of immune cells showed that disruption of BLT2 did not alter BLT1 expression or function. Mast cells from the C57BL/6 mice but not from the BLT2(-/-) mice showed intracellular calcium mobilization in response to 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid. In an autoantibody-induced inflammatory arthritis model, the BLT2(-/-) mice showed reduced incidence and severity of disease, including protection from bone and cartilage loss. Reciprocal bone marrow transplant experiments identified that loss of BLT2 expression on a bone marrow-derived cell lineage offers protection against severe disease(12).
13. Excessive synthesis of leukotrienes in the pathogenesis of systemic sclerosis
Systemic sclerosis (SSc, scleroderma) is an autoimmune disease characterized by widespread vascular injury and progressive fibrosis of the skin and internal organs. SSc-related involvement of the lungs, heart, kidneys and/or the gastrointestinal system accounts for the increased mortality of scleroderma patients. According to the Medical University of Bialystok, Leukotrienes play an important role in the regulation of all the processes vital to the pathogenesis of SSc, namely inflammation, vascular function and connective tissue remodeling. The available data suggests that an excessive synthesis of leukotrienes may contribute to the development and progression of SSc. Accordingly, blockade of leukotriene pathways appears to be a new, promising target for the treatment of SSc(13).
14. Inhibition of leukotriene D4 and eosinophilic gastroenteritis
Eosinophilic Gastroenteritis (EG) is a rare condition, caused by eosinophilic inflammatory infiltrates in the gastrointestinal tract. It is usually treated successfully with systemic glucocorticoids. According to the study by the Department of internal medicine, UZ Leuven, montelukast, a leukotriene receptor antagonist inhibits leukotriene D4, an important cytokine in the inflammatory cascade. Although montelukast could not replace steroid therapy, it acted as a steroid sparing agent in our patient(14).
15. Churg-Strauss and the Inhibition of leukotriene D4
Churg-Strauss syndrome (CSS) is a systemic small vessel vasculitis involving lungs, skin, heart, gastrointestinal tract and peripheral nerves. According to the study lead by Carlesimo M, there is a report of a 36-year-old woman with a necrotic lesion on the left foot of two months duration, associated with hypereosinophilia, patchy lung infiltrates, cardiac damage and a mononeuritis. The personal history was remarkable only for an asthma, treated with Montelukast, a leukotriene receptor antagonist (LRA). Clinical symptoms, laboratory exams and instrumental examinations led us to the diagnosis of CSS. In recent years several studies have reported the possible relationship between use of leukotriene receptor antagonist (LRA) and CSS expression(15).
16. Treatment of asthma with antileukotrienes and Churg-Strauss syndrome
Since antileukotriene treatment for asthma was introduced, there has been debate about whether such therapy can lead to Churg-Strauss Syndrome (CSS). According to Hospital Central de Asturias, Oviedo, Hospital Puerta de Hierro, there is a report of which suspected CSS in a patient with bronchopulmonary, cutaneous and analytical signs and whom we treated with oral steroids. After clinical improvement, one year later, steroids were replaced by antileukotrienes, after which the same clinical picture developed. The vasculitis characteristic of CSS was confirmed pathologically(16).
17. Leukotrienes: the immune-modulating lipid mediators of disease
The leukotrienes are important lipid mediators with immune modulatory and proinflammatory properties. When formed in excess, these compounds play a pathogenic role in several acute and chronic inflammatory diseases, such as asthma, rheumatoid arthritis, and inflammatory bowel disease. According to the study by the Department of Medical Biochemistry and Biophysics, Division of Chemistry 2, Karolinska Institutet, Classical bioactions of leukotrienes include chemotaxis, endothelial adherence, and activation of leukocytes, chemokine production, as well as contraction of smooth muscles in the microcirculation and respiratory tract. Recent genetic, morphological, and biochemical approaches, have pointed to the involvement of leukotrienes in cardiovascular diseases including atherosclerosis, myocardial infarction, stroke, and abdominal aortic aneurysm. Moreover, new insights have changed our previous notion of leukotrienes as mediators of inflammatory reactions to molecules that can fine-tune the innate and adaptive immune response(17).
18. Trihydroxyflavones and the inflammatory processes
In the study to evaluate the anti-inflammatory potential of a series of trihydroxyflavones by testing their ability to scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS) in cells and cell-free systems and to inhibit the proinflammatory pathways mediated by the enzymes cyclooxygenase (COX) and 5-lipoxygenase (5-LOX), in which reactive species have a proven involvement, showed that The tested trihydroxyflavones proved to be effective inhibitors of neutrophils' oxidative burst and were shown to scavenge different ROS and RNS in cell-free systems. The most active compound in the majority of the assays was 3,3',4'-trihydroxyflavone, which was somehow expected due to the presence of the ortho-dihydroxy in the B-ring, an important structural feature in terms of free radical scavenging activity and the compounds were able to inhibit the production of leukotriene B(4) by 5-LOX in activated neutrophils. 3,5,7-Trihydroxyflavone was able to inhibit both COX-1 and COX-2, which makes it a dual inhibitor of COX and 5-LOX pathways and, therefore, a promising candidate for a new therapeutic option in the treatment of inflammatory processes(18).
19. Leukotrienes and neuropathic/inflammatory pain
In the study to summarize the recent studies examining the expression of leukotrienes (LTs) and their receptors in nociceptive pathways, and their crucial roles in pathological pain conditions, by examininf of whether LTs were implicated in neuropathic pain following peripheral nerve injury. Using the SNI model in rats, investigating the expression of LT synthases and receptors mRNAs in the spinal cord and the roles on the pain behaviors, showed that the increase of LT synthesis in spinal microglia produced via p38 mitogen-activated protein kinase (MAPK) plays a role in the generation of neuropathic pain. We also examined the expression and roles on pain behaviors of LT receptors in the dorsal root ganglion (DRG) using a peripheral inflammation model. The data indicate CysLT2 expressed in DRG neurons may play a role as a modulator of P2X3, and contribute to the potentiation of the neuronal activity following peripheral inflammation(19).
20. Lukotrienes in the pathogenesis of dysmenorrhea in adolescent girls
In the study to determine the role of prostaglandins and leukotrienes in the pathogenesis of dysmenorrhea in a data of Twenty patients with dysmenorrhea aged 16.2+/-1.2 years and 20 healthy age-matched controls with eumenorrhea (absence of pain during menstruation) showed that there is a distinct pattern of leukotriene production during the menstrual cycle, but the changes in the systemic level are not responsible for their role in the pathogenesis of dysmenorrhea. Further studies at the local level in the target organ are necessary to elucidate the role of the lipid mediators in the pathogenesis of dysmenorrhea(20).
21. Urinary leukotriene E4 in children with severe atopic eczema/dermatitis syndrome
Leukotrienes are thought to play a role in the pathogenesis of atopic eczema/dermatitis syndrome (AEDS). Urinary leukotriene E4 (U-LTE4) is a marker of whole-body cysteinyl-leukotriene production. According to the study by the Department of Pediatrics, Rogaland Central Hospital, in the study to evaluate the role of leukotrienes in children with AEDS by measuring levels of U-LTE4, and to evaluate whether levels of U-LTE4 may reflect disease activity and allergic sensitization in AEDS, indicated that a role for leukotrienes in the pathogenesis of severe AEDS, and may support a role for leukotriene-antagonists in the treatment of this disorder. Levels of U-LTE4 may reflect the disease severity and sensitization to allergens in AEDS(21).
22. Leukotriene and eosinophil protein X in children with atopic asthma
In the study to examine the differences in urinary LTE4 and EPX concentrations between children with stable atopic asthma and healthy controls and to compare asthmatic children with different disease severity by evaluating the relationship between urinary LTE4 and EPX levels and lung function. LTE4 was also measured (enzyme immunoassay) together with EPX (radioimmunoassay) in urine and lung function tests were carried out in children with mild asthma (steroid-naive) (n=49), moderate to severe asthma (using inhaled steroids) (n=31) and healthy control subjects (n=28), showed that there were no differences in urinary LTE4 and EPX between the group of mild and the group of moderate to severe asthmatic children. There were significant associations between the urinary LTE4 and intrathoracic gas volume (ITGV), residual volume (RV), forced expiratory volume in one second (FEV1), forced expiratory capacity (FVC) and maximum expiratory flow rate at 25% of vital capacity (MEF25). Urinary EPX was only correlated with maximum expiratory flow rate at 75% of vital capacity (MEF75)(22).
23. Leukotriene and vasogenic edema
In the study to determine whether tissue leukotriene-like immunoreactivity was increased in intracranial tumors associated with peritumoral edema. 20 patients undergoing craniotomy tissue specimens were immediately frozen after removal and tissue leukotriene C4 levels were determined by radioimmunoassay, indicated that there was a significant correlation between brain edema and tissue leukotriene levels (p less than 0.003). Metastatic tumors (n = 8) had the highest leukotriene C4 level at 13.8 +/- 8.5 pg/mg tissue (mean +/- SE) and the highest index of edema 5.7 +/- 1.8. The mean leukotriene C4 level in the gliomas (n = 5) was 6.2 +/- 2.3 pg/mg tissue and the edema index was 2.1 +/- 0.6(23).
24. Leukotriene D4 in pulmonary edema fluid
In the examination by quantifying the pulmonary edema fluid concentrations of lipoxygenase and cyclooxygenase products to detemine the possible contribution of metabolites of arachidonic acid to the increased permeability of the alveolar-capillary barrier in the adult respiratory distress syndrome, indicated that The concentration of leukotriene D4 in pulmonary edema fluid of 10 patients with the adult respiratory distress syndrome (18.5 +/- 6.8 pmol/ml; mean +/- SD), assessed by specific radioimmunoassay after isolation of the mediator, was significantly higher (P less than 0.001) than that of five patients with cardiogenic pulmonary edema (4.4 +/- 1.1 pmol/ml). The concentrations of leukotrienes B4 and C4, prostaglandin E2, and thromboxane B2 in edema fluid were not significantly different in the adult respiratory distress syndrome patients than in the other subjects with pulmonary edema. The edema fluid concentration of leukotriene D4 correlated with the ratio of edema fluid to plasma concentrations of albumin (r = 0.64). Leukotriene D4 thus may contribute to the permeability defect which allows an accumulation of protein-rich alveolar fluid in the adult respiratory distress syndrome(24).
25. Syndrome of aspirin-exacerbated respiratory disease (AERD)
Chronic rhinosinusitis (CRS) with nasal polyposis (NP) may be associated with hypersensitivity to nonsteroidal anti-inflammatory drugs, representing a syndrome of aspirin-exacerbated respiratory disease (AERD). According to the study by the Jagiellonian University Medical College, among CRS subjects requiring functional endoscopic sinus surgery (FESS), as many as 33.3% may have AERD and respond to a small provocative dose of aspirin with bronchoconstriction and/or mucosal and skin edema. A simple and inexpensive measurement of uLTE4 (leukotriene E4) can help diagnose AERD in patients with CRS with sensitivity of 87.5%, but its specificity is limited and depends on the arbitrary threshold of uLTE4(25).
26. Leukotriene and uterine vascular responses to estrogen
In the study to test hypothesis of that the leukotrienes may be the mediators of the uterine vascular responses to estrogen, by giving FPL 55712, a selective leukotriene antagonist, to estrogen-primed, nonpregnant rabbits and measured regional blood flows by the radioactive microsphere technique, indicated that leukotrienes do not mediate, but rather inhibit, the uterine vascular responses to estrogen(26).
27. Leukotrienes and gastric hyperemia
In the study on anesthetized dogs to determine the role of eicosanoids in regulation of total, and mucosal gastric blood flow and oxygen consumption in the stomach damaged by the instillation of 25% ethanol, showed that The inhibition of prostaglandins generation by indomethacin caused an ischemia and hypoxia in the stomach. It was an evidence for their basal generation and tonic influence on circulation in this organ. OKY--a blocker of thromboxanes synthesis and NDGA--a blocker of 5-lipoxygenase did not alter circulatory and metabolic parameters in the stomach. Above findings indicate, that thromboxanes and leukotrienes are not involved in the physiological modulation of blood vessels activity and oxygen consumption in the stomach. But administration of 25% ethanol on gastric mucosa affected in a rise of total and mucosal blood flow and oxygen consumption. These effects were significantly potentiated by OKY and NDGA and suggesting, that damaged gastric mucosa is able to generate thromboxanes and leukotrienes which cause vasoconstriction. It seems, that endogenous prostaglandins also play an important role, because the gastric hyperemia and the increase in gastric oxygen consumption after alcohol were inhibited by indomethacin.(27).
28. Leukotriene (LT) D4 and coronary constriction
In the study the effects of leukotriene (LT) D4 (0.5 microgram/min) infusion into the left anterior descending coronary artery (LAD) of anesthetized pigs, in the absence or presence of indomethacin (5 mg/kg i.v.), indicated that the coronary constriction disappeared despite sustained LTD4 infusion and was followed by reactive hyperemia. Indomethacin did not affect the coronary flow or hemodynamic responses to LTD4 infusion. The A-V difference in prostanoids did not change during LTD4 administration. However, intracoronary bolus injection of LTD4 stimulated prostacyclin release from the vasculature in a dose-dependent manner causing significant reactive hyperemia after temporary blood flow cessation. Release of a LTD4-induced(28).
29. Leukotriene D4 (LTD4) and functional impairment
In the Glomerular micropuncture studies to evaluate the glomerular microcirculatory actions of leukotriene D4 (LTD4) in euvolemic, anesthetized, adult, male Munich-Wistar rats, indicated that in the preliminary experiments, intrarenal arterial administration of LTD4 (1 microgram X kg-1 X min-1) was found to cause a rise in mean systemic arterial pressure, a loss of plasma volume, and a fall in renal blood flow, effects identical to those previously reported for LTC4. glomerular microcirculatory dynamics were assessed during LTD4 infusion while constancy of renal perfusion pressure and plasma volume were maintained by partial aortic constriction and isoncotic plasma infusion, respectively, with saralasin (5 micrograms X kg-1 X min-1 iv) was also given throughout the study, LTD4 caused a significant increase in efferent arteriolar resistance in association with a fall in glomerular plasma flow rate (QA) and a rise in glomerular capillary hydraulic pressure. Despite the latter, single-nephron filtration rate fell due to combined reductions in QA and the glomerular ultrafiltration coefficient. These local glomerular constrictor actions of LTD4 support the possibility that this eicosanoid might play an important intermediary role in the functional impairment accompanying some forms of inflammatory injury(29).
30. Primary PGs (including prostacyclin), thromboxanes, and leukotrienes during benign or malignant pathological processes
Prostaglandins (PGs) are a family of lipid compounds synthesized from polyunsaturated fatty acids derived from phospholipids, and divided into three main classes: primary PGs (including prostacyclin), thromboxanes, and leukotrienes and presented in very low quantities under normal or resting condition. According to the study byRolland PH., Prostaglandins (PGs) showed a marked increase in levels during benign or malignant pathological processes as the results from loss of the physiological state of tissue dependence of the cells, which acquire functional autonomy and become endowed with properties which appear to be important in cancer dissemination processes(30).
Sources
(a) http://bmb.oxfordjournals.org/content/43/2/285
(1) http://www.ncbi.nlm.nih.gov/pubmed/23529572
(2) http://www.ncbi.nlm.nih.gov/pubmed/12088275
(3) http://www.ncbi.nlm.nih.gov/pubmed/19416143
(4) http://www.ncbi.nlm.nih.gov/pubmed/17397245
(5) http://www.ncbi.nlm.nih.gov/pubmed/16872537
(6) http://www.ncbi.nlm.nih.gov/pubmed/23063331
(7) http://www.ncbi.nlm.nih.gov/pubmed/6296237
(8) http://www.ncbi.nlm.nih.gov/pubmed/6096644
(9) http://www.ncbi.nlm.nih.gov/pubmed/15494818
(10) http://www.ncbi.nlm.nih.gov/pubmed/23529572
(11) http://www.ncbi.nlm.nih.gov/pubmed/22471357
(12) http://www.ncbi.nlm.nih.gov/pubmed/20656922
(13) http://www.ncbi.nlm.nih.gov/pubmed/22763975
(14) http://www.ncbi.nlm.nih.gov/pubmed/22319970
(15) http://www.ncbi.nlm.nih.gov/pubmed/22230414
(16) http://www.ncbi.nlm.nih.gov/pubmed/11181230
(17) http://www.ncbi.nlm.nih.gov/pubmed/23063073
(18) http://www.ncbi.nlm.nih.gov/pubmed/22806885
(19) http://www.ncbi.nlm.nih.gov/pubmed/21804200
(20) http://www.ncbi.nlm.nih.gov/pubmed/19227413
(21) http://www.ncbi.nlm.nih.gov/pubmed/15575936
(22) http://www.ncbi.nlm.nih.gov/pubmed/11106196
(23) http://www.ncbi.nlm.nih.gov/pubmed/3729313
(24) http://www.ncbi.nlm.nih.gov/pubmed/6511865
(25) http://www.ncbi.nlm.nih.gov/pubmed/22814420
(26) http://www.ncbi.nlm.nih.gov/pubmed/6695994
(27) http://www.ncbi.nlm.nih.gov/pubmed/1845317
(28) http://www.ncbi.nlm.nih.gov/pubmed/3568058
(29) http://www.ncbi.nlm.nih.gov/pubmed/3618788
(30) http://www.ncbi.nlm.nih.gov/pubmed/6815214
IV. Prostacyclin
Prostacyclin (or PGI2), also known as known as eicosanoids, a member of the family prostaglandins as a metabolite of arachidonic acid, inhibits platelet aggregation, and dilates blood vessels and is released by healthy endothelial cells and performs its function through a paracrine signaling cascade that involves G protein-coupled receptors on nearby platelets and endothelial cells(a).
