Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial cells synthesize prostacyclin (PGI(2)), an unstable prostaglandin that inhibits platelet aggregation and serotonin release. Because cyclooxygenase, which is necessary for synthesis of PGI(2), is inactivated by aspirin, we examined the effect of aspirin on PGI(2) production by cultured human endothelial cells. Endothelial cells synthesize PGI(2) (20.1+/-7.2 ng/10(6) cells, mean+/-SD) when stimulated with 20 muM sodium arachidonate for 2 min. PGI(2) production is inhibited by low-dose aspirin (5 muM); the t((1/2)) of inactivation is 6.0+/-1.3 min (mean+/-SEM, n = 3). Thus, endothelial cell cyclooxygenase is as sensitive to aspirin as the enzyme in platelets. After 1 h incubation with aspirin, endothelial cell PGI(2) production was inhibited 50% by 2.1+/-0.4 muM aspirin and was inhibited 90% by 6.2+/-0.9 muM aspirin (mean+/-SEM, n = 4). When endothelial cells were incubated with 100 muM aspirin, washed, and recultured, their ability to synthesize PGI(2) returned to control levels in 35.6+/-1.0 h (mean+/-SEM, n = 4). Recovery of endothelial PGI(2) production after aspirin depended on de novo protein synthesis because treatment with cycloheximide (3 mug/ml) inhibited recovery by 92%.These results indicate that although endothelial cell cyclooxygenase in vitro is inhibited by low concentrations of aspirin, endothelial cells rapidly resynthesize their cyclooxygenase after the aspirin is removed. This rapid resynthesis of cyclooxygenase lessens the likelihood that aspirin used in clinical doses promotes thrombosis.
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PMID:Recovery of endothelial cell prostacyclin production after inhibition by low doses of aspirin. 37 42

Celiac disease (CD) is characterized by diarrhea, growth retardation, and weight loss in genetically susceptible subjects on a gluten-containing diet. The exact pathogenesis of CD is still obscure, but it is considered to be immunologically mediated. We have previously shown elevated prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) content in small intestinal mucosa obtained from active celiac children. In the present study, we found significantly elevated PGE2, leukotriene B4 (LTB4), and leukotrienes C4, D4, and E4 (LTC4D4E4) content in small bowel mucosa from children suffering from CD on a gluten-containing diet in comparison to control subjects. PGE2 was 25,278 +/- 7,761 vs. 4,478 +/- 426 pg/mg of protein (mean +/- SEM), respectively. LTB4 was 8,807 +/- 3,706 vs. 403 +/- 63 pg/mg of protein (mean +/- SEM), respectively. LTC4D4E4 was 15,369 +/- 4,085 vs. 2,998 +/- 279 pg/mg of protein (mean +/- SEM), respectively. We conclude that the elevated content of arachidonic acid metabolic products via cyclooxygenase and lipoxygenase pathways may contribute to the diarrhea and may be involved in the pathogenesis of mucosal injury.
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PMID:Eicosanoids content in small intestinal mucosa of children with celiac disease. 133 47

Guinea pig alveolar macrophages obtained by bronchoalveolar lavage were isolated by adherence for 2 h and stimulated with 1 microM of N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) for different time intervals. The supernatants then were tested for their chemotactic effect on guinea pig peritoneal normodense eosinophils and for release of thromboxane B2, leukotriene B4 (LTB4), and platelet activating factor (PAF). The supernatant from fMLP-stimulated alveolar macrophages induced a significant eosinophil attraction (96.0 +/- 11.9, number of migrating eosinophils [mean +/- SEM], n = 17) as compared to unstimulated macrophages (4.8 +/- 1.4, n = 15). This effect was not accounted for by fMLP carry-over to the macrophages because, in contrast to human eosinophils, fMLP has no chemotactic effect on guinea pig eosinophils. Pretreatment of eosinophils with BN 52021 (100 microM), a specific PAF antagonist, and with indomethacin (10 microM), a cyclooxygenase inhibitor, failed to inhibit migration of eosinophils induced by supernatants from either stimulated or unstimulated alveolar macrophages. In contrast, inhibition of the 5-lipoxygenase enzyme with N-(3-phenoxycinamyl)-acetohydroxamic acid (1 microM) suppressed eosinophil migration by alveolar macrophage supernatants (94.1 +/- 2.6% of inhibition, n = 6). Desensitization of eosinophils by and to LTB4 (10 nM) inhibited migration induced by supernatants from stimulated alveolar macrophages (87.5 +/- 5.4% of desensitization toward LTB4 and 83.1 +/- 5.4% of desensitization toward supernatants, n = 5). Under the present experimental conditions, LTB4 is the only agent implicated in eosinophil migration induced by supernatants from fMLP-stimulated alveolar macrophages.
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PMID:Formation of LTB4 by fMLP-stimulated alveolar macrophages accounts for eosinophil migration in vitro. 131 47

