Role Of Cyclooxygenase Enzymes Research Articles

The Role of Cyclooxygenase Enzymes and Microparticles in Obstructive Sleep Apnea Related Cerebrovascular Incidents

Obstructive Sleep Apnea (OSA) is a sleep disorder caused by breathing problems that occur during sleep due to airway obstruction. Obstructive Sleep Apnea is quite common, but is often overlooked and misdiagnosed and untreated. Many studies have proven the relationship between OSA and pathological diseases such as cardiovascular disease and stroke. Intermittent Hypoxia (IH) that occurs in OSA patients can cause endothelial dysfunction and play a role in the atherogenesis of peripheral and central blood vessels of the brain. Hypoxic conditions cause the release of microparticles, inflammatory mediators and increase the expression of the enzyme Cyclooxygenase (COX) in the vascular endothelium. This causes an increase in inflammation-related prostanoid production which in turn causes endothelial damage and increases the risk of atherosclerotic plaque formation. This review article will discuss the role of inflammatory mediators, especially COX enzymes in OSA-related cerebrovascular incidents. Keywords: cerebrovascular incidents, cyclooxygenase, intermittent hypoxia, obstructive sleep apnea

The Role of Cyclooxygenase Enzymes in the Effects of Losartan and Lisinopril on the Contractions of Rat Thoracic Aorta.

It was suggested that prostaglandins which are synthesized by cyclooxygenase (COX) enzymes contribute to the actions of angiotensin-converting enzyme (ACE) inhibition and angiotensin AT1 receptor antagonism and there is an interaction between ACE signaling pathway and COX enzymes. We aim to investigate the role of COX enzymes in the effects of losartan, an angiotensin II (Ang II) receptor antagonist or lisinopril, an ACE inhibitor, on the contractions of rat thoracic aorta in isolated tissue bath. Responses of losartan (10-6, 10-5, 10-4 M), lisinopril (10-6, 10-5, 10-4 M), and non-selective COX inhibitor dipyrone (10-4, 7 × 10-4, 2 × 10-3 M) alone to the contractions induced by phenylephrine (Phe) (10-7 M), potassium chloride (KCl) (6 × 10-2 M), Ang II (10-8 M) and responses of losartan or lisinopril in combination with dipyrone to the contractions induced by Phe or KCl were recorded. When used alone, dipyrone and losartan inhibited Phe, KCl, and Ang II-induced contractions, whereas lisinopril inhibited only Phe and Ang II-induced contractions. Inhibition of COX enzymes (COX-3, COX-3 + COX-1, COX-1+ COX-2 + COX-3 by dipyrone 10-4, 7 × 10-4, 2 × 10-3 M, respectively) augmented the relaxant effects of losartan or lisinopril. Also, dipyrone potentiated the effect of lisinopril on KCl-induced contractions. We suggest that dipyrone increases the smooth-muscle relaxing effects of losartan or lisinopril and that COX enzyme inhibition may have a role in the enhancement of this relaxation.

Prostaglandin receptors are mediators of vascular function in endometrial pathologies

Prostaglandins are bioactive lipids produced from arachidonic acid by cyclooxygenase enzymes and specific terminal prostanoid synthase enzymes. Following biosynthesis, prostaglandins exert an autocrine/paracrine function by coupling to specific prostanoid G protein-coupled receptors to activate intracellular signaling and gene transcription. For many years prostaglandins have been recognised as key molecules in reproductive biology by regulating ovulation, endometrial physiology and proliferation of endometrial glands and menstruation. More recently a role for COX enzymes and prostaglandins has been ascertained in reproductive tract pathology, including dysmenorrhea, endometriosis, menorrhagia and cancer. Emerging evidence supports a role for COX enzymes, prostaglandins and prostaglandin receptor signaling pathways in a multitude of phenotypic changes in reproductive tissues including the promotion of angiogenesis and vascular function. Here we provide an overview of some of the findings from these studies with specific emphasis on the role of cyclooxygenase enzymes, prostaglandins and their receptors in benign and neoplastic pathologies of the human endometrium.