1. Obesity and endothelial dysfunction
Obesity is frequently associated with endothelial dysfunction. In the study to investigate the role of the 'endothelial' MR in obesity-induced endothelial dysfunction, the earliest stage in atherogenesis, with C57BL/6 mice exposed to a normal chow diet (ND) or a high-fat diet (HFD) alone or in combination with the MR antagonist eplerenone (200 mg/kg/day) for 14 weeks, showed that Obesity-induced endothelial dysfunction depends on the 'endothelial' mineralocorticoid receptor (MR) and is mediated by an imbalance of oxidative stress-modulating mechanisms. Therefore, MR antagonists may represent an attractive therapeutic strategy in the increasing population of obese patients to decrease vascular dysfunction and subsequent atherosclerotic complications(1).
2. Caloric restriction reverses high-fat diet-induced endothelial dysfunction
In the study to examine whether caloric restriction could reverse the detrimental vascular effects related to obesity with male C57Bl/6 mice were fed with normal-fat diet (fat 17%) or high-fat diet (fat 60%) for 150 days. After establishment of obesity at day 100, a subgroup of obese mice were put on caloric restriction (CR) (70% of ad libitum energy intake) for an additional 50 days. At day 100, aortic rings from obese mice receiving high-fat diet showed impaired endothelium-dependent vasodilation in response to acetylcholine (ACh), showed that Caloric restriction markedly attenuated vascular superoxide production. In obese mice on CR, endothelial denudation increased superoxide formation whereas vascular superoxide production was unaffected by L-NAME. Western blot analysis revealed decreased phosphorylated eNOS (Ser1177)-to-total eNOS expression ratio in obese mice as compared to lean controls, whereas the phospho-eNOS/NOS ratio in obese mice on CR did not differ from the lean controls. In conclusion, the present study suggests that caloric restriction reverses obesity induced endothelial dysfunction and vascular oxidative stress, and underscores the importance of uncoupled eNOS in the pathogenesis(2).
3. Prostacyclin receptor (IP-receptor) agonists anti-inflammatory and antiviral activity
Prostacyclin receptor (IP-receptor) agonists display anti-inflammatory and antiviral activity in cell-based assays and in preclinical models of asthma and chronic obstructive pulmonary disease. In the study to extended these observations by demonstrating that IP-receptor activation also can enhance the ability of glucocorticoids to induce genes with anti-inflammatory activity, found that IP-receptor agonists can augment the ability of glucocorticoids to induce anti-inflammatory genes in human airway epithelial cells by activating a cAMP/PKA-dependent mechanism. This observation may have clinical relevance in the treatment of airway inflammatory diseases that are either refractory or respond suboptimally to glucocorticoids(3).
4. Synthesis of prostacyclin effect on the contractile activity of the inflamed porcine uterus
In the study to estimate the content of prostacyclin (PGI(2)), the levels of PGI synthase (PTGIS) and receptor (PTGIR) protein expression, and the cellular localization of these factors in the inflammatory-changed porcine uterus, showed that inflammation of the porcine uterus upregulates PGI(2) synthesis and that PGI(2) increases contractility, which suggests that PGI(2) might be essential for the course of uterine inflammation(4).
5. Rosuvastatin and PGI(2)-peroxisome proliferator-activated receptor
Statins are reported to alleviate renal fibrosis in animal models with ureteral obstruction. Pressure force is an important mechanism contributing to induction and progression of tubulointerstitial fibrogenesis in ureteric obstruction. In the study to assess whether the influence of rosuvastatin on pressure-induced fibrotic responses in rat renal tubular cells (NRK-52E). We established an in vitro pressure culture system to study pressure-induced fibrotic responses in NRK-52E cells, indicated that rosuvastatin reduces pressure-induced fibrotic responses in renal tubular cells by enhancing the PGI(2)-peroxisome proliferator-activated receptor α pathway and reducing PGE(2) generation(5).
6. Prostacyclin and its prostacyclin receptor and cardio-protective effects
Prostacyclin and its prostacyclin receptor, the I Prostanoid (IP), play essential roles in regulating hemostasis and vascular tone and have been implicated in a range cardio-protective effects. In the study to investigate the influence of cholesterol on human IP [(h)IP] gene expression in cultured vascular endothelial and platelet-progenitor megakaryocytic cells, showed that cholesterol can regulate hIP expression, which may, at least in part, account for the combined cardio-protective actions of low serum cholesterol through its regulation of IP expression within the human vasculature(6).
7. Thromboxane A2 and prostacyclin and endothelial dysfunction
Endothelial dysfunction participates in the pathogenesis of many cardiovascular disorders. In the study to assess whether cyclooxygenase-2 (COX-2) activation is involved in the effects of chronic aldosterone treatment on endothelial function of mesenteric resistance arteries (MRA) from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR), showed that Aldosterone reduced acetylcholine relaxation in MRA from both strains. In MRA from both aldosterone-treated strains the COX-1/2 or COX-2 inhibitor (indomethacin and NS-398, respectively), TxA2 synthesis inhibitor (furegrelate), prostacyclin synthesis inhibitor (tranylcypromine) or TxA2/ PGH2 receptor antagonist (SQ 29 548), but not COX-1 inhibitor SC-560, increased acetylcholine relaxation. In untreated rats this response was increased only in SHR. Prostacyclin elicited a biphasic vasomotor response: lower concentrations elicited relaxation, whereas higher concentrations elicited contraction that was reduced by SQ 29 548. Aldosterone increased the acetylcholine-stimulated production of 6-oxo-PGF(1alpha) and TxB2 in MRA from both strains. COX-2 expression was higher in both strains of rats treated with aldosterone(7).
8. Prostacyclin in endothelial dysfunction
In the study to analyze the possible involvement of vasoconstrictors prostanoids on the reduced endothelium-dependent relaxations produced by chronic administration of aldosterone in Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), indicated that chronic treatment with aldosterone was able to produce endothelial dysfunction through COX-2 activation in normotensive and hypertensive conditions. PGI2 seems to be the main factor accounting for endothelial dysfunction in hypertensive rats, whereas other prostanoids besides PGI2 appear to be involved in endothelial dysfunction under normotensive conditions(8).
9. Prostacyclin-stimulating and/or thromboxane A2-inhibiting action in hypertensive pregnancy complications
Several gynecologic and obstetric disorders are characterized by abnormalities in prostacyclin and/or thromboxane A2. In primary menorrhagia the uterine release of prostacyclin is increased, and consequently menstrual blood loss can be reduced with various prostaglandin synthesis inhibitors. Prostacyclin relaxes the nonpregnant myometrium in vitro and may also do so in vivo, although intravenous infusion of prostacyclin has no effect upon the uterine contractility in nonpregnant or pregnant subjects. In the study to review the gynecologic and obstetric implications of the smooth muscle-relaxing, antiaggregatory prostacyclin and its endogenous antagonist, thromboxane A2, showed that patients with pelvic endometriosis may have increased levels of prostacyclin and thromboxane A2 metabolites in the peritoneal fluid. The prostacyclin/thromboxane A2 balance shifts to thromboxane A2 dominance in patients with gynecologic cancer. During pregnancy the production of prostacyclin and thromboxane A2 increases in the mother and fetoplacental tissue. Preeclampsia and other chronic placental insufficiency syndromes are accompanied by prostacyclin deficiency in the mother and in fetomaternal tissues and by an overproduction of thromboxane A2, at least in the placenta. These changes may account for the vasoconstriction and platelet hyperactivity, which are pathognomonic for hypertensive pregnancies. By directing the prostacyclin/thromboxane A2 balance to prostacyclin dominance (by dietary manipulation, administration of prostacyclin and/or its analogues, drugs with prostacyclin-stimulating and/or thromboxane A2-inhibiting action), it may be possible to prevent and/or treat hypertensive pregnancy complications in the future(9).
10. Prostacyclin, thromboxane A2, and hypertension
Prostacyclin and thromboxane A2, products of separate branches of the arachidonic acid cascade, can have opposing effects on kidney function and on the vascular musculature. According to the study by the Shandong Medical University, prostacyclin acts as a vasodilator while thromboxane A2 has a vasoconstrictor effect and the balance between these two compounds appears to contribute to the homeostatic regulation of normal blood pressure. In the hypertensive state, this balance is disrupted and, at least in animal models of hypertension, there is excessive production of both. The increase in prostacyclin formation may be a reaction to the elevated blood pressure, possibly due to mechanical stimulation of the vascular smooth muscle cells in the blood vessel wall. However, the increase in thromboxane A2 may be more directly involved in the development and maintenance of hypertension. Not only is thromboxane A2 a vasoconstrictor but it can also stimulate the growth and proliferation of vascular smooth muscle cells which may account for the vascular hypertrophy seen in hypertension(10).
11. Interrelationships between prostacyclin and thromboxane A2
Prostacyclin is a product of arachidonic acid metabolism generated by the vessel wall of all mammalian species studied including man. According to the study by Moncada S, Vane JR. ,prostacyclin is a potent vasodilator and the most potent inhibitor of platelet aggregation. It inhibits platelet aggregationand can also be a circulating hormone constantly released by the pulmonary circulation. In contrast to the vessel wall, in blood platelets arachidonic acid is converted by the enzyme thromboxane synthetase to a potent vasoconstrictor and proaggregating substance, thromboxane A2. Therefore arachidonic acid is metabolized in the vessel wall and the platelets to potent substances with opposing biological activities. The balance between the activities of these substances is important in the homeostatic interaction of the platelets and the vessel wall. The different ways of interfering with this balance and its impact in the development of thrombosis and atherosclerosis(11).
12. Prostacyclin's biosynthesis, actions and clinical potential
Prostacyclin (PGI2) is the product of arachidonic acid metabolism generated by the vessel wall of all mammalian species studies. According to the study by Moncada S, Vane JR., indicated that prostacyclin inhibits aggregation through stimulation of platelet adenyl cyclase leading to an increase in platelet cyclic AMP. In the vessel wall, the enzyme that synthesizes prostacyclin is concentrated in the endothelial layer. Prostacyclin can also be a circulating hormone released from the pulmonary circulation. Based on these observations we proposed that platelet aggregability in vivo is controlled via a prostacyclin mechanism. The discovery of prostacyclin has given a new insight into arachidonic acid metabolism and has led to a new hypothesis about mechanisms of haemostasis. Reductions in prostacyclin production in several diseases, including atherosclerosis and diabetes, have been described and implicated in the pathophysiology of these diseases. Additionally, since prostacyclin powerfully inhibits platelet aggregation and promotes their disaggregation, this agent could have an important use in the therapy of conditions in which increased platelet aggregation takes place and in which, perhaps, a prostacyclin deficiency exists. Prostacyclin has been used beneficially in humans during extracorporeal circulation procedures such as cardiopulmonary bypass, charcoal haemoperfusion and haemodialysis. Its possible use in other conditions such as peripheral vascular disease or transplant surgery(12).
13. Prostacyclin in vascular tissue
Prostacyclin (PGI2) generated by the vascular wall is a potent vasodilator, and the most potent endogenous inhibitor of platelet aggregation. According to the study by Moncada S, Vane JR., prostacyclin inhibits platelet aggregation by increasing cyclic AMP levels. Prostacyclin is a circulating hormone continually released by the lungs into the arterial circulation. Circulating platelets are, therefore, subjected constantly to prostacyclin stimulation and it is via this mechanism that platelet aggregability in vivo is controlled. Moreover, phosphodiesterase inhibitors such as dipyridamole or theophylline exert their antithrombotic actions by potentiating circulating prostacyclin. The prostacyclin:thromboxane A2 ratio is important in the control of thrombus formation; manipulation of this ratio by small doses of aspirin (which will inhibit mainly platelet cyclooxygenase), a selective inhibitor of thromboxane formation, or the dietary use of a fatty acid like eicosapentaenoic acid (which would be the precursor for a delta17-prostacyclin (PGI3) but is transformed by the platelets into nonaggregating thromboxane A3) might have beneficial effects as antithrombotic therapies. Prostacyclin has interesting potential for clinical application in conditions where enhanced platelet aggregation is involved or to increase biocompatibility of extracorporeal circulation systems(13).
14. Prostacyclin reduces cardiopulmonary bypass-induced pulmonary endothelial dysfunction
Cardiopulmonary bypass triggers a systemic inflammatory response that alters pulmonary endothelial function, which can contribute to pulmonary hypertension. According to the study by the Montreal Heart Institute, prophylactic use of inhaled prostacyclin has a favorable impact on the pulmonary endothelial dysfunction induced by cardiopulmonary bypass associated with preservation of pulmonary intravascular cyclic adenosine monophosphate content and the pulmonary vascular tone(14).
15. Healthy vascular endothelium
Healthy vascular endothelium is a powerful generator of nitric oxide (NO), prostacyclin (PGI2), prostaglandin E2 (PGE2), and plasminogen activator (t-PA). These endothelial products protect vascular wall against aggression from activated blood platelets and leukocytes. According to the study by Jagiellonian University, In particular they protect against thrombosis, promote thrombolysis, maintain tissue perfusion, and inhibit remodeling of vascular and cardiac walls. Endothelial dysfunction appears on one hand as suppression in the release of the above mediators, and on the other as deleterious discharge of prostaglandin endoperoxides (PGH2, PGG2), superoxide anion O2-, peroxynitrite (ONOO-), and plasminogen activator inhibitor (PAI-1)(15).
16. Vasoprotective function of endothelial cells
Vasoprotective function of endothelial cells is associated, among others, with biosynthesis and release of nitric oxide (NO), prostacyclin (PGI2), prostaglandin E2 (PGE2), carbon monoxide (CO) and plasminogen activator (t-PA). According to the study by the Jagiellonian University, These endothelial mediators calm down activated platelets and leukocytes, prevent the occurrence of parietal thrombotic events, promote thrombolysis, maintain tissue perfusion and protect vascular wall against acute damage and against chronic remodeling. Endothelial dysfunction in patients suffering from atherosclerosis or diabetes type 2 is associated not only with suppression in release of the above mediators but also with deleterious discharge of prostaglandin endoperoxides (PGH2, PGG2), superoxide anion (O2-, peroxynitrite (ONOO-), and plasminogen activator inhibitor (PAI-1). We looked for mechanisms of protective endothelial function, with a special respect to the differences between peripheral and pulmonary circulation(16).
17. Endothelial dysfunction in sepsis
The endothelium takes part in the regulation of numerous physiological functions and lies at the interface of circulating blood and the vessel wall. Under physiological conditions, it is responsible for anticoagulant and anti-adhesive properties, and it regulates vasomotor tone and vascular homeostasis. According to the study by Hôpitaux Universitaires de Strasbourg, septic shock is associated with hypotension and frequently with disseminated intravascular coagulation contributing to multiple organ failure and a high mortality rate. Impairment of endothelial function leads to phenotypic and physical changes of the endothelium, with deregulated release of potent vasodilators nitric oxide and prostacyclin, reduction of vascular reactivity to vasoconstrictors, associated with leukocytes' and platelets' aggregation, and increase in inducible nitric oxide synthase expression that can exert a negative feedback on endothelial nitric oxide synthase expression, with subsequent deregulation of nitric oxide signaling. Endothelial dysfunction therefore plays a major role in the pathophysiology of septic shock and organ dysfunction, and has been suggested to be a predictor of mortality in sepsis(17).
18. Endothelial dysfunction and coagulation
In the study to review endothelial properties and to establish how these unperturbed properties contribute to the maintenance of endothelium anticoagulant activity and to better understand the relative contributions of endothelial cells and monocytes in sepsis-induced altered coagulation, showed that Unperturbed endothelial cells provide anticoagulant properties; exposure to inflammatory and/or septic stimuli can rapidly lead to procoagulant behavior. Sepsis alters endothelial cell surface and induces tissue factor synthesis at the endothelial and subendothelial levels. During endotoxemia, endothelial cells generate adhesion molecules that bind leukocytes and monocytes, increasing local procoagulant reactions. Tissue factor expression is also increased at the level of the monocyte; the relative importance of endothelial injury and monocyte activation in coagulation disorders was recently assessed. Endothelium protection before induction of septic shock was not associated with any reduction in monocyte tissue factor expression, suggesting that altered coagulation was present despite normal endothelial cell function. On the other hand, decreased monocyte tissue factor expression was associated with a marked reduction in endothelial injury, increased endothelium-derived relaxation, and improved survival rate in treated animals(18).
19. Endothelial cells and coagulation abnormalities
Endothelial cells have two important anticoagulant systems, heparan sulfate-antithrombin system and thrombomodulin-protein C system. Under physiological conditions, these two systems inhibit activation of coagulation on endothelial cells. According to the study by the Kumamoto University School of Medicine, under inflammatory conditions, tumor necrosis factor(TNF)-alpha or other cytokines produced by monocytes reduce the anticoagulant properties of endothelial cell by downregulating expression of heparan sulfate and thrombomodulin on endothelial cells. Antithrombin stimulates prostacyclin generation from endothelial cells by interacting with heparan sulfate of endothelial cells and generated prostacyclin inhibits TNF-alpha production by monocytes. Activated protein C inhibits TNF-alpha production by monocyte dependent of its protease activity. Thus, antithrombin and activated protein C might inhibit the endothelial perturbation induced by cytokines. Antithrombin regulates TNF-alpha induced tissue factor expression on endothelial cells by an unknown mechanism. Thus, antithrombin and activated protein C might be useful agents for treating coagulation abnormalities associated with sepsis or other inflammation because these agents inhibit not only coagulation but also downregulation of anticoagulant activities of endothelial cells(19).