The effect of indomethacin on the capacity of LTE4 to enhance airway histamine responsiveness was evaluated in eight mild asthmatic subjects. Subjects attended the laboratory on three separate pairs of study days when inhalation challenges with methacholine or LTE4 were performed and the airway responses to histamine were measured 4 and 7 h later. An open pair of study days was followed by a pair of study days during ingestion of either placebo or indomethacin capsules. The dose of agonist that produced a 35% fall in specific airways conductance (PD35 SGaw) was obtained by linear interpolation from the logarithmic dose-response curve. Indomethacin treatment did not affect baseline SGaw or methacholine airway responsiveness. However, indomethacin significantly inhibited LTE4-induced histamine hyperresponsiveness. Maximum enhancement of histamine responsiveness by LTE4 on the open and placebo study days was 4.1 +/- 0.9- (mean +/- SEM) and 5.7 +/- 1.2-fold, respectively (p = 0.36). Maximal enhancement on the indomethacin day was 1.68 +/- 0.46, and this was significantly decreased compared with that on the placebo day (p = 0.02). This suggests that LTE4-induced enhanced responsiveness to histamine is mediated in part by cyclooxygenase pathway-derived products.
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PMID:Effect of indomethacin on leukotriene4-induced histamine hyperresponsiveness in asthmatic subjects. 133 40

The effect of the cyclooxygenase inhibitor, indomethacin, on choroidal (ChBF) and retinal (RBF) blood flow during hypercarbia was examined in 16 paralyzed and mechanically ventilated piglets less than 8 d old. The animals were randomly assigned to a control group (mean +/- SEM: wt, 1.66 +/- 0.1 kg; n = 8) that received a placebo infusion or to an indomethacin treatment group (wt, 1.68 +/- 0.2 kg; n = 8) that received an infusion of indomethacin (5 mg/kg i.v. over 30 min). Baseline ChBF and RBF were measured using radiolabeled microspheres in room air before and 15 min after the administration of placebo or indomethacin. Animals were then exposed to 30 min of hypercarbia (6-7% CO2, arterial CO2 pressure 8-10 kPa) and measurements were repeated. There were no significant differences in RBF between control (40 +/- 3 mL/min/100 g) and indomethacin-treated animals (40 +/- 3 mL/min/100 g) before administration of placebo or indomethacin. However, RBF decreased significantly in the indomethacin-treated animals (28 +/- 2 mL/min/100 g) compared to the control group (42 +/- 4 mL/min/100 g) 15 min after administration of placebo or indomethacin. Furthermore, an increase in RBF occurred during hypercarbia in the control group (86 +/- 6 mL/min/100 g), but this change was blunted in the indomethacin-treated animals (33 +/- 5 mL/min/100 g) (p less than 0.001). In contrast, ChBF did not differ significantly between the control and indomethacin groups during the periods studied. These results suggest that the increase in RBF during hypercarbia is at least partially mediated by cyclooxygenase by-products of arachidonic acid metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of cyclooxygenase inhibition on retinal and choroidal blood flow during hypercarbia in newborn piglets. 154 39