Cyclooxygenase-2 mediates ischemic, anesthetic, and pharmacologic preconditioning in vivo.

Cyclooxygenase-2 (COX-2) mediates the late phase of ischemic preconditioning (IPC), but whether this enzyme modulates early IPC, anesthetic-induced preconditioning (APC), or other forms of pharmacologic preconditioning (PPC) is unknown. The authors tested the hypothesis that COX-2 is an essential mediator of IPC, APC, and PPC in vivo. Barbiturate-anesthetized dogs (n = 91) were instrumented for measurement of hemodynamics and randomly assigned to receive IPC (four 5-min coronary occlusions interspersed with 5-min reperfusions), APC (1.0 minimum alveolar concentration of isoflurane for 30 min), or PPC (selective mitochondrial K(ATP) channel opener diazoxide, 2.5 mg/kg intravenous) in the presence or absence of pretreatment with oral aspirin (650 mg), the selective COX-2 inhibitor celecoxib (200 mg), or acetaminophen (500 mg) administered 24, 12, and 2 h before experimentation in 12 separate experimental groups. All dogs were subjected to a 60-min coronary artery occlusion followed by 3 h of reperfusion. Myocardial infarct size and coronary collateral blood flow were quantified with triphenyltetrazolium staining and radioactive microspheres, respectively. Myocardial 6-keto-prostaglandin F1alpha, a stable metabolite of prostacyclin, was measured (enzyme immunoassay) in separate experiments (n = 8) before and after isoflurane administration, in the presence or absence of celecoxib. No significant differences in baseline hemodynamics or the left ventricular area at risk for infarction were observed between groups. IPC, isoflurane, and diazoxide all decreased myocardial infarct size (9 +/- 1, 12 +/- 2, and 11 +/- 1%, respectively) as compared with control (30 +/- 1%). Celecoxib alone had no effect on infarct size (26 +/- 3%) but abolished IPC (30 +/-3%), APC (30 +/- 3%), and PPC (26 +/- 1%). Aspirin (24 +/- 3%) and acetaminophen alone (29 +/- 2%) did not alter infarct size or abolish APC-induced protection (18 +/- 1 and 19 +/- 1%, respectively). Isoflurane increased myocardial 6-keto-prostaglandin F1alpha to 463 +/- 267% of baseline in the absence but not in the presence (94 +/- 13%) of celecoxib. The results indicate that COX-2 is a critical mediator of IPC, APC, and PPC in dogs. The role of cyclooxygenase enzymes as obligatory mediators of myocardial protection produced by diverse preconditioning stimuli may have implications for the clinical use of COX-2 inhibitors.

Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium.

Prostaglandins are bioactive lipids produced from arachidonic acid by cyclooxygenase (COX) enzymes and specific terminal prostanoid synthase enzymes. After biosynthesis, prostaglandins exert an autocrine-paracrine function by coupling to specific prostanoid G protein-coupled receptors to activate intracellular signalling and gene transcription. For many years, prostaglandins have been recognized as key molecules in reproductive biology by regulating ovulation, endometrial physiology and proliferation of endometrial glands and menstruation. More recently, a role for COX enzymes and prostaglandins has been ascertained in reproductive tract pathology, including carcinomas, menorrhagia, dysmenorrhoea and endometriosis. Although the mechanism by which prostaglandins modulate these pathologies is still unclear, a large body of evidence supports a role for COX enzymes, prostaglandins and prostaglandin receptor signalling pathways in angiogenesis, apoptosis and proliferation, tissue invasion and metastases and immunosuppression. Here, an overview is provided of some of the findings from these studies with specific emphasis on the role of COX enzymes, prostaglandin E(2) and F(2alpha) in disorders of endometrial proliferation and menstruation in non-pregnant women.

Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium

Prostaglandins are bioactive lipids produced from arachidonic acid by cyclooxygenase (COX) enzymes and specific terminal prostanoid synthase enzymes. After biosynthesis, prostaglandins exert an autocrine-paracrine function by coupling to specific prostanoid G protein-coupled receptors to activate intracellular signalling and gene transcription. For many years, prostaglandins have been recognized as key molecules in reproductive biology by regulating ovulation, endometrial physiology and proliferation of endometrial glands and menstruation. More recently, a role for COX enzymes and prostaglandins has been ascertained in reproductive tract pathology, including carcinomas, menorrhagia, dysmenorrhoea and endometriosis. Although the mechanism by which prostaglandins modulate these pathologies is still unclear, a large body of evidence supports a role for COX enzymes, prostaglandins and prostaglandin receptor signalling pathways in angiogenesis, apoptosis and proliferation, tissue invasion and metastases and immunosuppression. Here, an overview is provided of some of the findings from these studies with specific emphasis on the role of COX enzymes, prostaglandin E(2) and F(2alpha) in disorders of endometrial proliferation and menstruation in non-pregnant women.

Role of cyclooxygenase enzymes in a murine model of experimental cholera.

Nonsteroidal anti-inflammatory drugs (e.g., indomethacin) inhibit and reduce the fluid secretion responses elicited by cholera toxin (CT), but it has not been conclusively determined which cyclooxygenase (COX) isoform is involved in CT's action. This study evaluated the role of the COX enzymes and their arachidonic acid metabolites in experimental cholera. Swiss-Webster mice were dosed with celecoxib and rofecoxib and challenged with CT in ligated small intestinal loops, and intestinal segments from mice deficient in COX-1 and COX-2 were challenged with CT. The effects of CT on fluid accumulation, prostaglandin E(2) production, mucosal tissue injury, and markers of oxidative stress were measured. Celecoxib and rofecoxib given at 160 micro g per mouse inhibited CT-induced fluid accumulation by 48% and 31%, respectively, but there was no significant difference among cox-1(-/-) and cox-2(-/-) mice in response to CT compared to wild-type controls. CT elevated tissue levels of oxidized glutathione and lipid peroxides and elicited small intestinal tissue injury in two of five cox-1(-/-) and four of five cox-2(-/-) mice. A role for COX-2 in CT's mechanism of action has previously been suggested by the effectiveness of COX-2 inhibitors in reducing CT-induced fluid secretion, but CT challenge of COX-1 and COX-2 knockout mice did not corroborate the pharmacological data. The results of this study show that CT induced oxidative stress in COX-deficient mice and suggest a tissue-protective role for arachidonic acid metabolites in the small intestine against oxidative stress.

Adverse reactions to aspirin and nonsteroidal antiinflammatory drugs (NSAIDs).

Aspirin can provoke reactions ranging from respiratory to cutaneous in those susceptible individuals. There has been particular attention looking at the role of cyclooxygenase enzymes and 2 and their role in aspirin exacerbated respiratory disease. Patients who present with a spectrum of allergic and pseudoallergic reactions to aspirin pose a special challenge for the physician. This article discusses proposed classification system, clinical manifestations, pathogenesis of disease, and current treatment options of aspirin related disease. Relevant articles in the medical literature were. derived from searching the MEDLINE database. Sources also include review articles, randomized control trials, and standard textbooks of allergy and immunology. Aspirin-exacerbated respiratory disease remains a complex, heterogeneous disease with manvaried clinical presentations. There have been many advances in trying to elucidate the pathogenesis of this disease. The classification system presented will provide greater ease when reading the literature and communicating with one another. Oral aspirin challenge remains the diagnostic test of choice for both respiratory and cutaneous reactions. Aspirin desensitization is an option for those with refractory respiratory disease or who require aspirin for other medical conditions. This review discusses the challenges in classification, diagnosis and treatment of those patients with a sensitivity to aspirin. Special attention is made to the possible mechanisms mediating disease progression and how specific. Therapies, such as the leukotriene modifiers may be helpful.

Aspirin-intolerant asthma: role of cyclo-oxygenase enzymes.