20. Antithrombin (AT) can promote the endothelial production of prostacyclin
Antithrombin (AT) is an important inhibitor of the coagulation system, acting at many different levels of the coagulation cascade. This inhibitory action is enhanced several-fold by the glycosaminoglycan heparin. According to the study by the Sahlgrenska University Hospital, Göteborg University , data from cell culture and animal experiments have demonstrated that AT can promote the endothelial production of prostacyclin and may therefore have anti-inflammatory actions. This effect is based on the interaction of AT with glycosaminoglycans in the cell membrane, and is independent of heparin. The role of AT in vessel wall antithrombogenicity is being increasingly appreciated. The concept of neointimal hyperplasia following vascular injury involves thrombin as an important mediator and thus, in addition to the anti-inflammatory effects of AT, new horizons in which AT may have an important role in the prevention of post-traumatic hyperplastic response are also evolving(20).
21. The anti-inflammatory properties of antithrombin III
Antithrombin III (AT III) supplementation has proven to be effective in the treatment of disseminated intravascular coagulation. According to the study by the Kumamoto University School of Medicine , administration of AT III is also useful for prevention of organ failure in animals challenged with endotoxin or bacteria and it increases the survival rate of such animals. Since inhibition of coagulation abnormalities failed to prevent organ failure in animals given bacteria, AT III may exert a therapeutic effect independent of its anticoagulant effect. This therapeutic mechanism of AT III has been explored using an animal model of septicemia. AT III prevented pulmonary vascular injury by inhibiting leukocyte activation in rats given endotoxin. This effect is mediated by the promotion of endothelial release of prostacyclin which inhibits leukocyte activation. Interaction of AT III with heparin-like glycosaminoglycans (GAGs) on the endothelial cell surface appears to be important for this effect. Heparin inhibits these therapeutic effects of AT III by preventing AT III from interacting with the cell surface heparin-like GAGs. This activity of AT III may explain why AT III prevents organ failure as well as coagulation abnormalities in patients with sepsis(21).
22. Thrombin and Prostaglandin I2 (PGI2 or prostacyclin)
In the study role of blood clotting in the interaction of Platelet and vessel wall interaction found that vascular damage initiates not only the adhesion and aggregation of blood platelets but also coagulation, which is of mixed (intrinsic and extrinsic) origin. Evidence is presented that thrombin, generated as a result of the injury, is a prerequisite for platelet aggregation. Platelets, after activation, in their turn promote coagulation. Prostaglandin I2 (PGI2 or prostacyclin) inhibits coagulation induced by damaged vascular tissue. This effect of PGI2 is mediated by the inhibition of platelets in their participation in the generation of factor Xa and thrombin(22).
Sources
(a) http://en.wikipedia.org/wiki/Prostacyclin
(1) http://www.ncbi.nlm.nih.gov/pubmed/23594590
(2) http://www.ncbi.nlm.nih.gov/pubmed/20512454
(3) http://www.ncbi.nlm.nih.gov/pubmed/19880449
(4) http://www.ncbi.nlm.nih.gov/pubmed/23218395
(5) http://www.ncbi.nlm.nih.gov/pubmed/23276663
(6) http://www.ncbi.nlm.nih.gov/pubmed/22969152
(7) http://www.ncbi.nlm.nih.gov/pubmed/18500359
(8) http://www.ncbi.nlm.nih.gov/pubmed/15956108
(9) http://www.ncbi.nlm.nih.gov/pubmed/3890549
(10) http://www.ncbi.nlm.nih.gov/pubmed/2078914
(11) http://www.ncbi.nlm.nih.gov/pubmed/6258879
(12) http://www.ncbi.nlm.nih.gov/pubmed/6117893
(13) http://www.ncbi.nlm.nih.gov/pubmed/215463
(14) http://www.ncbi.nlm.nih.gov/pubmed/15224029
(15) http://www.ncbi.nlm.nih.gov/pubmed/12056503
(16) http://www.ncbi.nlm.nih.gov/pubmed/11208485
(17) http://www.ncbi.nlm.nih.gov/pubmed/23506494
(18) http://www.ncbi.nlm.nih.gov/pubmed/11445732
(19) http://www.ncbi.nlm.nih.gov/pubmed/10810875
(20) http://www.ncbi.nlm.nih.gov/pubmed/10102492
(21) http://www.ncbi.nlm.nih.gov/pubmed/9515777
(22) http://www.ncbi.nlm.nih.gov/pubmed/6117897
V. Thromboxane
Thromboxane is memeber of member of the family of lipids known as eicosanoids, containing 2 major thromboxanes, Thromboxane A2, a potent stimulator of platelet aggregation, and thromboxane B2, a metabolite of thromboxane A2 which is known to be highly unstable under physiological conditions.
1. The thromboxane synthase and receptor signaling pathway in cancer
Thromboxane A(2) (TXA(2)) is a biologically active metabolite of arachidonic acid formed by the action of the terminal synthase, thromboxane A(2) synthase (TXA(2)S), on prostaglandin endoperoxide (PGH(2)). TXA(2) is responsible for multiple biological processes through its cell surface receptor, the T-prostanoid (TP) receptor. According to the study by the Wayne State University, potential involvement of TXA(2)S and TP in tumor progression, especially tumor cell proliferation, migration, and invasion that are key steps in cancer progression. In addition, the regulation of neovascularization by TP has been identified as a potent source of control during oncogenesis(1).
2. Pesveratrol to modulate the immune system and to inhibit platelet aggregation in thromboembolic episodes
Platelet aggregation around migrating cancer cells protects them against the activity of natural killer cells (NKCs). The inability of immune system to response results in the progression of malignant diseases. In the study to evaluate the effects of resveratrol (3, 4', 5-trihydroxystilbene) on platelet aggregation and NKCs activity and the platelet aggregation, production of thromboxane B2 (TXB2), estimation of expression of the platelet receptor GpIIb/IIIa (major biological markers for platelet aggregation) and functional activity of the NKCs against the K562 cancer cell line after incubation with various concentrations of reveratrol, found that resveratrol can be used as an additional supplement to modulate the immune system and to inhibit platelet aggregation in thromboembolic episodes. Further clinical investigation in vivo could lead to specific concentrations that may maximize the beneficial effect of resveratrol(2).
3. Thromboxane synthase (TXAS) and thromboxane receptor (TP) beta isoform and Bladder cancer
Increased expression of thromboxane synthase (TXAS) and thromboxane receptor (TP) beta isoform are found in the tissues of patients with bladder cancer. In the study by the University of South Carolina to determine if the changes observed in the tissues of patients with bladder cancer were mirrored by changes in the urine of these patients, found that increased levels of thromboxane B(2) (TXB(2)) the major metabolite of TXAS and increased levels of the TPβ receptor. These results raised the possibility that patients with bladder cancer may be followed for progression or remission of their disease by quantitation of these substances in their urine(3).
4. Thromboxane synthase and Non small cell cancer
Thromboxane synthase (TXS) metabolises prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. In the study toexamine the TXS expression in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression, indicated that TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC(4).
5. Endogenous levels of AA and selected eicosanoids and colon cancer
Cumulative evidence shows that eicosanoids such as prostaglandins, leukotrienes, thromboxanes and hydroxy eicosatetraenoic acids play an important role in associating inflammation with human colorectal cancer (CRC). In the study In the study of an ultra-pressure liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) method was developed and validated for the targeted profiling of eight relevant eicosanoids and the major metabolic precursor, arachidonic acid (AA), in human colon, applied for the clinical profiling of matched pairs of cancerous and normal colon mucosae obtained from eight colorectal cancer patients, indicated that Endogenous levels of AA and selected eicosanoids such as prostaglandin E(2) (PGE(2)), prostacyclin (PGI(2)) [assayed as its stable hydrolytic product 6-keto-prostaglandin(1α) (6-k PGF(1α))] and 12-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12-HETE) were found to be significantly different (p <0.05; paired t-test) between cancerous and normal mucosae(5).
6. The role of thromboxane A(2) (TxA(2)) in smoking-associated lung cancer
The role of thromboxane A(2) (TxA(2)) in smoking-associated lung cancer is poorly understood. In the study to examine the role of TxA(2) in smoking carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-promoted cell survival and growth in human lung cancer cells, found that NNK stimulates TxA(2) synthesis and activates its receptor in lung cancer cells. The increased TxA(2) may then activate CREB through PI3K/Akt and extracellular ERK pathways, thereby contributing to the NNK-promoted survival and growth of lung cancer cells(6).
7. Prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer
Prostacyclin synthase and thromboxane synthase signaling via arachidonic acid metabolism affects a number of tumor cell survival pathways such as cell proliferation, apoptosis, tumor cell invasion and metastasis, and angiogenesis. While prostacyclin synthase is generally believed to be anti-tumor, a pro-carcinogenic role for thromboxane synthase has been demonstrated in a variety of cancers. According to the study by the St. James's Hospital, the expression and activity of this enzyme may protect against tumor development. In this review, we discuss the aberrant expression and known functions of both prostacyclin synthase and thromboxane synthase in cancer. The study also discusses the effects of these enzymes on a range of tumor cell survival pathways, such as tumor cell proliferation, induction of apoptosis, invasion and metastasis, and tumor cell angiogenesis. As downstream signaling pathways of these enzymes have also been implicated in cancer states, we examine the role of downstream effectors of PGIS and TXS activity in tumor growth and progression. Finally, the current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer(7).
8. Increased cyclooxygenase-2 and thromboxane synthase expression in human erythroleukemia cells
Diosgenin is a very interesting natural product because, depending on the specific dose used, its biological effect is very different in HEL (human erythroleukemia) cells. For example, at 10 microM, diosgenin induced megakaryocytic differentiation, in contrast to 40 microM diosgenin, which induced apoptosis in HEL cells previously demonstrated using sedimentation field-flow fractionation (SdFFF). In the study by the Université de Limoges, indicated that the implication of COX-2 and TxS in diosgenin-induced megakaryocytic differentiation in HEL cells. Furthermore, we showed that the analytical technique of SdFFF may be used as a tool to confirm our results as a function of the degree of cell differentiation(8).
9. Cyclooxygenase-2 and thromboxane synthase in non-endocrine and endocrine tumors
Prostaglandins (PG) are members of a large group of hormonally active fatty acids derived from free fatty acids. They are formed from arachidonic acid-the major PG precursor. Cyclooxygenase (COX)-1 and -2 are the rate-limiting steps in PG synthesis. COX-2 is overexpressed in many human non-endocrine and endocrine tumors including colon, breast, prostate, brain, thyroid, and pituitary. According to the study by the Mayo Clinic College of Medicine, Thromboxane synthase (TS) catalyzes the synthesis of thromboxane A2 (TXA2), which is derived from arachidonic acid and prostaglandin H2 and is a vasoconstrictor and inducer of platelet aggregation. TXA2 stimulates tumor growth and spread of some tumors and TS appears to have a critical role in tumorigenesis in some organ systems. The accumulating evidence points to an increasingly important role of COX-2 and TS in tumor progression and metastasis(9).
10. Activation of the thromboxane A2 pathway in human prostate cancer correlates
In the study to investigate the potential involvement of the thromboxane A(2) (TXA(2)) pathway in human prostate cancer (PCa) by analyzing the expression of cyclooxygenase-2 (COX-2), TXA(2) synthase (TXS), and TXA(2) receptors (TPRs), the main actors of the TXA(2) pathway, was analyzed on serial tissue sections from 46 human PCa specimens, found that Proteins specifically involved in the TXA(2) pathway are up-regulated in human PCa and their level of expression is associated with tumor extraprostatic extension and loss of differentiation. The study is the first to examine simultaneously all key proteins involved in this pathway including TXA(2) receptors and results suggest that the TXA(2) pathway may be a potential target for PCa prevention/therapy(10).
11. Expression of thromboxane synthase, TBXAS1 and the thromboxane A2 receptor, TBXA2R, in human breast cancer
Thromboxane synthase (TxS) metabolizes the cyclooxygenase product, prostaglandin H(2), into thromboxanes. Some of the thromboxanes are known to be biologically active on cancer cells. In the study to investigate the expression of thromboxane synthases, TBXAS1 and the thromboxane A2 receptor, TBXA2R in a cohort of human breast cancer patients and also to assess their potential clinical relevance, showed that thromboxane synthases are differentially expressed in human breast cancer. While TBXA2R is highly expressed in aggressive tumours and linked with poor prognosis, TBXAS1 is expressed at significantly low levels in high grade tumours and tumour patients with poor prognosis. TBXA2R thus has a significant prognostic value in clinical breast cancer(11).
Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/22037941
(2) http://www.ncbi.nlm.nih.gov/pubmed/23617069
(3) http://www.ncbi.nlm.nih.gov/pubmed/21983220
(4) http://www.ncbi.nlm.nih.gov/pubmed/21388528
(5) http://www.ncbi.nlm.nih.gov/pubmed/21337637
(6) http://www.ncbi.nlm.nih.gov/pubmed/20818420
(7) http://www.ncbi.nlm.nih.gov/pubmed/20122998
(8( http://www.ncbi.nlm.nih.gov/pubmed/18549804
(9) http://www.ncbi.nlm.nih.gov/pubmed/16627914
(10) http://www.ncbi.nlm.nih.gov/pubmed/16522350
(11) http://www.ncbi.nlm.nih.gov/pubmed/16250911
II. Prostaglandins
Prostaglandins, are a group of lipid mediators, found and isolated from human semen in the 1930s by Ulf von Euler of Sweden, responsible for inflammation features, such as swelling, pain, stiffness, redness and warmth. The hormones are produced by almost all nucleated cells and synthesized in the cell from the essential fatty acids (EFAs), include prostacyclin I2 (PGI2), prostaglandin E2 (PGE2), and prostaglandin F2α (PGF2α)
1. Prostaglandins and other lipid mediators in Alzheimer's disease
In the central nervous system (CNS), prostaglandin (PG) and other bioactive lipids regulate vital aspects of neural membrane biology, including protein-lipid interactions, trans-membrane and trans-synaptic signaling. According to the study by Louisiana State University Health Sciences Center, showed that biochemical mechanisms of PLA2 overactivation and its pathophysiological consequences on CNS structure and function have been extensively studied using animal models and brain cells in culture triggered with PLA2 inducers, PGs, cytokines, and related lipid mediators. Moreover, the expression of both COX-2 and PLA2 appears to be strongly activated during Alzheimer's disease (AD), indicating the importance of inflammatory gene pathways as a response to brain injury. How brain PLA2 and brain PGs are early and key players in acute neural trauma and in brain-cell damage associated with chronic neurodegenerative diseases such as AD.(1).
2. Prostaglandins in labor and delivery
Prostaglandins are produced by almost every tissue in the body and serve as important messengers or effectors in a wide variety of functions. The pivotal role of prostaglandins in contraction of the smooth muscle of the uterus and the biophysical changes associated with cervical ripening, however, point to a major problem with their clinical use. According to the study of the role of prostaglandins in labor and delivery by University of South Florida College of Medicine, found that unlike oxytocin which requires an induction of receptors that does not usually occur until the later part of pregnancy, prostaglandins receptors always are present in myometrial tissue. This allows for the use of prostaglandins in usual doses throughout pregnancy. Although both F and E series prostaglandins result in uterine contractions, E series prostaglandins are relatively more uteroselective and are clearly superior to F series prostaglandins in producing cervical ripening. Modification of the naturally occurring prostaglandins by blocking the sites that are affected during their usual rapid metabolism, results in products with much longer durations of action, efficacy at much lower concentrations, and a potential for significant savings in cost(2).
3. Prostaglandins and inflammation
Prostaglandins are lipid autacoids derived from arachidonic acid. They both sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. They are generated from arachidonate by the action of cyclooxygenase isoenzymes, and their biosynthesis is blocked by nonsteroidal antiinflammatory drugs, including those selective for inhibition of cyclooxygenase-2. Despite the clinical efficacy of nonsteroidal antiinflammatory drugs, prostaglandins may function in both the promotion and resolution of inflammation, according to the study by University of Pennsylvania(3).
4. Brain prostaglandins that promote neuroinflammation
Phospholipase A(2)(PLA(2)) enzymes are considered the primary source of arachidonic acid for cyclooxygenase (COX)-mediated biosynthesis of prostaglandins. According to the study in MAGL-disrupted animals, showed that a distinct pathway exists in brain, where monoacylglycerol lipase (MAGL) hydrolyzes the endocannabinoid 2-arachidonoylglycerol to generate a major arachidonate precursor pool for neuroinflammatory prostaglandins(4).
5. Prostaglandins and human glioma cells
In many types of cancer, prostaglandin E2 (PGE2) is associated with tumour related processes including proliferation, migration, angiogenesis and apoptosis. In the study on the proliferative, migratory, and apoptotic effects of PGE1, PGE2 and Ibuprofen (IBP) observed in the T98G human glioma cell line in vitro, found that treatments which alter PGE1 and PGE2 metabolism influence the proliferative and apoptotic indices of T98G glioma cells. The migratory capacity of the cells was also significantly affected by the change in prostaglandin metabolism. Modifying PG metabolism remains an interesting target for future studies in gliomas(5).