The present study examined whether the dual cyclooxygenase/lipoxygenase inhibitor phenidone would protect stroke-prone spontaneously hypertensive rats (SHRSP) from stroke and hypertensive renal disease. Vehicle-treated SHRSP (N = 6), fed stroke-prone rodent diet and 1% saline, exhibited severe systolic blood pressure elevation (261 +/- 10 mm Hg, mean +/- SEM), marked proteinuria (90 +/- 12 mg/day), and stroke, with an average age at death of 14 +/- 1 weeks. In a second group of six saline-loaded SHRSP, treatment with phenidone (60 mg/kg/day) was started at 8.4 weeks of age. Despite establishment of severe hypertension in this group (274 +/- 10 mm Hg), proteinuria remained at basal levels (28 +/- 13 mg/day), and signs of stroke were absent (P less than .01 v vehicle) through at least 16 weeks of age. Phenidone treatment also prevented the declines in body weight and food intake observed in vehicle-treated SHRSP, and maintained urine volume and saline intake. Serum 12-hydroxy-eicosatetraenoic acid (12-HETE) generation was significantly inhibited greater than 50% in incubates of whole blood from phenidone-treated SHRSP. We have previously shown that agents which interfere with the renin-angiotensin system afford protection from renal and cerebrovascular injury in saline-loaded SHRSP; cyclooxygenase inhibition alone will hasten the onset of these pathologic changes. Whether phenidone, which has been reported to attenuate angiotensin II-mediated effects, affords vascular protection by interference with a lipoxygenase-mediated action of angiotensin II remains to be elucidated.
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PMID:The lipoxygenase inhibitor phenidone protects against proteinuria and stroke in stroke-prone spontaneously hypertensive rats. 155 Jun 66

We have reported previously that fish oil rich in omega-3 fatty acids added to a butter-cholesterol atherogenic diet for swine resulted in marked retardation of the atherosclerotic process which many regard as largely an inflammatory response to injury by excessive lipids in the intima. In this report on the same swine we present serum levels of several eicosanoids derived from arachidonic acid via the cyclooxygenase and lipoxygenase pathways. The study involves six swine fed a high fat, high cholesterol diet (BT group) for 4 months, six swine fed the same diet but with 30 ml/day fish oil added (BT + FO), and five swine fed a low fat, low cholesterol mash diet (MA). The serum eicosanoids were measured by radioimmunoassay. Thromboxane B2 levels (ng/dl: means +/- SEM) were 543 +/- 49 for MA, 231 +/- 12 for BT, and 105 +/- 20 for BT + FO, and all differences were statistically highly significant, 6-Keto PGF1 alpha (a relatively stable prostacyclin metabolite) levels were 249 +/- 31 for MA, 184 +/- 12 for BT, and 101 +/- 10 for BT + FO, and all differences were significant. Leukotriene B4 levels at 4 months were 151 +/- 25 for MA, 112 +/- 11 for BT, and 84 +/- 11 for BT + FO. BT + FO was significantly different from both MA and BT, but BT was not significantly different from MA. Leukotriene C4 levels were not significantly different among the three groups. Of special interest was the effect of the BT diet without the FO additive in reducing several eicosanoid levels compared to MA values. The affected eicosanoid levels were reduced still further by the fish oil additive, indicating its ability to inhibit both the cyclooxygenase and the lipoxygenase pathways. The relation of the fish oil-induced inhibition to the observed retardation of atherogenesis is not as yet clear but there are several theoretical possibilities, including reduction in recruitment of monocytes and in proliferation of smooth muscle cells.
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PMID:Reductions in serum thromboxane, prostacyclin, and leukotriene B4 levels in swine fed a fish oil supplement to an atherogenic diet. 165 49

The capacity to convert exogenous leukotriene A4 to lipoxins (LXs) was investigated in platelet suspensions from patients with myeloproliferative disorders (MPD) (n = 22) and healthy control subjects (n = 14). Platelets isolated from the controls produced mainly LXA4, but also 6(S)-LXA4 and the all-trans isomers of lipoxins A4 and B4, as determined by high-performance liquid chromatography and computerized UV spectroscopy. In comparison to control levels, the mean LX synthesis was significantly lower in platelets from the MPD patients (438.7 +/- 62.8 and 157.4 +/- 31.2 pmol LXA4 per 10(9) platelets, respectively; mean +/- SEM; P = .0001). Platelets from six of the patients showed a particularly low capacity to produce LXs, resulting in LX levels below the detection limit or less than 7% of mean control levels. Notably, all these patients were in blastic crisis of chronic myelogenous leukemia (CML). This severely deficient LX production was paralleled by a dramatically attenuated conversion of arachidonic acid to 12-HETE (12-hydroxyheptadecatrienoic acid), a product formed via the prostaglandin endoperoxide synthase pathway, was normal. In addition, longitudinal studies of CML patients showed that blastic metamorphosis was associated with a markedly reduced capability to synthesize LXs, while this capacity improved after retransformation into a second chronic phase. The results reveal deficient LX synthesis as a novel platelet dysfunction in MPD, particularly in blastic crisis of CML in which an essentially abolished 12-lipoxygenase activity may be a general phenomenon.
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PMID:Deficient lipoxin synthesis: a novel platelet dysfunction in myeloproliferative disorders with special reference to blastic crisis of chronic myelogenous leukemia. 165 70