Aspirin-induced asthma and rhinitis (AIAR) appear to be precipitated by the inhibition of cyclo-oxygenase (COX). By inhibiting COX pathway aspirin diverts arachidonic acid metabolites to the lipoxygenase pathway. There are two isoforms of COX, namely COX-1 and COX-2. Metabolites derived from COX-1 are involved in cellular housekeeping functions. COX-2 can be induced in cells exposed to proinflammatory substances and growth factors. Recent studies have reported that patients with AIAR have decreased activity of COX-2 and lower production of PGE(2) in the upper airway and peripheral blood cells. Considering the protective effect of exogenous PGE(2) on aspirin-induced bronchoconstriction and the interdependence of PGE(2) and cisteinyl leukotriene production, a reduced PGE(2) synthesis may render aspirin-sensitive patients more susceptible to the inhibitory effect of NSAIDs drugs and also lead to an increase in cysteinyl leukotriene release.

The role of cyclooxygenase enzymes in the growth of human gall bladder cancer cells

Information suggests that the cyclooxygenase (COX) metabolites, the prostanoids, play a role in gall bladder physiology and disease. Non-steroidal anti-inflammatory drugs which inhibit COX enzymes have been shown in vivo and in vitro to alter the growth patterns of intestinal epithelial cells, and specific COX-2 inhibitors have been shown to decrease mitogenesis in intestinal epithelial cells. The present study was intended to evaluate the effect of specific COX inhibitors on the growth patterns of gall bladder cancer cells. Employing a human gall bladder cancer cell line, mitogenesis, apoptosis and prostaglandin E 2 (PGE 2 ) formation were evaluated in response to serum and hepatocyte growth factor and transforming growth factor α stimulation in the presence and absence of specific COX-1 and -2 inhibitors. The effect of the mitogens on COX enzyme expression was also evaluated. Serum and the growth factors increased COX enzyme expression and mitogenesis, and decreased apoptosis as evaluated by the percentage of cells that were floating in culture media rather than attached. There was more DNA degradation in floating than in attached cells. The specific COX-2 inhibitor, but not the COX-1 inhibitor, decreased mitogenesis and increased gall bladder cell apoptosis as evaluated by the number of floating versus attached cells and the number of floating cells in the terminal phase of apoptosis or dead. The inhibition of mitogenesis and the increased apoptosis produced by the COX-2 inhibitor was associated with decreased PGE 2 production. The inhibition of replication of gall bladder cancer cells and the increase in apoptosis produced by the selective COX-2 inhibitor suggests that the COX enzymes and the prostanoids may play a role in the development of gall bladder cancer and that the COX-2 inhibitors may have a therapeutic role in the prevention of gall bladder neoplasms.

The role of cyclooxygenase enzymes in the growth of human gall bladder cancer cells

Information suggests that the cyclooxygenase (COX) metabolites, the prostanoids, play a role in gall bladder physiology and disease. Non-steroidal anti-inflammatory drugs which inhibit COX enzymes have been shown in vivo and in vitro to alter the growth patterns of intestinal epithelial cells, and specific COX-2 inhibitors have been shown to decrease mitogenesis in intestinal epithelial cells. The present study was intended to evaluate the effect of specific COX inhibitors on the growth patterns of gall bladder cancer cells. Employing a human gall bladder cancer cell line, mitogenesis, apoptosis and prostaglandin E(2) (PGE(2)) formation were evaluated in response to serum and hepatocyte growth factor and transforming growth factor alpha stimulation in the presence and absence of specific COX-1 and -2 inhibitors. The effect of the mitogens on COX enzyme expression was also evaluated. Serum and the growth factors increased COX enzyme expression and mitogenesis, and decreased apoptosis as evaluated by the percentage of cells that were floating in culture media rather than attached. There was more DNA degradation in floating than in attached cells. The specific COX-2 inhibitor, but not the COX-1 inhibitor, decreased mitogenesis and increased gall bladder cell apoptosis as evaluated by the number of floating versus attached cells and the number of floating cells in the terminal phase of apoptosis or dead. The inhibition of mitogenesis and the increased apoptosis produced by the COX-2 inhibitor was associated with decreased PGE(2) production. The inhibition of replication of gall bladder cancer cells and the increase in apoptosis produced by the selective COX-2 inhibitor suggests that the COX enzymes and the prostanoids may play a role in the development of gall bladder cancer and that the COX-2 inhibitors may have a therapeutic role in the prevention of gall bladder neoplasms.