6. Prostaglandins in cancer cell adhesion, migration, and invasion
Prostaglandins exert a profound influence over the adhesive, migratory, and invasive behavior of cells during the development and progression of cancer. According to the study by the University of Texas MD Anderson Cancer Center, cyclooxygenase-2 (COX-2) and microsomal prostaglandin E(2) synthase-1 (mPGES-1) are upregulated in inflammation and cancer. This results in the production of prostaglandin E(2) (PGE(2)), which binds to and activates G-protein-coupled prostaglandin E(1-4) receptors (EP(1-4)). Selectively targeting the COX-2/mPGES-1/PGE(2)/EP(1-4) axis of the prostaglandin pathway can reduce the adhesion, migration, invasion, and angiogenesis. Combining the use of COX-2/mPGES-1/PGE(2)/EP(1-4) axis-targeted molecules with those targeting cell surface adhesion receptors or their downstream signaling molecules may enhance cancer therapy(6).
7. Prostaglandin E2 promotes lung cancer cell migration
Many human cancers express elevated levels of cyclooxygenase-2 (COX-2), an enzyme responsible for the biosynthesis of prostaglandins. Available clinical data establish the protective effect of COX-2 inhibition on human cancer progression. According to the study by Medical College of Georgia, showed that the COX-2 product prostaglandin E(2) (PGE(2)) acts on cognate receptor EP4 to promote the migration of A549 lung cancer cells. Treatment with PGE(2) enhances tyrosine kinase c-Src activation, and blockade of c-Src activity represses the PGE(2)-mediated lung cancer cell migration. PGE(2) affects target cells by activating four receptors named EP1 to EP4. Use of EP subtype-selective ligand agonists suggested that EP4 mediates prostaglandin-induced A549 lung cancer cell migration, and this conclusion was confirmed using a short hairpin RNA approach to specifically knock down EP4 expression(7).
8. Prostaglandins and hepatocellular carcinoma cells
Prostaglandin E2 has been implicated in cell growth and metastasis in many types of cancers. According to the study by Nanjing Medical University, showed that PGE2 treatment significantly increased the cell adhesion, migration, and invasion in hepatocellular carcinoma (HCC) cells. In addition, the effects of PGE2 were found to be associated with focal adhesion kinase (FAK). PGE2 treatment increased the phosphorylation and synthesis of FAK in a dose-dependent manner. RNA interference targeting FAK suppressed PGE2-mediated cell adhesion and migration. Furthermore, the downstream proteins of FAK, paxillin and Erk2, were also activated by PGE2. PGE2 treatment increased the phosphorylation and synthesis of paxillin in a dose-dependent manner. PGE2 treatment also induced the phosphorylation of Erk2(8).
9. Caspase-3 and prostaglandins in cancer regrowth
Chemo- and radio-therapeutic regimens frequently kill cancer cells by inducing apoptosis, a cell-death subroutine that involves the activation of a particular class of proteases called caspases. According to the study of Caspase-3 and prostaglandins signal for tumor regrowth in cancer therapy,. indicated in a recent issue of Nature Medicine, Huang et al. (2011) show that caspase activation in dying tumor cells causes the release of soluble lipid messengers, notably prostaglandin E(2), that stimulate tumor cell proliferation(9).
10. Physiological regulation of prostaglandins in the kidney
Cyclooxygenase-derived prostanoids exert complex and diverse functions within the kidney. The biological effect of each prostanoid is controlled at multiple levels, including (a) enzymatic reactions catalyzed sequentially by cyclooxygenase and prostanoid synthase for the synthesis of bioactive prostanoid and (b) the interaction with its receptors that mediate its functions. Cyclooxygenase-derived prostanoids act in an autocrine or a paracrine fashion and can serve as physiological buffers, protecting the kidney from excessive functional changes during physiological stress. According to the study by Vanderbilt University, and Veterans Affair Medical Center, alhrough these actions, prostanoids play important roles in maintaining renal function, body fluid homeostasis, and blood pressure. Renal cortical COX2-derived prostanoids, particularly PGI2 and PGE2, play critical roles in maintaining blood pressure and renal function in volume-contracted states. Renal medullary COX2-derived prostanoids appear to have an antihypertensive effect in individuals challenged with a high-salt diet. Loss of EP2 or IP receptor is associated with salt-sensitive hypertension. COX2 also plays a role in maintaining renal medullary interstitial cell viability in the hypertonic environment of the medulla. Cyclooxygenase-derived prostanoids also are involved in certain pathological processes. The cortical COX2-derived PGI2 participates in the pathogenesis of renal vascular hypertension through stimulating renal renin synthesis and release. COX-derived prostanoids also appear to be involved in the pathogenesis of diabetic nephropathy(10).
11. Prostaglandins and the kidney
In the review of a summary and assessment of research involving renal prostaglandins (Arachidonic acid released from phospholipids is converted by prostaglandin cyclo-oxygenase in the kidney to PGF2, PGF2alpha, PGD2, and, possibly, to PGI2 and thromboxane A2. Production of PGE2 and PGF2alpha is predominately but not exclusively in the medulla, whereas degradative enzymes are present in both cortex and medulla. Prostaglandins enter the tubular lumen by facilitated transport and are partially reabsorbed from the urine in the distal nephron. Urine prostaglandins probably reflect renal synthesis. PGE2 and endoperoxides stimulate and PGF2alpha and indomethacin inhibit renal renin synthesis. In response to ischemia, vasoconstriction, or angiotensin II the kidney increases prostaglandin synthesis to modulate renal vascular resistance), found that in conscious animals or man no role has been established for prostaglandins in the maintenance of basal renal blood flow or renal sodium excretion. PGE influences renal water excretion by inhibiting the action vasopressin. Despite conflicting data there is evidence that renal prostaglandins are involved either primarily or secondarily in many types of hypertension. Inhibitors of prostaglandin cyclooxygenase have been used with success in Bartter's syndrome. Conflicting results in many areas of investigation may be resolved by the use of more accurate and reliable assays, careful handling of samples, and the use of urine to further investigate renal prostaglandin synthesis(11).
12. Prostaglandins in regulating the contraction and relaxation of smooth muscle tissue
According to the Nelson, Randy F. (2005). "An introduction to behavioral endocrinology (3rd ed.). Sunderland, Mass: Sinauer Associates", hormone prostaglandins play an important role in numbers of physiological effects, including the function of regulating the contraction and relaxation of smooth muscle tissue, by ligating a sub-family of cell surface seven-transmembrane receptors, G-protein-coupled receptors.
13. Prostaglandins and platelet aggregation
Prostaglandins which are derivatives of arachidonic acid including prostaglandin, endoperoxides, thromboxane A2, prostaglandin E2, prostaglandin D2 and prostacyclin. may induce or inhibit platelet aggregation and constrict ro dilate blood vessels. According to the study by Dr. Smith JB., it exacerbates ischaemic damage because of a selective increase in vascular resistance due to coronary vasospasm and platelet aggregation which acts to decrease myocardial blood flow. The stable prostaglandins PGD2 and PGE2 are also of interest as both are formed during platelet aggregation. Like PGI2, PGD2 inhibits platelet aggregation(13).
14. Prostaglandin I2 (PGI2) and disaggregation of platelets
In the study to examine the synergistic platelet disaggregating effects among the products of endothelial cells using urokinase, prostaglandin I2 (PGI2), and sodium nitroprusside (SNP) (which is the chemical substitute as nitric oxide(NO)-donor) for endothelium-derived relaxing factor (EDRF), showed that platelet disaggregation rate was increased in a dose-dependent manner and decreased in a time-dependent manner, and the combined use of two or three agents had synergistic effects on platelet disaggregation. Furthermore, flow cytometric analysis showed decreases in the binding of fibrinogen to activated platelets by the addition of PGI2 or SNP. . In addition our data revealed that PGI2 and SNP can act synergistically with fibrinolytic agents. These findings suggest a potential strategy for improving the efficacy of thrombolytic therapy by a combination of these products or their substitutes(14).
15. Platelet prostaglandin H synthase-1 (PGHS-1) deficiency and Bleeding disorder
Defective platelet prostaglandin H synthase (PGHS) activity has been recognized as a cause of bleeding disorders. In the study of a tatal of three female patients aged 37, 48 and 55 who presented with a mild bleeding disorder due to platelet dysfunction, showed that human platelet PGHS-1 deficiency is due to two types of enzyme defects: type 1 defect is manifested by an undetectable PGHS-1 protein in platelets whereas the type 2 defect is manifested by a normal quantity of PGHS-1 protein which has an impaired catalytic activity(15).
16. Prostaglandins E2 and labor
In the study to determine safety of induction of labor with vaginal Prostaglandins (E2) in Grand Multipara., showed that in a total of 50% cases were induced for past dates, the ceasarean rate was high in the induction group (19.5%) compared to the control (12.5%) OR 1.69 RR 1.37(95% CI-1.07-1.75) difference was statistically significant. Adverse neonatal outcome was found to be similar in both groups. Special Care Baby Unit (SCBU) admissions were 19 in the induction group and 21 in the control group, which was not statistically significant. No severe maternal complications were observed such as infection or uterine rupture(16).
17. Hormone Prostaglandins sensitize spinal neurons to pain
A number of prostaglandins (PGs) sensitize dorsal root ganglion (DRG) neurons and contribute to inflammatory hyperalgesia by signaling through specific G protein-coupled receptors (GPCRs). According to the study by the Washington University Pain Center, suggested that 15d-PGJ2 induces activation followed by persistent inhibition of TRPA1 channels in DRG sensory neurons in vitro and in vivo. Moreover, we demonstrate novel evidence that 15d-PGJ2 is analgesic in mouse models of pain via a TRPA1-dependent mechanism. Collectively, our studies support that TRPA1 agonists may be useful as pain therapeutics(17).
18. Hormone Prostaglandins and Intraocular pressure (IOP)
Intraocular pressure (IOP) reduction is currently the only therapeutic approach demonstrated to preserve visual function in patients with glaucoma. According to the study by Universit Joseph Fourier (UJF), Grenoble, in the study to review of published studies evaluating the efficacy and tolerability of the IOP-lowering unfixed and fixed combination therapies with PGAs, indicated that
α(2)-adrenergic agonists-PGA and carbonic anhydrase inhibitor-PGA combinations seem to be at least as effective at reducing IOP as the β-blocker-PGA combinations. As for the fixed combinations, the review shows that the three PGA-timolol fixed combinations are more effective than their component medications used separately as monotherapy and are better tolerated than the three respective prostaglandins(18).
19. prostaglandins and inflammatory mediation
Overproduction of prostaglandins has been considered in mediation of inflammation and carcinogenic process. In the study to search for anti-inflammatory and chemopreventive agents from natural products, bioassay-guided fractionation led to the isolation of curdione from the rhizome of Curcuma zedoaria with the inhibitory effect on the production of prostaglandin E2 in lipopolysaccharide (LPS)-stimulated mouse macrophage RAW 264.7 cells in a concentration-dependent manner (IC50 = 1.1 microM). Mechanistic studies suggest that the suppression of cyclooxygenase-2 (COX-2) mRNA expression is, at least in part, involved in this inhibitory activity of curdione, according to the study by the Ewha Womans University, Seoul.(19).
20. Prostaglandin E2 and tooth movement
In the study to to investigate the occurrence of orthodontic root resorption in connection with local injection of prostaglandin E2 (PGE2) consisting 25 male Wistar rats, in the duration of experiments was 3 days, 7 days, and 10 days, showed that the maxillary first molars on both sides were each moved mesially by means of a coil spring. On the right side 0.1 ml of PGE2 0.1 micrograms/microliters was injected in the gingiva on the buccal side of the upper first molar on days 0, 3, 5, and 7. On the left side no injection of PGE2 was performed. In three animals in the 7-day group the vehicle (Waymouth medium) was injected. There was no significant difference in root resorption between the experimentally moved teeth with and without local injection of PGE2, but a trend towards more root resorption was registered on the teeth where such injections had been performed(20).
21. Prostaglandin E2 (PGE2) and orthodontic tooth movement and bone metabolism
In the study to to investigate and compare the in vivo effects of prostaglandin E2 (PGE2) administered by different methods on orthodontic tooth movement and bone metabolism macroscopically, histopatologically, and biochemically, showed that Tooth movement was observed in the experimental and positive control groups, but the intraligamentous PGE2 group had the highest values of all analyzed parameters, including serum calcium and phosphorus levels and osteoclastic and osteoblastic populations (p < 0.001)(21).
22. Prostaglandin E2 and voltage-dependent calcium channels
According to the study by the University of Occupational and Environmental Health, in the study of The effects of PGE2 on voltage-dependent Ca2+ channel currents in dissociated rat melanotrophs by the whole-cell configuration of the patch-clamp technique, indicated that PGE2 inhibits P/Q- and L-type Ca2+ channels of rat melanotrophs via EP1 and EP3 receptors, which are coupled to pertussis toxin-sensitive G proteins, and produces both voltage-sensitive and -insensitive inhibition of Ca2+ channels(22).
23. Prostaglandins in pregnancy and parturition
Prostaglandin (PG) production by intrauterine tissues plays a key part in the control of pregnancy and parturition. In the study to to investigate the role of placenta-derived CRH and CRH-related peptides in the regulation of PG synthesis and metabolism, showed that CRH and CRH-related peptides act on CRH-R1 and CRH-R2 to exert different effects on PG biosynthetic enzymes cPLA2 and COX-2 and thereby modulate output of PGs from placenta, which would be important for controlling pregnancy and parturition(23).
24. Prostaglandins in regulation of PPARγ function in adipocytes
Adipocytes and fat cells play critical roles in the regulation of energy homeostasis. Adipogenesis (adipocyte differentiation) is regulated via a complex process including coordinated changes in hormone sensitivity and gene expression. According to the study by the Osaka University of Pharmaceutical Sciences, Prostaglandins (PGs), which are lipid mediators, are associated with the regulation of PPARγ function in adipocytes. Prostacyclin promotes the differentiation of adipocyte-precursor cells to adipose cells via activation of the expression of C/EBPβ and δ. These proteins are important transcription factors in the activation of the early phase of adipogenesis, and they activate the expression of PPARγ, which event precedes the maturation of adipocytes. PGE(2) and PGF(2α) strongly suppress the early phase of adipocyte differentiation by enhancing their own production via receptor-mediated elevation of the expression of cycloxygenase-2, and they also suppress the function of PPARγ(24).
25. Prostaglandins in prevulatory phase
In the study to to evaluate the effect of luteinizing hormone (LH), steroids, prostaglandins (PGs) and peptides on the oviductal contraction and secretion of PGs and endothelin (ET-1) in cows, showed that the preovulatory LH surge, together with increasing E(2) levels from the Graafian follicle and a basal P(4) from regressing corpora lutea (CL), stimulates maximum oviductal production of PG and ET-1, resulting in oviductal contraction for a rapid transport of gametes. OT released from the newly-formed CL may block these mechanisms, and slow contractions for transport of the embryo to the uterus(25).
26. Prostaglandins hormone regulation
The optimal oviductal environment, including contractile activity for gamete transport, fertilization and early embryonic development, is mediated by physiological and anatomical changes in the oviduct during the estrous cycle. In the study by the University of Peradeniya, indicated that the preovulatory LH surge, together with locally re-circulated high levels of E2 from the Graafian follicle and basal P4 from regressing corpus luteum (CL), induces the maximum stimulatory effect on oviductal PGE2, PGF2 alpha and ET-1 production during the periovulatory period. Consequently, the elevated local ET-1 concentration during periovulatory period may induce the high contractile activity of the oviduct and, at the same time, the stimulation of PG production. Thus, ET-1 may act as a local amplifier for oviductal PG production stimulated by LH and ovarian steroids(26).
27. Prostaglandin D2 and Oral cancer
Prostaglandins are secreted by oral carcinomas and may be involved in eosinophil infiltration. In the study to determine the factors contributing to eosinophil migration and potential anti-neoplastic effects on oral squamous carcinoma (OSC), eosinophil degranulation was evaluated by measuring release of eosinophil peroxidase (EPO), showed that growth inhibition of the OSC cell line, SCC-9, during co-culture with human eosinophils, in vitro, which correlated with EPO activity that possesses growth inhibitory activity. The PGD2 synthase inhibitor, HQL-79, abrogated migration towards SCC-9. Our data suggest that OSC-derived PGD2 may play an important role via CRTH2 (the PGD2 receptor on eosinophils) in eosinophil recruitment and subsequent anti-tumor activity through the action of eosinophil cationic proteins(27).
28. Prostaglandins in T cells activation
In the study to investigate the role of PGE(2), which binds to the E-prostanoid family of G protein-coupled receptors through four subtypes of receptors called EP 1-4, in the regulation of CD46 expression and function, showed that addition of PGE(2) strongly downregulates CD46 expression in activated T cells. Moreover, PGE(2) differentially affects T cell activation, cytokine production, and phenotype depending on the activation signals received by the T cells. This was correlated with a distinct pattern of the PGE(2) receptors expressed, with EP4 being preferentially induced by CD46 activation. Indeed, addition of an EP4 antagonist could reverse the effects observed on cytokine production after CD46 costimulation. These data demonstrate a novel role of the PGE(2)-EP4 axis in CD46 functions, which might at least partly explain the diverse roles of PGE(2) in T cell functions(28).