To determine if acute exposure to ozone can cause changes in the production of cyclooxygenase metabolites of arachidonic acid (AA) in the lung which are associated with changes in lung mechanics, we exposed mongrel dogs to 0.5 ppm ozone for two hours. We measured pulmonary resistance (RL) and dynamic compliance (Cdyn) and obtained methacholine dose response curves and bronchoalveolar lavagate (BAL) before and after the exposures. We calculated the provocative dose of methacholine necessary to increase RL 50% (PD50) and analyzed the BAL for four cyclooxygenase metabolites of AA: a stable hydrolysis product of prostacyclin, 6-keto-prostaglandin F1 alpha (6-keto-PgF1 alpha); prostaglandin E2 (PgE2); a stable hydrolysis product of thromboxane A2, thromboxane B2 (TxB2); and prostaglandin F2 alpha (PgF2 alpha). Following ozone exposure, RL increased from 4.75 +/- 1.06 to 6.08 +/- 1.3 cm H2O/L/sec (SEM) (p less than 0.05), Cdyn decreased from 0.0348 +/- 0.0109 TO .0217 +/- .0101 L/cm H2O (p less than 0.05), and PD50 decreased from 4.32 +/- 2.41 to 0.81 +/- 0.49 mg/cc (p less than 0.05). The baseline metabolite levels were as follows: 6-keto PgF1 alpha: 96.1 +/- 28.8 pg/ml; PgE2: 395.8 +/- 67.1 pg/ml; TxB2: 48.5 +/- 11.1 pg/ml; PgF2 alpha: 101.5 +/- 22.6 pg/ml. Ozone had no effect on any of these prostanoids. These studies quantify the magnitude of cyclooxygenase products of AA metabolism in BAL from dog lungs and demonstrate that changes in their levels are not prerequisites for ozone-induced changes in lung mechanics or airway reactivity.
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PMID:Effects of ozone on lung mechanics and cyclooxygenase metabolites in dogs. 179 49

Enzymes involved in prostaglandin I2 (PGI2) and thromboxane A2 (TXA2) synthesis were studied in maternal and fetal platelets and venous endothelium from normotensive pregnant controls (n = 70), women with mild preeclampsia (MP, n = 45), and severe preeclampsia (SP, n = 34). Activities of phospholipase A2 (PHA2), cyclooxygenase (PGHS), and PGI2 synthetase (PGIS) or TXA2 synthetase (TXAS) were determined in platelets and in endothelial cells. The PGHS enzyme was studied further by immunoblot methodology. In maternal platelets: Vmax (per 10(-10) mol/mg protein) and Michaelis-Menten constant (Km) (10(-7) mol, mean +/- SEM) of PHA2 were 3.0 +/- 0.8, 3.0 +/- 0.7, and 31.7 +/- 10.9* maximum velocity (Vmax) and 1.8 +/- 0.3, 2.0 +/- 0.8, and 0.8 +/- 0.2 (Km) in normal control (NC), mild preeclampsia (MP), and severe preeclampsia (SP), respectively (*P less than 0.05 against NC). The apparent overall PGHS plus TXAS activity was 10.2 +/- 1.8, 23.8 +/- 7.1, and 68.8 +/- 18.8* (Vmax) and 3.2 +/- 1.3, 5.4 +/- 1.4, and 6.9 +/- 1.2* (Km, *P less than 0.05 against NC). TXA synthesis in fetal platelets demonstrated PHA2 activity of 6.4 +/- 1.4, 12.0 +/- 1.3, and 17.2 +/- 3.2* (Vmax) and 3.5 +/- 0.9, 2.2 +/- 1.5, and 0.7 +/- 0.3* (Km, *P less than 0.05 against NC), respectively, whereas an apparent overall PGHS plus TXAS activity was 18.5 +/- 2.8, 87.5 +/- 12.5*, and 3.6 +/- 0.1* (Vmax) and 4.8 +/- 1.0, 8.8 +/- 1.2, and 0.8 +/- 0.3* (Km, *P less than 0.05 against NC).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of prostaglandins in pregnancy-induced hypertension. 189 31


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