29. Prostaglandins and lymphangiogenesis
One of the hallmarks of inflammation is lymphangiogesis that drains the interstitial fluids. During chronic inflammation, angiogenesis is induced by a variety of inflammatory mediators, such as prostaglandins (PGs). According to the study by the Kitasato University School of Medicine, suggested that COX-2 and prostaglandin E2-EP3/EP4 signaling contributes to lymphangiogenesis in proliferative inflammation, possibly via induction of VEGF-C and VEGF-D, and may become a therapeutic target for controlling lymphangiogenesis(29).
30. Prostaglandin E2 and colorectal carcinoma cells
Chronic use of nonsteroidal anti-inflammatory drugs results in a significant reduction of risk and mortality from colorectal cancer in humans. They are known to inhibit cyclooxygenase activity. The cyclooxygenase enzymes catalyze a key reaction in the conversion of arachidonic acid to prostaglandins, such as prostaglandin E(2) (PGE(2)). In the study to demonstrate that PGE(2) treatment of LS-174 human colorectal carcinoma cells leads to increased motility and changes in cell shape by Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, indicated that
PGE(2) treatment results in an activation of phosphatidylinositol 3-kinase/protein kinase B pathway that is required for the PGE(2)-induced changes in carcinoma cell motility and colony morphology. PGE(2) might enhance the invasive potential of colorectal carcinoma cells via activation of major intracellular signal transduction pathways not previously reported to be regulated by prostaglandins(30).
31. Prostaglandin E(2) and fever
Systemic inflammation is accompanied by changes in body temperature, either fever or hypothermia. Rat and mouse have become the predominant animal models, and new species-specific tools (recombinant antibodies and other proteins) and genetic manipulations have been applied to study fever and hypothermia. According to the study by the St. Joseph's Hospital and Medical Center, an indispensable role of PGE2 in the febrile response to LPS has been demonstrated in studies with targeted disruption of genes encoding either PGE2-synthesizing enzymes or PGE2 receptors. The PGE2-synthesizing enzymes include numerous phospholipases (PL) A2, cyclooxygenases (COX)-1 and 2, and several newly discovered terminal PGE synthases (PGES). It has been realized that the "physiological," low-scale production of PGE2 and the accelerated synthesis of PGE2 in inflammation are catalyzed by different sets of these enzymes. The "inflammatory" set includes several isoforms of PLA2 and inducible isoforms of COX (COX-2) and microsomal (m) PGES (mPGES-1). The PGE2 receptors are multiple; one of them, EP3 is likely to be a primary "fever receptor." The effector pathways of fever start from EP3-bearing preoptic neurons. These neurons have been found to project to the raphe pallidus, where premotor sympathetic neurons driving thermogenesis in the brown fat and skin vaso-constriction are located(31).
32. Prostaglandins and the Inhibition of acid secretion
In the study to evaluate the inhibition of acid secretion in isolated canine parietal cells by prostaglandins, indcated that PGE2 was the most potent inhibitor of acid secretion, with a 50% inhibition of maximal acid secretion (ID50) at 7.5 X 10(-8) M. PGI2 and PGF2 alpha also inhibited acid secretion, but at higher concentrations. The ID50 for PGI2 and PGF2 alpha was 10(-5) M. PGD2 was inactive at inhibiting acid secretion and suggested that both endogenous and exogenous PGs inhibit acid secretion directly at the parietal cells and that PGE2 is most likely the PG produced locally to modulate parietal cell acid secretion.(32).
33. Synthetic prostaglandins and abortion
In general, termination of second trimester pregnancy is associated with three to five times higher morbidity and mortality risks than termination during the first trimester. According to the study by Bygdeman M. the procedures mainly used are extra- or intra-amniotic administration of solutions such as hypertonic saline, ethacridine lactate, PGF2 alpha and PGE2. In comparison with these procedures, the use of prostaglandin analogues may offer important advantages, the most important one being the possibility of using non-invasive routes of administration. Pretreatment with prostaglandin analogues also reduces the risk of both operative and postoperative complications. The prostaglandins also offer a possibility as a non-surgical procedure for termination of very early pregnancy. Both vaginal and intramuscular administration of the latest generation of PG analogues have been shown in several studies to be equally as effective as vacuum aspiration if the treatment is restricted to the first three weeks following the first missed menstrual period. Gastrointestinal side-effects are still a problem although of significantly less importance than if natural prostaglandins are used(33).
34. Synthetic prostaglandins in prevention of closure of patent ductus arteriosu
Patent ductus arteriosus is a congenital disorder in the heart, with symptoms of increased work of breathing and poor weight gain in the first uear of the new born. According to the study by Rudolph AM, Heymann MA., prostaglandin administered by aortic infusion prevents ductus closure when this is desirable--as in term infants with pulmonary atresia or critical pulmonic stenosis--raising arterial oxygen tension to levels compatible with life. On the other hand, in prematures with persistent patency of the ductus, administering indomethacin inhibits prostaglandin sysnthesis, inducing closure, and can obviate surgery(34).
35. Synthetic prostaglandins and gastric ulcer
In the study to examine the role of macrophage colony-stimulating factor (M-CSF)-dependent macrophages in the healing of gastric ulcers in mice with male M-CSF-deficient (op/op) and M-CSF-expressing heterozygote (+/?) mice were used. Gastric ulcers were induced by thermal cauterization under ether anesthesia, and healing was observed for 14 days after ulceration, found that M-CSF-dependent macrophages play an important role in the healing of gastric ulcers, and that this action may be associated with angiogenesis promoted by upregulation of COX-2/PGE(2) production(35).
36. Synthetic prostaglandins and Raynaud's phenomenon
Raynaud's phenomenon is episodic vasospasm of the peripheral vessels, causing pallor followed by cyanosis and redness with pain and sometimes paraesthesia, and, rarely, ulceration of the fingers and toes. Raynaud's phenomenon can be primary (idiopathic) or secondary to several different conditions and causes.According to the study by Ariane Herrick, Intravenous iloprost (a prostaglandin) reduces the frequency and severity of attacks compared with placebo in people with Raynaud's phenomenon secondary to systemic sclerosis(36).
37. Synthetic prostaglandins and pulmonary hypertension
Iloprost (a prostaglandin) has been used to test acute pulmonary vasoreactivity in idiopathic pulmonary arterial hypertension (PAH). In the study to investigate the acute hemodynamic and oxygenation responses and tolerability to 20 µg aerosolized Iloprost in Chinese patients with pulmonary hypertension, found that Inhalation of 20 µg Iloprost showed potent and selective pulmonary hemodynamic effects and was well tolerated in the Chinese pulmonary hypertension patients. Patients with idiopathic PAH and less severe pulmonary hypertension responded more favorably to inhalation of Iloprost(37).
38. Synthetic prostaglandins and glaucoma
In the study to compare the ocular hypotensive effect of tafluprost with prostaglandin analogues (PGAs) in glaucoma patients, found that the comparison between latanoprost and tafluprost and travoprost and tafluprost did not show any statistically significant difference in mean daily IOP and at each time point. The comparison between bimatoprost and tafluprost showed a statistically significant difference in mean daily IOP (P < 0.05) and at each time point (P < 0.05). After 3 months of switching tafluprost showed an overall IOP lowering effect similar to others PGAs. When each PGA was compared with tafluprost, bimatoprost showed to provide a statistically significant additional IOP lowering effect(38).
39. Synthetic prostaglandin and erectile dysfunction
The global burden of erectile dysfunction (ED) is increasing. It is estimated that 8-19% of men in Europe have ED and that by 2025 the prevalence of ED worldwide will reach 322 million. According to the study by the University of Montpellier I, it has a fast onset of effect and a good safety profile, with no occurrences of priapism, fibrosis (as seen with intracavernosal injection) or the typical systemic effects observed with oral ED pharmacological treatments. Intraurethral alprostadil has been associated with high patient preference, acceptance rates and quality of life versus intracavernosal injection due to its ease of administration. Evidence has shown that combination treatment with sildenafil may be a possible efficient alternative when single oral or local treatment has failed. Intraurethral alprostadil can be administered in all patients irrespective of ED origin and should be the first option in patients with ED for whom therapy with PDE5 inhibitors has failed or is contraindicated(39).
40. Synthetic prostaglandin and alopecia areata of eyelashes and eyebrows
Latanoprost is an analogue of prostaglandin F(2alpha) which is used to treat glaucoma. Increases in eyelash number, thickness, and pigmentation have been reported as latanoprost side effects. In the study to evaluate if topical use of this drug can be used as a treatment of alopecia areata of eyebrows and eyelashes or not of a total of 26 patients with symmetrical eyelash and eyebrow alopecia areata were treated over 4 months with topical latanoprost for one side and the other side was not treated with any drug, showed that only one of the latanoprost-treated cases showed partial hair regrowth on the treated side. The relationship between hair regrowth and latanoprost application was not statistically significant (P = 1) by Fisher test. Based on the results, topical latanoprost has no efficacy in the treatment of alopecia areata. More studies with a larger sample size, longer study duration, and higher concentration of medication are suggested(40).
Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/12432919
(2) http://www.ncbi.nlm.nih.gov/pubmed/8665768
(3) http://www.ncbi.nlm.nih.gov/pubmed/21508345
(4) http://www.ncbi.nlm.nih.gov/pubmed/22021672
(5) http://www.ncbi.nlm.nih.gov/pubmed/23231886
(6) http://www.ncbi.nlm.nih.gov/pubmed/22505934
(7) http://www.ncbi.nlm.nih.gov/pubmed/20353998
(8) http://www.ncbi.nlm.nih.gov/pubmed/19082453
(9) http://www.researchgate.net/publication/51685919_Caspase-3_and_prostaglandins_signal_for_tumor_regrowth_in_cancer_therapy
(10) http://www.ncbi.nlm.nih.gov/pubmed/17988207
(11) http://www.ncbi.nlm.nih.gov/pubmed/333946
(13) http://www.ncbi.nlm.nih.gov/pubmed/7034481
(14) http://www.ncbi.nlm.nih.gov/pubmed/10839560
(15) http://www.ncbi.nlm.nih.gov/pubmed/8562397
(16) http://www.ncbi.nlm.nih.gov/pubmed/22224182
(17) http://www.ncbi.nlm.nih.gov/pubmed/23013719
(18) http://www.ncbi.nlm.nih.gov/pubmed/22686588
(19) http://www.ncbi.nlm.nih.gov/pubmed/18038902
(20) http://www.ncbi.nlm.nih.gov/pubmed/1717297
(21) http://www.ncbi.nlm.nih.gov/pubmed/23112942
(22) http://www.ncbi.nlm.nih.gov/pubmed/9832416
(23) http://www.ncbi.nlm.nih.gov/pubmed/18325997
(24) http://www.ncbi.nlm.nih.gov/pubmed/23319937
(25) http://www.ncbi.nlm.nih.gov/pubmed/11139776
(26) http://www.ncbi.nlm.nih.gov/pubmed/10735120
(27) http://www.ncbi.nlm.nih.gov/pubmed/23369060
(28) http://www.ncbi.nlm.nih.gov/pubmed/22544928
(29) http://www.ncbi.nlm.nih.gov/pubmed/21311040
(30) http://www.ncbi.nlm.nih.gov/pubmed/11278548
(31) http://www.ncbi.nlm.nih.gov/pubmed/15970487
(32) http://www.ncbi.nlm.nih.gov/pubmed/6799643
(33) http://www.ncbi.nlm.nih.gov/pubmed/6391777
(34) http://www.ncbi.nlm.nih.gov/pubmed/557025
(35) http://www.ncbi.nlm.nih.gov/pubmed/22100845
(36) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907943/
(37) http://www.ncbi.nlm.nih.gov/pubmed/22932074
(38) http://www.ncbi.nlm.nih.gov/pubmed/22606063
(39) http://www.ncbi.nlm.nih.gov/pubmed/23170913
(40) http://www.ncbi.nlm.nih.gov/pubmed/19620039
III. Leukotrienes
According to the study of Prostaglandins and leukotrienes as inflammatory mediators by John A Salmon and Gerald A Higgs(a), Leukotrienes is produced in leukocytes as a result of oxidative metabolism of arachidonic acid by the enzyme arachidonate 5-lipoxygenase, belonging to the family of eicosanoid inflammatory mediators(a). Its production is usually accompanied by the production of histamine and prostaglandins.
1. Leukotrienes in immunopathogenesis of rheumatoid arthritis
Leukotrienes are a family of paracrine agents derived from oxidative metabolism of arachidonic acid. According to the study by the Tehran University of Medical Sciences, Leukotrienes (often leukotriene B4) as potent chemotactic agents can provoke most signs and symptoms in rheumatoid arthritis by initiating, coordinating, sustaining, and amplifying the inflammatory response, through recruitment of leukocytes. A number of studies have reported that pharmacological modulation in this field can significantly attenuate clinical manifestations associated with different inflammatory pathologies(1).
2. Leukotrienes and inflammatory and allergic response
According to the study to Department of Medical Biochemistry and Biophysics, Karolinska Institutet,
Leukotrienes are recognized as important signal molecules in a variety of inflammatory and allergic conditions affecting the skin, joints, gastrointestinal and respiratory systems typified by local pain, tissue edema, hyperemia and functional losses. In the tissues, immunocompetent cells accumulate at the site of injury which contribute to tissue damage and perpetuation of the disease process. Leukotrienes can elicit most, if not all, of these signs and symptoms. Thus, leukotriene B4 is one of the most powerful chemotactic agents known to date and participates in the recruitment of leukocytes. The cysteinyl leukotrienes, on the other hand, contract smooth muscles, particularly in the peripheral airways and microcirculation of that function leading to the formation of drugs which block the formation and action of leukotrienes introduced as novel antiasthmatic medications.(2).
3. Leukotrienes in asthma and allergic rhinitis
Leukotrienes have been shown to mediate diverse features of allergic conditions including inflammatory cell chemotaxis/activation and smooth muscle contraction. Cysteinyl leukotrienes (LTC(4), LTD(4) and, LTE(4)) and the dihydroxy leukotriene LTB(4) generated by a series of enzymes/proteins constituting the LT synthetic pathway or 5-lipoxygenase (5-LO) pathway to mediate the interaction of multiple receptors. Leukotriene receptor antagonists (LTRA) and LT synthesis inhibitors (LTSI) have shown clinical efficacy in asthma and more recently in allergic rhinitis. Despite growing knowledge of leukotriene biology, the molecular regulation of these inflammatory mediators remains to be fully understood. Genes encoding enzymes of the 5-LO pathway (i.e. ALOX5, LTC4S and LTA4H) and encoding for LT receptors (CYSLTR1/2 and LTB4R1/2) provide excellent candidates for disease susceptibility and severity(3).
4. Treatment heterogeneity in asthma with leukotriene modifiers
Despite advances in treatment, asthma continues to be a significant health and economic burden. According to the study by the Centers for Clinical Pediatric Pharmacology & Pharmacogenetics, Jacksonville, two classes of LT modifiers are 5-lipoxygenase (ALOX5) inhibitors (zileuton) and leukotriene receptor antagonists (LTRAs) [montelukast, pranlukast, and zarfirlukast]. LT modifiers can be used as alternatives to low-dose inhaled corticosteroids (ICS) in mild persistent asthma, as add-on therapy to low- to medium-dose ICS in moderate persistent asthma, and as add-on to high-dose ICS and a long-acting ss2 agonist in severe persistent asthma. Studies have reported that genetic variation in ALOX5, LTA4H, LTC4S, and ABCC1 influences response to LT modifiers. Plasma concentrations of LTRAs vary considerably among patients(4).
5. Leukotrienes and Fibroblasts
Fibroblasts are implicated in sub-epithelial fibrosis in remodeled asthmatic airways and contribute to airway inflammation by releasing cytokines and other mediators. In the study to investigate the expression of leukotriene biosynthetic enzymes and receptors in primary fibroblasts from the bronchi of normal and asthmatic adult subjects using RT-PCR, Western blotting, immunocytochemistry and flow cytometry, indicated that human bronchial fibroblasts may not only respond to exogenous leukotrienes but also generate leukotrienes implicated in narrowing, inflammation and remodeling of the asthmatic airway(5).
6. Leukotriene and skin inflammation
Scratching triggers skin flares in atopic dermatitis. According to the study by the Boston Children's Hospital, in mice, tape stripping of mouse skin cause neutrophil influx was largely dependent on the generation of leukotriene B4 (LTB4) by neutrophils and their expression of the LTB4 receptor BLT1. Allergic skin inflammation in response to epicutaneous (EC) application of ovalbumin to tape-stripped skin was severely impaired in Ltb4r1(-/-) mice and required expression of BLT1 on both T cells and non-T cells. Cotransfer of wild-type (WT) neutrophils, but not neutrophils deficient in BLT1 or the LTB4-synthesizing enzyme LTA4H, restored the ability of WT CD4(+) effector T cells to transfer allergic skin inflammation to Ltb4r1(-/-) recipients(6).
7. Leukotriene and local effects
In the study to assess the local effects of intracutaneous injections into humans of 1-3 nmol of five products of arachidonic acid metabolism, leukotrienes (LT) C4, D4, E4, and B4 from the 5-lipoxygenase pathways and prostaglandin (PG) D2 from the cyclooxygenase pathway, clinically and histologically, showed that The dermal vascular sites affected by LTD4 and PGD2 included capillaries, superficial and deep venules, and arterioles. LTB4 elicited a transient wheal and flare, followed in 3-4 hr by induration that was characterized by a dermal infiltrate comprised predominantly of neutrophils. The combination of LTB4 and PGD2 elicited tenderness and increased induration associated with a more intense neutrophil infiltration(7).
8. The functions of The leukotrienes
Leukotrienes (LTs) are metabolites of arachidonic acid formed by a 5-lipoxygenase and generated during immunological challenge or by reactions which involve changes in calcium levels. According to the study by the, Leukotriene B4 (LTB4), a dihydroxy metabolite, has been shown to exert marked chemotactic effect in many different animal species. LTB4 probably plays a role in inflammatory responses, and has been detected in several pathologic conditions. Reaction of LTA4, another lipoxygenase metabolite of arachidonic acid, with glutathione yields peptidolipid leukotrienes, LTC4, LTD4, and LTE4; these are components of slow reacting substance (SRS and SRS-A). The peptidolipid leukotrienes are potent bronchoconstrictors and enhance mucus production in the lungs. Furthermore, they constrict coronary arteries and have a negative inotropic effect. They probably play an important role in asthma and anaphylaxis. LTB4 and the peptidolipid leukotrienes may be important in several other organs, too, e.g., the skin and the eye. They may exert effects on a variety of smooth muscles and have neuronal and immunological effects(8).
9. Acetylsalicylic acid (aspirin) in regulation of LTB4 and LTC4
In the sttudy to to investigate the effect of the non-steroidal anti-inflammatory agent, acetylsalicylic acid (ASA) at different concentrations on the release rates of the pro-inflammatory mediators, leukotriene B4 (LTB4) and leukotriene C4 (LTC4), indicated that ASA treatment at 3 different concentrations (15, 75 and 150 microg/ml), the release rates of LTB4 and LTC4 were increased from melanocytes of the normal individuals (13%, 7.5% and 30%; 7.2%, 51.4% and 60.7%, p<0.001). However, in patients with active vitiligo, the release rate of LTB4 from melanocytes was decreased (2.9%, 14.4% and 7.4%, p<0.05), whereas that of LTC4 was increased (3.9%, 93.8% and 101.4%, p<0.001)(9).
10. Leukotrienes in rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory disorder of joints for which there is no strict cure. According to the study by the Tehran University of Medical Sciences, Leukotrienes (often leukotriene B4) as potent chemotactic agents can provoke most signs and symptoms in rheumatoid arthritis by initiating, coordinating, sustaining, and amplifying the inflammatory response, through recruitment of leukocytes. A number of studies have reported that pharmacological modulation in this field can significantly attenuate clinical manifestations associated with different inflammatory pathologies(10).
11. Bradykinin, prostaglandins and leukotrienes and Osteoarthritis
Osteoarthritis (OA) of the knee and hip is among the most frequent and debilitating arthritic conditions. According to the study by the McMaster University Faculty of Health Sciences, despite the central involvement of hyaline cartilage in OA pathogenesis, the source of pain likely stems from the richly innervated synovium, subchondral bone and periosteum components of the joint. Tissue damage during joint degeneration generates nociceptive stimuli. The presence of inflammatory mediators, including bradykinin, prostaglandins and leukotrienes, lowers the threshold of the Aδ and C pain fibres, resulting in a heightened response to painful stimuli. it is important to base and centre the management of OA patients on the severity of patient-important outcomes, rather than purely an assessment of damage to the joint. The joint damage, as interpreted from radiographs, is not necessarily representative of the symptoms experienced(11).
12. Leukotriene B4 receptors BLT1 and BLT2 in inflammatory arthritis
Lipid mediators derived from arachidonic acid through the cyclooxygenase and lipoxygenase pathways are known to be important mediators of inflammation. According to the study by the
James Graham Brown Cancer Center, Louisville, in the study of study of developed mice deficient in BLT2 by targeted disruption, indicated that the BLT2(-/-) mice developed normally, and analysis of immune cells showed that disruption of BLT2 did not alter BLT1 expression or function. Mast cells from the C57BL/6 mice but not from the BLT2(-/-) mice showed intracellular calcium mobilization in response to 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid. In an autoantibody-induced inflammatory arthritis model, the BLT2(-/-) mice showed reduced incidence and severity of disease, including protection from bone and cartilage loss. Reciprocal bone marrow transplant experiments identified that loss of BLT2 expression on a bone marrow-derived cell lineage offers protection against severe disease(12).
13. Excessive synthesis of leukotrienes in the pathogenesis of systemic sclerosis
Systemic sclerosis (SSc, scleroderma) is an autoimmune disease characterized by widespread vascular injury and progressive fibrosis of the skin and internal organs. SSc-related involvement of the lungs, heart, kidneys and/or the gastrointestinal system accounts for the increased mortality of scleroderma patients. According to the Medical University of Bialystok, Leukotrienes play an important role in the regulation of all the processes vital to the pathogenesis of SSc, namely inflammation, vascular function and connective tissue remodeling. The available data suggests that an excessive synthesis of leukotrienes may contribute to the development and progression of SSc. Accordingly, blockade of leukotriene pathways appears to be a new, promising target for the treatment of SSc(13).
14. Inhibition of leukotriene D4 and eosinophilic gastroenteritis
Eosinophilic Gastroenteritis (EG) is a rare condition, caused by eosinophilic inflammatory infiltrates in the gastrointestinal tract. It is usually treated successfully with systemic glucocorticoids. According to the study by the Department of internal medicine, UZ Leuven, montelukast, a leukotriene receptor antagonist inhibits leukotriene D4, an important cytokine in the inflammatory cascade. Although montelukast could not replace steroid therapy, it acted as a steroid sparing agent in our patient(14).
15. Churg-Strauss and the Inhibition of leukotriene D4
Churg-Strauss syndrome (CSS) is a systemic small vessel vasculitis involving lungs, skin, heart, gastrointestinal tract and peripheral nerves. According to the study lead by Carlesimo M, there is a report of a 36-year-old woman with a necrotic lesion on the left foot of two months duration, associated with hypereosinophilia, patchy lung infiltrates, cardiac damage and a mononeuritis. The personal history was remarkable only for an asthma, treated with Montelukast, a leukotriene receptor antagonist (LRA). Clinical symptoms, laboratory exams and instrumental examinations led us to the diagnosis of CSS. In recent years several studies have reported the possible relationship between use of leukotriene receptor antagonist (LRA) and CSS expression(15).
16. Treatment of asthma with antileukotrienes and Churg-Strauss syndrome
Since antileukotriene treatment for asthma was introduced, there has been debate about whether such therapy can lead to Churg-Strauss Syndrome (CSS). According to Hospital Central de Asturias, Oviedo, Hospital Puerta de Hierro, there is a report of which suspected CSS in a patient with bronchopulmonary, cutaneous and analytical signs and whom we treated with oral steroids. After clinical improvement, one year later, steroids were replaced by antileukotrienes, after which the same clinical picture developed. The vasculitis characteristic of CSS was confirmed pathologically(16).
17. Leukotrienes: the immune-modulating lipid mediators of disease
The leukotrienes are important lipid mediators with immune modulatory and proinflammatory properties. When formed in excess, these compounds play a pathogenic role in several acute and chronic inflammatory diseases, such as asthma, rheumatoid arthritis, and inflammatory bowel disease. According to the study by the Department of Medical Biochemistry and Biophysics, Division of Chemistry 2, Karolinska Institutet, Classical bioactions of leukotrienes include chemotaxis, endothelial adherence, and activation of leukocytes, chemokine production, as well as contraction of smooth muscles in the microcirculation and respiratory tract. Recent genetic, morphological, and biochemical approaches, have pointed to the involvement of leukotrienes in cardiovascular diseases including atherosclerosis, myocardial infarction, stroke, and abdominal aortic aneurysm. Moreover, new insights have changed our previous notion of leukotrienes as mediators of inflammatory reactions to molecules that can fine-tune the innate and adaptive immune response(17).
18. Trihydroxyflavones and the inflammatory processes
In the study to evaluate the anti-inflammatory potential of a series of trihydroxyflavones by testing their ability to scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS) in cells and cell-free systems and to inhibit the proinflammatory pathways mediated by the enzymes cyclooxygenase (COX) and 5-lipoxygenase (5-LOX), in which reactive species have a proven involvement, showed that The tested trihydroxyflavones proved to be effective inhibitors of neutrophils' oxidative burst and were shown to scavenge different ROS and RNS in cell-free systems. The most active compound in the majority of the assays was 3,3',4'-trihydroxyflavone, which was somehow expected due to the presence of the ortho-dihydroxy in the B-ring, an important structural feature in terms of free radical scavenging activity and the compounds were able to inhibit the production of leukotriene B(4) by 5-LOX in activated neutrophils. 3,5,7-Trihydroxyflavone was able to inhibit both COX-1 and COX-2, which makes it a dual inhibitor of COX and 5-LOX pathways and, therefore, a promising candidate for a new therapeutic option in the treatment of inflammatory processes(18).
19. Leukotrienes and neuropathic/inflammatory pain
In the study to summarize the recent studies examining the expression of leukotrienes (LTs) and their receptors in nociceptive pathways, and their crucial roles in pathological pain conditions, by examininf of whether LTs were implicated in neuropathic pain following peripheral nerve injury. Using the SNI model in rats, investigating the expression of LT synthases and receptors mRNAs in the spinal cord and the roles on the pain behaviors, showed that the increase of LT synthesis in spinal microglia produced via p38 mitogen-activated protein kinase (MAPK) plays a role in the generation of neuropathic pain. We also examined the expression and roles on pain behaviors of LT receptors in the dorsal root ganglion (DRG) using a peripheral inflammation model. The data indicate CysLT2 expressed in DRG neurons may play a role as a modulator of P2X3, and contribute to the potentiation of the neuronal activity following peripheral inflammation(19).
20. Lukotrienes in the pathogenesis of dysmenorrhea in adolescent girls
In the study to determine the role of prostaglandins and leukotrienes in the pathogenesis of dysmenorrhea in a data of Twenty patients with dysmenorrhea aged 16.2+/-1.2 years and 20 healthy age-matched controls with eumenorrhea (absence of pain during menstruation) showed that there is a distinct pattern of leukotriene production during the menstrual cycle, but the changes in the systemic level are not responsible for their role in the pathogenesis of dysmenorrhea. Further studies at the local level in the target organ are necessary to elucidate the role of the lipid mediators in the pathogenesis of dysmenorrhea(20).
21. Urinary leukotriene E4 in children with severe atopic eczema/dermatitis syndrome
Leukotrienes are thought to play a role in the pathogenesis of atopic eczema/dermatitis syndrome (AEDS). Urinary leukotriene E4 (U-LTE4) is a marker of whole-body cysteinyl-leukotriene production. According to the study by the Department of Pediatrics, Rogaland Central Hospital, in the study to evaluate the role of leukotrienes in children with AEDS by measuring levels of U-LTE4, and to evaluate whether levels of U-LTE4 may reflect disease activity and allergic sensitization in AEDS, indicated that a role for leukotrienes in the pathogenesis of severe AEDS, and may support a role for leukotriene-antagonists in the treatment of this disorder. Levels of U-LTE4 may reflect the disease severity and sensitization to allergens in AEDS(21).
22. Leukotriene and eosinophil protein X in children with atopic asthma
In the study to examine the differences in urinary LTE4 and EPX concentrations between children with stable atopic asthma and healthy controls and to compare asthmatic children with different disease severity by evaluating the relationship between urinary LTE4 and EPX levels and lung function. LTE4 was also measured (enzyme immunoassay) together with EPX (radioimmunoassay) in urine and lung function tests were carried out in children with mild asthma (steroid-naive) (n=49), moderate to severe asthma (using inhaled steroids) (n=31) and healthy control subjects (n=28), showed that there were no differences in urinary LTE4 and EPX between the group of mild and the group of moderate to severe asthmatic children. There were significant associations between the urinary LTE4 and intrathoracic gas volume (ITGV), residual volume (RV), forced expiratory volume in one second (FEV1), forced expiratory capacity (FVC) and maximum expiratory flow rate at 25% of vital capacity (MEF25). Urinary EPX was only correlated with maximum expiratory flow rate at 75% of vital capacity (MEF75)(22).
23. Leukotriene and vasogenic edema
In the study to determine whether tissue leukotriene-like immunoreactivity was increased in intracranial tumors associated with peritumoral edema. 20 patients undergoing craniotomy tissue specimens were immediately frozen after removal and tissue leukotriene C4 levels were determined by radioimmunoassay, indicated that there was a significant correlation between brain edema and tissue leukotriene levels (p less than 0.003). Metastatic tumors (n = 8) had the highest leukotriene C4 level at 13.8 +/- 8.5 pg/mg tissue (mean +/- SE) and the highest index of edema 5.7 +/- 1.8. The mean leukotriene C4 level in the gliomas (n = 5) was 6.2 +/- 2.3 pg/mg tissue and the edema index was 2.1 +/- 0.6(23).
24. Leukotriene D4 in pulmonary edema fluid
In the examination by quantifying the pulmonary edema fluid concentrations of lipoxygenase and cyclooxygenase products to detemine the possible contribution of metabolites of arachidonic acid to the increased permeability of the alveolar-capillary barrier in the adult respiratory distress syndrome, indicated that The concentration of leukotriene D4 in pulmonary edema fluid of 10 patients with the adult respiratory distress syndrome (18.5 +/- 6.8 pmol/ml; mean +/- SD), assessed by specific radioimmunoassay after isolation of the mediator, was significantly higher (P less than 0.001) than that of five patients with cardiogenic pulmonary edema (4.4 +/- 1.1 pmol/ml). The concentrations of leukotrienes B4 and C4, prostaglandin E2, and thromboxane B2 in edema fluid were not significantly different in the adult respiratory distress syndrome patients than in the other subjects with pulmonary edema. The edema fluid concentration of leukotriene D4 correlated with the ratio of edema fluid to plasma concentrations of albumin (r = 0.64). Leukotriene D4 thus may contribute to the permeability defect which allows an accumulation of protein-rich alveolar fluid in the adult respiratory distress syndrome(24).
25. Syndrome of aspirin-exacerbated respiratory disease (AERD)
Chronic rhinosinusitis (CRS) with nasal polyposis (NP) may be associated with hypersensitivity to nonsteroidal anti-inflammatory drugs, representing a syndrome of aspirin-exacerbated respiratory disease (AERD). According to the study by the Jagiellonian University Medical College, among CRS subjects requiring functional endoscopic sinus surgery (FESS), as many as 33.3% may have AERD and respond to a small provocative dose of aspirin with bronchoconstriction and/or mucosal and skin edema. A simple and inexpensive measurement of uLTE4 (leukotriene E4) can help diagnose AERD in patients with CRS with sensitivity of 87.5%, but its specificity is limited and depends on the arbitrary threshold of uLTE4(25).
26. Leukotriene and uterine vascular responses to estrogen
In the study to test hypothesis of that the leukotrienes may be the mediators of the uterine vascular responses to estrogen, by giving FPL 55712, a selective leukotriene antagonist, to estrogen-primed, nonpregnant rabbits and measured regional blood flows by the radioactive microsphere technique, indicated that leukotrienes do not mediate, but rather inhibit, the uterine vascular responses to estrogen(26).
27. Leukotrienes and gastric hyperemia
In the study on anesthetized dogs to determine the role of eicosanoids in regulation of total, and mucosal gastric blood flow and oxygen consumption in the stomach damaged by the instillation of 25% ethanol, showed that The inhibition of prostaglandins generation by indomethacin caused an ischemia and hypoxia in the stomach. It was an evidence for their basal generation and tonic influence on circulation in this organ. OKY--a blocker of thromboxanes synthesis and NDGA--a blocker of 5-lipoxygenase did not alter circulatory and metabolic parameters in the stomach. Above findings indicate, that thromboxanes and leukotrienes are not involved in the physiological modulation of blood vessels activity and oxygen consumption in the stomach. But administration of 25% ethanol on gastric mucosa affected in a rise of total and mucosal blood flow and oxygen consumption. These effects were significantly potentiated by OKY and NDGA and suggesting, that damaged gastric mucosa is able to generate thromboxanes and leukotrienes which cause vasoconstriction. It seems, that endogenous prostaglandins also play an important role, because the gastric hyperemia and the increase in gastric oxygen consumption after alcohol were inhibited by indomethacin.(27).
28. Leukotriene (LT) D4 and coronary constriction
In the study the effects of leukotriene (LT) D4 (0.5 microgram/min) infusion into the left anterior descending coronary artery (LAD) of anesthetized pigs, in the absence or presence of indomethacin (5 mg/kg i.v.), indicated that the coronary constriction disappeared despite sustained LTD4 infusion and was followed by reactive hyperemia. Indomethacin did not affect the coronary flow or hemodynamic responses to LTD4 infusion. The A-V difference in prostanoids did not change during LTD4 administration. However, intracoronary bolus injection of LTD4 stimulated prostacyclin release from the vasculature in a dose-dependent manner causing significant reactive hyperemia after temporary blood flow cessation. Release of a LTD4-induced(28).
29. Leukotriene D4 (LTD4) and functional impairment
In the Glomerular micropuncture studies to evaluate the glomerular microcirculatory actions of leukotriene D4 (LTD4) in euvolemic, anesthetized, adult, male Munich-Wistar rats, indicated that in the preliminary experiments, intrarenal arterial administration of LTD4 (1 microgram X kg-1 X min-1) was found to cause a rise in mean systemic arterial pressure, a loss of plasma volume, and a fall in renal blood flow, effects identical to those previously reported for LTC4. glomerular microcirculatory dynamics were assessed during LTD4 infusion while constancy of renal perfusion pressure and plasma volume were maintained by partial aortic constriction and isoncotic plasma infusion, respectively, with saralasin (5 micrograms X kg-1 X min-1 iv) was also given throughout the study, LTD4 caused a significant increase in efferent arteriolar resistance in association with a fall in glomerular plasma flow rate (QA) and a rise in glomerular capillary hydraulic pressure. Despite the latter, single-nephron filtration rate fell due to combined reductions in QA and the glomerular ultrafiltration coefficient. These local glomerular constrictor actions of LTD4 support the possibility that this eicosanoid might play an important intermediary role in the functional impairment accompanying some forms of inflammatory injury(29).
30. Primary PGs (including prostacyclin), thromboxanes, and leukotrienes during benign or malignant pathological processes
Prostaglandins (PGs) are a family of lipid compounds synthesized from polyunsaturated fatty acids derived from phospholipids, and divided into three main classes: primary PGs (including prostacyclin), thromboxanes, and leukotrienes and presented in very low quantities under normal or resting condition. According to the study byRolland PH., Prostaglandins (PGs) showed a marked increase in levels during benign or malignant pathological processes as the results from loss of the physiological state of tissue dependence of the cells, which acquire functional autonomy and become endowed with properties which appear to be important in cancer dissemination processes(30).
Sources
(a) http://bmb.oxfordjournals.org/content/43/2/285
(1) http://www.ncbi.nlm.nih.gov/pubmed/23529572
(2) http://www.ncbi.nlm.nih.gov/pubmed/12088275
(3) http://www.ncbi.nlm.nih.gov/pubmed/19416143
(4) http://www.ncbi.nlm.nih.gov/pubmed/17397245
(5) http://www.ncbi.nlm.nih.gov/pubmed/16872537
(6) http://www.ncbi.nlm.nih.gov/pubmed/23063331
(7) http://www.ncbi.nlm.nih.gov/pubmed/6296237
(8) http://www.ncbi.nlm.nih.gov/pubmed/6096644
(9) http://www.ncbi.nlm.nih.gov/pubmed/15494818
(10) http://www.ncbi.nlm.nih.gov/pubmed/23529572
(11) http://www.ncbi.nlm.nih.gov/pubmed/22471357
(12) http://www.ncbi.nlm.nih.gov/pubmed/20656922
(13) http://www.ncbi.nlm.nih.gov/pubmed/22763975
(14) http://www.ncbi.nlm.nih.gov/pubmed/22319970
(15) http://www.ncbi.nlm.nih.gov/pubmed/22230414
(16) http://www.ncbi.nlm.nih.gov/pubmed/11181230
(17) http://www.ncbi.nlm.nih.gov/pubmed/23063073
(18) http://www.ncbi.nlm.nih.gov/pubmed/22806885
(19) http://www.ncbi.nlm.nih.gov/pubmed/21804200
(20) http://www.ncbi.nlm.nih.gov/pubmed/19227413
(21) http://www.ncbi.nlm.nih.gov/pubmed/15575936
(22) http://www.ncbi.nlm.nih.gov/pubmed/11106196
(23) http://www.ncbi.nlm.nih.gov/pubmed/3729313
(24) http://www.ncbi.nlm.nih.gov/pubmed/6511865
(25) http://www.ncbi.nlm.nih.gov/pubmed/22814420
(26) http://www.ncbi.nlm.nih.gov/pubmed/6695994
(27) http://www.ncbi.nlm.nih.gov/pubmed/1845317
(28) http://www.ncbi.nlm.nih.gov/pubmed/3568058
(29) http://www.ncbi.nlm.nih.gov/pubmed/3618788
(30) http://www.ncbi.nlm.nih.gov/pubmed/6815214
IV. Prostacyclin
Prostacyclin (or PGI2), also known as known as eicosanoids, a member of the family prostaglandins as a metabolite of arachidonic acid, inhibits platelet aggregation, and dilates blood vessels and is released by healthy endothelial cells and performs its function through a paracrine signaling cascade that involves G protein-coupled receptors on nearby platelets and endothelial cells(a).
1. Obesity and endothelial dysfunction
Obesity is frequently associated with endothelial dysfunction. In the study to investigate the role of the 'endothelial' MR in obesity-induced endothelial dysfunction, the earliest stage in atherogenesis, with C57BL/6 mice exposed to a normal chow diet (ND) or a high-fat diet (HFD) alone or in combination with the MR antagonist eplerenone (200 mg/kg/day) for 14 weeks, showed that Obesity-induced endothelial dysfunction depends on the 'endothelial' mineralocorticoid receptor (MR) and is mediated by an imbalance of oxidative stress-modulating mechanisms. Therefore, MR antagonists may represent an attractive therapeutic strategy in the increasing population of obese patients to decrease vascular dysfunction and subsequent atherosclerotic complications(1).
2. Caloric restriction reverses high-fat diet-induced endothelial dysfunction
In the study to examine whether caloric restriction could reverse the detrimental vascular effects related to obesity with male C57Bl/6 mice were fed with normal-fat diet (fat 17%) or high-fat diet (fat 60%) for 150 days. After establishment of obesity at day 100, a subgroup of obese mice were put on caloric restriction (CR) (70% of ad libitum energy intake) for an additional 50 days. At day 100, aortic rings from obese mice receiving high-fat diet showed impaired endothelium-dependent vasodilation in response to acetylcholine (ACh), showed that Caloric restriction markedly attenuated vascular superoxide production. In obese mice on CR, endothelial denudation increased superoxide formation whereas vascular superoxide production was unaffected by L-NAME. Western blot analysis revealed decreased phosphorylated eNOS (Ser1177)-to-total eNOS expression ratio in obese mice as compared to lean controls, whereas the phospho-eNOS/NOS ratio in obese mice on CR did not differ from the lean controls. In conclusion, the present study suggests that caloric restriction reverses obesity induced endothelial dysfunction and vascular oxidative stress, and underscores the importance of uncoupled eNOS in the pathogenesis(2).
3. Prostacyclin receptor (IP-receptor) agonists anti-inflammatory and antiviral activity
Prostacyclin receptor (IP-receptor) agonists display anti-inflammatory and antiviral activity in cell-based assays and in preclinical models of asthma and chronic obstructive pulmonary disease. In the study to extended these observations by demonstrating that IP-receptor activation also can enhance the ability of glucocorticoids to induce genes with anti-inflammatory activity, found that IP-receptor agonists can augment the ability of glucocorticoids to induce anti-inflammatory genes in human airway epithelial cells by activating a cAMP/PKA-dependent mechanism. This observation may have clinical relevance in the treatment of airway inflammatory diseases that are either refractory or respond suboptimally to glucocorticoids(3).
4. Synthesis of prostacyclin effect on the contractile activity of the inflamed porcine uterus
In the study to estimate the content of prostacyclin (PGI(2)), the levels of PGI synthase (PTGIS) and receptor (PTGIR) protein expression, and the cellular localization of these factors in the inflammatory-changed porcine uterus, showed that inflammation of the porcine uterus upregulates PGI(2) synthesis and that PGI(2) increases contractility, which suggests that PGI(2) might be essential for the course of uterine inflammation(4).
5. Rosuvastatin and PGI(2)-peroxisome proliferator-activated receptor
Statins are reported to alleviate renal fibrosis in animal models with ureteral obstruction. Pressure force is an important mechanism contributing to induction and progression of tubulointerstitial fibrogenesis in ureteric obstruction. In the study to assess whether the influence of rosuvastatin on pressure-induced fibrotic responses in rat renal tubular cells (NRK-52E). We established an in vitro pressure culture system to study pressure-induced fibrotic responses in NRK-52E cells, indicated that rosuvastatin reduces pressure-induced fibrotic responses in renal tubular cells by enhancing the PGI(2)-peroxisome proliferator-activated receptor α pathway and reducing PGE(2) generation(5).
6. Prostacyclin and its prostacyclin receptor and cardio-protective effects
Prostacyclin and its prostacyclin receptor, the I Prostanoid (IP), play essential roles in regulating hemostasis and vascular tone and have been implicated in a range cardio-protective effects. In the study to investigate the influence of cholesterol on human IP [(h)IP] gene expression in cultured vascular endothelial and platelet-progenitor megakaryocytic cells, showed that cholesterol can regulate hIP expression, which may, at least in part, account for the combined cardio-protective actions of low serum cholesterol through its regulation of IP expression within the human vasculature(6).
7. Thromboxane A2 and prostacyclin and endothelial dysfunction
Endothelial dysfunction participates in the pathogenesis of many cardiovascular disorders. In the study to assess whether cyclooxygenase-2 (COX-2) activation is involved in the effects of chronic aldosterone treatment on endothelial function of mesenteric resistance arteries (MRA) from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR), showed that Aldosterone reduced acetylcholine relaxation in MRA from both strains. In MRA from both aldosterone-treated strains the COX-1/2 or COX-2 inhibitor (indomethacin and NS-398, respectively), TxA2 synthesis inhibitor (furegrelate), prostacyclin synthesis inhibitor (tranylcypromine) or TxA2/ PGH2 receptor antagonist (SQ 29 548), but not COX-1 inhibitor SC-560, increased acetylcholine relaxation. In untreated rats this response was increased only in SHR. Prostacyclin elicited a biphasic vasomotor response: lower concentrations elicited relaxation, whereas higher concentrations elicited contraction that was reduced by SQ 29 548. Aldosterone increased the acetylcholine-stimulated production of 6-oxo-PGF(1alpha) and TxB2 in MRA from both strains. COX-2 expression was higher in both strains of rats treated with aldosterone(7).
8. Prostacyclin in endothelial dysfunction
In the study to analyze the possible involvement of vasoconstrictors prostanoids on the reduced endothelium-dependent relaxations produced by chronic administration of aldosterone in Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), indicated that chronic treatment with aldosterone was able to produce endothelial dysfunction through COX-2 activation in normotensive and hypertensive conditions. PGI2 seems to be the main factor accounting for endothelial dysfunction in hypertensive rats, whereas other prostanoids besides PGI2 appear to be involved in endothelial dysfunction under normotensive conditions(8).
9. Prostacyclin-stimulating and/or thromboxane A2-inhibiting action in hypertensive pregnancy complications
Several gynecologic and obstetric disorders are characterized by abnormalities in prostacyclin and/or thromboxane A2. In primary menorrhagia the uterine release of prostacyclin is increased, and consequently menstrual blood loss can be reduced with various prostaglandin synthesis inhibitors. Prostacyclin relaxes the nonpregnant myometrium in vitro and may also do so in vivo, although intravenous infusion of prostacyclin has no effect upon the uterine contractility in nonpregnant or pregnant subjects. In the study to review the gynecologic and obstetric implications of the smooth muscle-relaxing, antiaggregatory prostacyclin and its endogenous antagonist, thromboxane A2, showed that patients with pelvic endometriosis may have increased levels of prostacyclin and thromboxane A2 metabolites in the peritoneal fluid. The prostacyclin/thromboxane A2 balance shifts to thromboxane A2 dominance in patients with gynecologic cancer. During pregnancy the production of prostacyclin and thromboxane A2 increases in the mother and fetoplacental tissue. Preeclampsia and other chronic placental insufficiency syndromes are accompanied by prostacyclin deficiency in the mother and in fetomaternal tissues and by an overproduction of thromboxane A2, at least in the placenta. These changes may account for the vasoconstriction and platelet hyperactivity, which are pathognomonic for hypertensive pregnancies. By directing the prostacyclin/thromboxane A2 balance to prostacyclin dominance (by dietary manipulation, administration of prostacyclin and/or its analogues, drugs with prostacyclin-stimulating and/or thromboxane A2-inhibiting action), it may be possible to prevent and/or treat hypertensive pregnancy complications in the future(9).
10. Prostacyclin, thromboxane A2, and hypertension
Prostacyclin and thromboxane A2, products of separate branches of the arachidonic acid cascade, can have opposing effects on kidney function and on the vascular musculature. According to the study by the Shandong Medical University, prostacyclin acts as a vasodilator while thromboxane A2 has a vasoconstrictor effect and the balance between these two compounds appears to contribute to the homeostatic regulation of normal blood pressure. In the hypertensive state, this balance is disrupted and, at least in animal models of hypertension, there is excessive production of both. The increase in prostacyclin formation may be a reaction to the elevated blood pressure, possibly due to mechanical stimulation of the vascular smooth muscle cells in the blood vessel wall. However, the increase in thromboxane A2 may be more directly involved in the development and maintenance of hypertension. Not only is thromboxane A2 a vasoconstrictor but it can also stimulate the growth and proliferation of vascular smooth muscle cells which may account for the vascular hypertrophy seen in hypertension(10).
11. Interrelationships between prostacyclin and thromboxane A2
Prostacyclin is a product of arachidonic acid metabolism generated by the vessel wall of all mammalian species studied including man. According to the study by Moncada S, Vane JR. ,prostacyclin is a potent vasodilator and the most potent inhibitor of platelet aggregation. It inhibits platelet aggregationand can also be a circulating hormone constantly released by the pulmonary circulation. In contrast to the vessel wall, in blood platelets arachidonic acid is converted by the enzyme thromboxane synthetase to a potent vasoconstrictor and proaggregating substance, thromboxane A2. Therefore arachidonic acid is metabolized in the vessel wall and the platelets to potent substances with opposing biological activities. The balance between the activities of these substances is important in the homeostatic interaction of the platelets and the vessel wall. The different ways of interfering with this balance and its impact in the development of thrombosis and atherosclerosis(11).
12. Prostacyclin's biosynthesis, actions and clinical potential
Prostacyclin (PGI2) is the product of arachidonic acid metabolism generated by the vessel wall of all mammalian species studies. According to the study by Moncada S, Vane JR., indicated that prostacyclin inhibits aggregation through stimulation of platelet adenyl cyclase leading to an increase in platelet cyclic AMP. In the vessel wall, the enzyme that synthesizes prostacyclin is concentrated in the endothelial layer. Prostacyclin can also be a circulating hormone released from the pulmonary circulation. Based on these observations we proposed that platelet aggregability in vivo is controlled via a prostacyclin mechanism. The discovery of prostacyclin has given a new insight into arachidonic acid metabolism and has led to a new hypothesis about mechanisms of haemostasis. Reductions in prostacyclin production in several diseases, including atherosclerosis and diabetes, have been described and implicated in the pathophysiology of these diseases. Additionally, since prostacyclin powerfully inhibits platelet aggregation and promotes their disaggregation, this agent could have an important use in the therapy of conditions in which increased platelet aggregation takes place and in which, perhaps, a prostacyclin deficiency exists. Prostacyclin has been used beneficially in humans during extracorporeal circulation procedures such as cardiopulmonary bypass, charcoal haemoperfusion and haemodialysis. Its possible use in other conditions such as peripheral vascular disease or transplant surgery(12).
13. Prostacyclin in vascular tissue
Prostacyclin (PGI2) generated by the vascular wall is a potent vasodilator, and the most potent endogenous inhibitor of platelet aggregation. According to the study by Moncada S, Vane JR., prostacyclin inhibits platelet aggregation by increasing cyclic AMP levels. Prostacyclin is a circulating hormone continually released by the lungs into the arterial circulation. Circulating platelets are, therefore, subjected constantly to prostacyclin stimulation and it is via this mechanism that platelet aggregability in vivo is controlled. Moreover, phosphodiesterase inhibitors such as dipyridamole or theophylline exert their antithrombotic actions by potentiating circulating prostacyclin. The prostacyclin:thromboxane A2 ratio is important in the control of thrombus formation; manipulation of this ratio by small doses of aspirin (which will inhibit mainly platelet cyclooxygenase), a selective inhibitor of thromboxane formation, or the dietary use of a fatty acid like eicosapentaenoic acid (which would be the precursor for a delta17-prostacyclin (PGI3) but is transformed by the platelets into nonaggregating thromboxane A3) might have beneficial effects as antithrombotic therapies. Prostacyclin has interesting potential for clinical application in conditions where enhanced platelet aggregation is involved or to increase biocompatibility of extracorporeal circulation systems(13).
14. Prostacyclin reduces cardiopulmonary bypass-induced pulmonary endothelial dysfunction
Cardiopulmonary bypass triggers a systemic inflammatory response that alters pulmonary endothelial function, which can contribute to pulmonary hypertension. According to the study by the Montreal Heart Institute, prophylactic use of inhaled prostacyclin has a favorable impact on the pulmonary endothelial dysfunction induced by cardiopulmonary bypass associated with preservation of pulmonary intravascular cyclic adenosine monophosphate content and the pulmonary vascular tone(14).
15. Healthy vascular endothelium
Healthy vascular endothelium is a powerful generator of nitric oxide (NO), prostacyclin (PGI2), prostaglandin E2 (PGE2), and plasminogen activator (t-PA). These endothelial products protect vascular wall against aggression from activated blood platelets and leukocytes. According to the study by Jagiellonian University, In particular they protect against thrombosis, promote thrombolysis, maintain tissue perfusion, and inhibit remodeling of vascular and cardiac walls. Endothelial dysfunction appears on one hand as suppression in the release of the above mediators, and on the other as deleterious discharge of prostaglandin endoperoxides (PGH2, PGG2), superoxide anion O2-, peroxynitrite (ONOO-), and plasminogen activator inhibitor (PAI-1)(15).
16. Vasoprotective function of endothelial cells
Vasoprotective function of endothelial cells is associated, among others, with biosynthesis and release of nitric oxide (NO), prostacyclin (PGI2), prostaglandin E2 (PGE2), carbon monoxide (CO) and plasminogen activator (t-PA). According to the study by the Jagiellonian University, These endothelial mediators calm down activated platelets and leukocytes, prevent the occurrence of parietal thrombotic events, promote thrombolysis, maintain tissue perfusion and protect vascular wall against acute damage and against chronic remodeling. Endothelial dysfunction in patients suffering from atherosclerosis or diabetes type 2 is associated not only with suppression in release of the above mediators but also with deleterious discharge of prostaglandin endoperoxides (PGH2, PGG2), superoxide anion (O2-, peroxynitrite (ONOO-), and plasminogen activator inhibitor (PAI-1). We looked for mechanisms of protective endothelial function, with a special respect to the differences between peripheral and pulmonary circulation(16).
17. Endothelial dysfunction in sepsis
The endothelium takes part in the regulation of numerous physiological functions and lies at the interface of circulating blood and the vessel wall. Under physiological conditions, it is responsible for anticoagulant and anti-adhesive properties, and it regulates vasomotor tone and vascular homeostasis. According to the study by Hôpitaux Universitaires de Strasbourg, septic shock is associated with hypotension and frequently with disseminated intravascular coagulation contributing to multiple organ failure and a high mortality rate. Impairment of endothelial function leads to phenotypic and physical changes of the endothelium, with deregulated release of potent vasodilators nitric oxide and prostacyclin, reduction of vascular reactivity to vasoconstrictors, associated with leukocytes' and platelets' aggregation, and increase in inducible nitric oxide synthase expression that can exert a negative feedback on endothelial nitric oxide synthase expression, with subsequent deregulation of nitric oxide signaling. Endothelial dysfunction therefore plays a major role in the pathophysiology of septic shock and organ dysfunction, and has been suggested to be a predictor of mortality in sepsis(17).
18. Endothelial dysfunction and coagulation
In the study to review endothelial properties and to establish how these unperturbed properties contribute to the maintenance of endothelium anticoagulant activity and to better understand the relative contributions of endothelial cells and monocytes in sepsis-induced altered coagulation, showed that Unperturbed endothelial cells provide anticoagulant properties; exposure to inflammatory and/or septic stimuli can rapidly lead to procoagulant behavior. Sepsis alters endothelial cell surface and induces tissue factor synthesis at the endothelial and subendothelial levels. During endotoxemia, endothelial cells generate adhesion molecules that bind leukocytes and monocytes, increasing local procoagulant reactions. Tissue factor expression is also increased at the level of the monocyte; the relative importance of endothelial injury and monocyte activation in coagulation disorders was recently assessed. Endothelium protection before induction of septic shock was not associated with any reduction in monocyte tissue factor expression, suggesting that altered coagulation was present despite normal endothelial cell function. On the other hand, decreased monocyte tissue factor expression was associated with a marked reduction in endothelial injury, increased endothelium-derived relaxation, and improved survival rate in treated animals(18).
19. Endothelial cells and coagulation abnormalities
Endothelial cells have two important anticoagulant systems, heparan sulfate-antithrombin system and thrombomodulin-protein C system. Under physiological conditions, these two systems inhibit activation of coagulation on endothelial cells. According to the study by the Kumamoto University School of Medicine, under inflammatory conditions, tumor necrosis factor(TNF)-alpha or other cytokines produced by monocytes reduce the anticoagulant properties of endothelial cell by downregulating expression of heparan sulfate and thrombomodulin on endothelial cells. Antithrombin stimulates prostacyclin generation from endothelial cells by interacting with heparan sulfate of endothelial cells and generated prostacyclin inhibits TNF-alpha production by monocytes. Activated protein C inhibits TNF-alpha production by monocyte dependent of its protease activity. Thus, antithrombin and activated protein C might inhibit the endothelial perturbation induced by cytokines. Antithrombin regulates TNF-alpha induced tissue factor expression on endothelial cells by an unknown mechanism. Thus, antithrombin and activated protein C might be useful agents for treating coagulation abnormalities associated with sepsis or other inflammation because these agents inhibit not only coagulation but also downregulation of anticoagulant activities of endothelial cells(19).
20. Antithrombin (AT) can promote the endothelial production of prostacyclin
Antithrombin (AT) is an important inhibitor of the coagulation system, acting at many different levels of the coagulation cascade. This inhibitory action is enhanced several-fold by the glycosaminoglycan heparin. According to the study by the Sahlgrenska University Hospital, Göteborg University , data from cell culture and animal experiments have demonstrated that AT can promote the endothelial production of prostacyclin and may therefore have anti-inflammatory actions. This effect is based on the interaction of AT with glycosaminoglycans in the cell membrane, and is independent of heparin. The role of AT in vessel wall antithrombogenicity is being increasingly appreciated. The concept of neointimal hyperplasia following vascular injury involves thrombin as an important mediator and thus, in addition to the anti-inflammatory effects of AT, new horizons in which AT may have an important role in the prevention of post-traumatic hyperplastic response are also evolving(20).
21. The anti-inflammatory properties of antithrombin III
Antithrombin III (AT III) supplementation has proven to be effective in the treatment of disseminated intravascular coagulation. According to the study by the Kumamoto University School of Medicine , administration of AT III is also useful for prevention of organ failure in animals challenged with endotoxin or bacteria and it increases the survival rate of such animals. Since inhibition of coagulation abnormalities failed to prevent organ failure in animals given bacteria, AT III may exert a therapeutic effect independent of its anticoagulant effect. This therapeutic mechanism of AT III has been explored using an animal model of septicemia. AT III prevented pulmonary vascular injury by inhibiting leukocyte activation in rats given endotoxin. This effect is mediated by the promotion of endothelial release of prostacyclin which inhibits leukocyte activation. Interaction of AT III with heparin-like glycosaminoglycans (GAGs) on the endothelial cell surface appears to be important for this effect. Heparin inhibits these therapeutic effects of AT III by preventing AT III from interacting with the cell surface heparin-like GAGs. This activity of AT III may explain why AT III prevents organ failure as well as coagulation abnormalities in patients with sepsis(21).
22. Thrombin and Prostaglandin I2 (PGI2 or prostacyclin)
In the study role of blood clotting in the interaction of Platelet and vessel wall interaction found that vascular damage initiates not only the adhesion and aggregation of blood platelets but also coagulation, which is of mixed (intrinsic and extrinsic) origin. Evidence is presented that thrombin, generated as a result of the injury, is a prerequisite for platelet aggregation. Platelets, after activation, in their turn promote coagulation. Prostaglandin I2 (PGI2 or prostacyclin) inhibits coagulation induced by damaged vascular tissue. This effect of PGI2 is mediated by the inhibition of platelets in their participation in the generation of factor Xa and thrombin(22).
Sources
(a) http://en.wikipedia.org/wiki/Prostacyclin
(1) http://www.ncbi.nlm.nih.gov/pubmed/23594590
(2) http://www.ncbi.nlm.nih.gov/pubmed/20512454
(3) http://www.ncbi.nlm.nih.gov/pubmed/19880449
(4) http://www.ncbi.nlm.nih.gov/pubmed/23218395
(5) http://www.ncbi.nlm.nih.gov/pubmed/23276663
(6) http://www.ncbi.nlm.nih.gov/pubmed/22969152
(7) http://www.ncbi.nlm.nih.gov/pubmed/18500359
(8) http://www.ncbi.nlm.nih.gov/pubmed/15956108
(9) http://www.ncbi.nlm.nih.gov/pubmed/3890549
(10) http://www.ncbi.nlm.nih.gov/pubmed/2078914
(11) http://www.ncbi.nlm.nih.gov/pubmed/6258879
(12) http://www.ncbi.nlm.nih.gov/pubmed/6117893
(13) http://www.ncbi.nlm.nih.gov/pubmed/215463
(14) http://www.ncbi.nlm.nih.gov/pubmed/15224029
(15) http://www.ncbi.nlm.nih.gov/pubmed/12056503
(16) http://www.ncbi.nlm.nih.gov/pubmed/11208485
(17) http://www.ncbi.nlm.nih.gov/pubmed/23506494
(18) http://www.ncbi.nlm.nih.gov/pubmed/11445732
(19) http://www.ncbi.nlm.nih.gov/pubmed/10810875
(20) http://www.ncbi.nlm.nih.gov/pubmed/10102492
(21) http://www.ncbi.nlm.nih.gov/pubmed/9515777
(22) http://www.ncbi.nlm.nih.gov/pubmed/6117897
V. Thromboxane
Thromboxane is memeber of member of the family of lipids known as eicosanoids, containing 2 major thromboxanes, Thromboxane A2, a potent stimulator of platelet aggregation, and thromboxane B2, a metabolite of thromboxane A2 which is known to be highly unstable under physiological conditions.
1. The thromboxane synthase and receptor signaling pathway in cancer
Thromboxane A(2) (TXA(2)) is a biologically active metabolite of arachidonic acid formed by the action of the terminal synthase, thromboxane A(2) synthase (TXA(2)S), on prostaglandin endoperoxide (PGH(2)). TXA(2) is responsible for multiple biological processes through its cell surface receptor, the T-prostanoid (TP) receptor. According to the study by the Wayne State University, potential involvement of TXA(2)S and TP in tumor progression, especially tumor cell proliferation, migration, and invasion that are key steps in cancer progression. In addition, the regulation of neovascularization by TP has been identified as a potent source of control during oncogenesis(1).
2. Pesveratrol to modulate the immune system and to inhibit platelet aggregation in thromboembolic episodes
Platelet aggregation around migrating cancer cells protects them against the activity of natural killer cells (NKCs). The inability of immune system to response results in the progression of malignant diseases. In the study to evaluate the effects of resveratrol (3, 4', 5-trihydroxystilbene) on platelet aggregation and NKCs activity and the platelet aggregation, production of thromboxane B2 (TXB2), estimation of expression of the platelet receptor GpIIb/IIIa (major biological markers for platelet aggregation) and functional activity of the NKCs against the K562 cancer cell line after incubation with various concentrations of reveratrol, found that resveratrol can be used as an additional supplement to modulate the immune system and to inhibit platelet aggregation in thromboembolic episodes. Further clinical investigation in vivo could lead to specific concentrations that may maximize the beneficial effect of resveratrol(2).
3. Thromboxane synthase (TXAS) and thromboxane receptor (TP) beta isoform and Bladder cancer
Increased expression of thromboxane synthase (TXAS) and thromboxane receptor (TP) beta isoform are found in the tissues of patients with bladder cancer. In the study by the University of South Carolina to determine if the changes observed in the tissues of patients with bladder cancer were mirrored by changes in the urine of these patients, found that increased levels of thromboxane B(2) (TXB(2)) the major metabolite of TXAS and increased levels of the TPβ receptor. These results raised the possibility that patients with bladder cancer may be followed for progression or remission of their disease by quantitation of these substances in their urine(3).
4. Thromboxane synthase and Non small cell cancer
Thromboxane synthase (TXS) metabolises prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. In the study toexamine the TXS expression in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression, indicated that TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC(4).
5. Endogenous levels of AA and selected eicosanoids and colon cancer
Cumulative evidence shows that eicosanoids such as prostaglandins, leukotrienes, thromboxanes and hydroxy eicosatetraenoic acids play an important role in associating inflammation with human colorectal cancer (CRC). In the study In the study of an ultra-pressure liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) method was developed and validated for the targeted profiling of eight relevant eicosanoids and the major metabolic precursor, arachidonic acid (AA), in human colon, applied for the clinical profiling of matched pairs of cancerous and normal colon mucosae obtained from eight colorectal cancer patients, indicated that Endogenous levels of AA and selected eicosanoids such as prostaglandin E(2) (PGE(2)), prostacyclin (PGI(2)) [assayed as its stable hydrolytic product 6-keto-prostaglandin(1α) (6-k PGF(1α))] and 12-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12-HETE) were found to be significantly different (p <0.05; paired t-test) between cancerous and normal mucosae(5).
6. The role of thromboxane A(2) (TxA(2)) in smoking-associated lung cancer
The role of thromboxane A(2) (TxA(2)) in smoking-associated lung cancer is poorly understood. In the study to examine the role of TxA(2) in smoking carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-promoted cell survival and growth in human lung cancer cells, found that NNK stimulates TxA(2) synthesis and activates its receptor in lung cancer cells. The increased TxA(2) may then activate CREB through PI3K/Akt and extracellular ERK pathways, thereby contributing to the NNK-promoted survival and growth of lung cancer cells(6).
7. Prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer
Prostacyclin synthase and thromboxane synthase signaling via arachidonic acid metabolism affects a number of tumor cell survival pathways such as cell proliferation, apoptosis, tumor cell invasion and metastasis, and angiogenesis. While prostacyclin synthase is generally believed to be anti-tumor, a pro-carcinogenic role for thromboxane synthase has been demonstrated in a variety of cancers. According to the study by the St. James's Hospital, the expression and activity of this enzyme may protect against tumor development. In this review, we discuss the aberrant expression and known functions of both prostacyclin synthase and thromboxane synthase in cancer. The study also discusses the effects of these enzymes on a range of tumor cell survival pathways, such as tumor cell proliferation, induction of apoptosis, invasion and metastasis, and tumor cell angiogenesis. As downstream signaling pathways of these enzymes have also been implicated in cancer states, we examine the role of downstream effectors of PGIS and TXS activity in tumor growth and progression. Finally, the current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer(7).
8. Increased cyclooxygenase-2 and thromboxane synthase expression in human erythroleukemia cells
Diosgenin is a very interesting natural product because, depending on the specific dose used, its biological effect is very different in HEL (human erythroleukemia) cells. For example, at 10 microM, diosgenin induced megakaryocytic differentiation, in contrast to 40 microM diosgenin, which induced apoptosis in HEL cells previously demonstrated using sedimentation field-flow fractionation (SdFFF). In the study by the Université de Limoges, indicated that the implication of COX-2 and TxS in diosgenin-induced megakaryocytic differentiation in HEL cells. Furthermore, we showed that the analytical technique of SdFFF may be used as a tool to confirm our results as a function of the degree of cell differentiation(8).
9. Cyclooxygenase-2 and thromboxane synthase in non-endocrine and endocrine tumors
Prostaglandins (PG) are members of a large group of hormonally active fatty acids derived from free fatty acids. They are formed from arachidonic acid-the major PG precursor. Cyclooxygenase (COX)-1 and -2 are the rate-limiting steps in PG synthesis. COX-2 is overexpressed in many human non-endocrine and endocrine tumors including colon, breast, prostate, brain, thyroid, and pituitary. According to the study by the Mayo Clinic College of Medicine, Thromboxane synthase (TS) catalyzes the synthesis of thromboxane A2 (TXA2), which is derived from arachidonic acid and prostaglandin H2 and is a vasoconstrictor and inducer of platelet aggregation. TXA2 stimulates tumor growth and spread of some tumors and TS appears to have a critical role in tumorigenesis in some organ systems. The accumulating evidence points to an increasingly important role of COX-2 and TS in tumor progression and metastasis(9).
10. Activation of the thromboxane A2 pathway in human prostate cancer correlates
In the study to investigate the potential involvement of the thromboxane A(2) (TXA(2)) pathway in human prostate cancer (PCa) by analyzing the expression of cyclooxygenase-2 (COX-2), TXA(2) synthase (TXS), and TXA(2) receptors (TPRs), the main actors of the TXA(2) pathway, was analyzed on serial tissue sections from 46 human PCa specimens, found that Proteins specifically involved in the TXA(2) pathway are up-regulated in human PCa and their level of expression is associated with tumor extraprostatic extension and loss of differentiation. The study is the first to examine simultaneously all key proteins involved in this pathway including TXA(2) receptors and results suggest that the TXA(2) pathway may be a potential target for PCa prevention/therapy(10).
11. Expression of thromboxane synthase, TBXAS1 and the thromboxane A2 receptor, TBXA2R, in human breast cancer
Thromboxane synthase (TxS) metabolizes the cyclooxygenase product, prostaglandin H(2), into thromboxanes. Some of the thromboxanes are known to be biologically active on cancer cells. In the study to investigate the expression of thromboxane synthases, TBXAS1 and the thromboxane A2 receptor, TBXA2R in a cohort of human breast cancer patients and also to assess their potential clinical relevance, showed that thromboxane synthases are differentially expressed in human breast cancer. While TBXA2R is highly expressed in aggressive tumours and linked with poor prognosis, TBXAS1 is expressed at significantly low levels in high grade tumours and tumour patients with poor prognosis. TBXA2R thus has a significant prognostic value in clinical breast cancer(11).
Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/22037941
(2) http://www.ncbi.nlm.nih.gov/pubmed/23617069
(3) http://www.ncbi.nlm.nih.gov/pubmed/21983220
(4) http://www.ncbi.nlm.nih.gov/pubmed/21388528
(5) http://www.ncbi.nlm.nih.gov/pubmed/21337637
(6) http://www.ncbi.nlm.nih.gov/pubmed/20818420
(7) http://www.ncbi.nlm.nih.gov/pubmed/20122998
(8( http://www.ncbi.nlm.nih.gov/pubmed/18549804
(9) http://www.ncbi.nlm.nih.gov/pubmed/16627914
(10) http://www.ncbi.nlm.nih.gov/pubmed/16522350
(11) http://www.ncbi.nlm.nih.gov/pubmed/16250911
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