6-ketoprostaglandin-f1-alpha and Leukopenia

Neutrophil elastase decreases production of PGI2 by cultured endothelial cells. Thus, neutrophil elastase may play an important role in gastric mucosal injury by decreasing the tissue level of PGI2, an important gastric cytoprotective substance. We examined whether activated neutrophils inhibit gastric PGI2 production in rats subjected to water-immersion restraint stress. Gastric 6-keto-PGF1alpha levels were determined by enzyme immunoassay. Gastric mucosal blood flow was determined by laser-Doppler flowmeter. Gastric microvascular permeability was determined by Evans blue leakage. Gastric levels of 6-keto-PGF1alpha were transiently increased 0.5 hr after the stress, followed by a decrease to below baseline at 6 hr, when mucosal blood flow fell to 60% of baseline. Gastric levels of 6-keto-PGF1alpha were significantly higher in animals with nitrogen mustard-induced leukocytopenia than in controls 1 and 6 hr after the stress. In leukocytopenic animals, levels 6 hr after stress were not lower than those preceding stress. Leukocytopenia markedly limited both the decrease in mucosal blood flow and the increase in gastric microvascular permeability. The level of gastric mucosal injury observed 6 hr after the stress was markedly attenuated by leukocytopenia. Pretreatment with neutrophil elastase inhibitors (ONO-5046 and Eglin C) or an anti-P-selectin monoclonal antibody produced effects similar to leukocytopenia. Neutrophil elastase is involved in the stress-induced gastric mucosal injury by decreasing gastric production of PGI2. Thus, pharmacologic inhibition of neutrophil elastase should help to prevent stress-induced gastric mucosal injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Capillary Permeability; Cytoprotection; Enzyme Inhibitors; Epoprostenol; Gastric Mucosa; Iloprost; Immersion; Leukocyte Elastase; Leukopenia; Male; Microcirculation; Neutrophils; Peroxidase; Rats; Rats, Wistar; Regional Blood Flow; Restraint, Physical; Stomach; Stomach Diseases

We investigated whether, in rats, gastric prostacyclin (PGI2) prevented gastric mucosal injury that was induced by water-immersion restraint stress by inhibiting leukocyte activation. Gastric levels of 6-keto-PGF1alpha, a stable metabolite of PGI2, increased transiently 30 min after stress, followed by a decrease to below the baseline 6-8 h after stress. Gastric mucosal blood flow decreased to approximately 40% of the baseline level 8 h after stress. Myeloperoxidase activity was significantly increased 8 h after stress. Treatment with indomethacin before stress inhibited the increase in 6-keto-PGF1alpha levels and markedly reduced mucosal blood flow. It also markedly increased leukocyte accumulation and mucosal lesion formation. Iloprost, a stable PGI2 analog, inhibited the indomethacin-induced decrease in mucosal blood flow, mucosal lesion exacerbation, and increase in leukocyte accumulation. Nitrogen mustard-induced leukocytopenia inhibited the indomethacin-associated lesion exacerbation and the increase in leukocyte accumulation, but not the decreases in mucosal blood flow. These observations indicate that gastric PGI2 decreases gastric mucosal lesion formation primarily by inhibiting leukocyte accumulation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Epoprostenol; Gastric Mucosa; Indomethacin; Leukocytes; Leukopenia; Male; Mechlorethamine; Peroxidase; Rats; Rats, Wistar; Regional Blood Flow; Stress, Physiological

To examine whether activated leukocytes may impair the endothelial production of prostaglandin (PG) I2, an important cytoprotective agent in gastric mucosa, we investigated the effects of leukocyte depletion and ONO-5046, a specific inhibitor of granulocyte elastase, on the gastric level of this prostaglandin and gastric mucosal injury in rats subjected to water-immersion restraint stress (WIR). Gastric 6-keto-PGF1 alpha was increased after 30 min of WIR, followed by a decrease to below baseline after 6 h of stress. Gastric levels of 6-keto-PGF1 alpha in leukopenic animals or animals pretreated with ONO-5046 after 1 h of stress were significantly higher than those of controls, levels after 6 h of stress were not lower than those preceding stress. Leukocytopenia or ONO-5046 significantly inhibited WIR-induced gastric mucosa lesion formation. Iloprost, a stable derivative of PGI2, prevented stress-induced lesions. These results suggest that activated leukocytes may play an important role in stress-induced gastric mucosal lesion formation by inhibiting production of PGI2.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Gastric Mucosa; Glycine; Iloprost; Leukocyte Elastase; Leukocytes; Leukopenia; Male; Rats; Rats, Wistar; Serine Proteinase Inhibitors; Stress, Physiological; Sulfonamides

We investigated the novel role of prostacyclin (PGI2) in gastric mucosal lesion formation induced by stress in rats. Gastric 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) levels were significantly increased 30 minutes after water-immersion restraint stress (WIR). Subcutaneous indomethacin (IM) (5 mg/kg) inhibited this increase but significantly exacerbated gastric mucosal lesion formation in rats subjected to WIR. Although gastric myeloperoxidase (MPO) activity was not increased by WIR, it significantly increased with time after WIR in animals pretreated with IM. NS-398, a selective inhibitor of cyclooxygenase-2, did not inhibit the WIR-induced increase in gastric 6-keto-PGF1alpha. Neither the gastric lesion index nor gastric MPO activity were affected in animals pretreated with NS-398 and subjected to WIR. WIR-induced mucosal lesion formation was significantly inhibited in animals given iloprost, a stable analog of PGI2, and in those with nitrogen mustard-induced leukocytopenia. Iloprost prevented the gastric leukocyte accumulation and exacerbation of gastric mucosal lesions induced by IM in animals subjected to WIR. These IM-induced events also were prevented in animals subjected to WIR with nitrogen mustard-induced leukocytopenia. These observations implicate leukocytes in the process leading to gastric mucosal lesions induced by WIR. The increase in WIR-induced gastric PGI2 synthesis, mainly mediated by cyclooxygenase-1, appears important in preventing lesion formation, not only by maintaining gastric mucosal blood flow but also by inhibiting leukocyte activation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Epoprostenol; Gastric Mucosa; Iloprost; Indomethacin; Isoenzymes; Leukopenia; Male; Mechlorethamine; Nitrobenzenes; Peroxidase; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Restraint, Physical; Stress, Psychological; Sulfonamides; Time Factors

Acute respiratory distress syndrome (ARDS) adversely affects the outcome of patients with disseminated intravascular coagulation (DIC) associated with sepsis. To determine whether antithrombin III (AT III) is useful for the treatment of ARDS in sepsis, we evaluated the effect of AT III on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats. Although the intravenous administration of AT III (250 U/kg) prevented LPS-induced pulmonary accumulation of leukocytes, increases in pulmonary vascular permeability, and coagulation abnormalities, inactivated factor Xa, a selective inhibitor of thrombin generation, did not prevent such events other than the coagulation abnormalities. AT III promotes the endothelial release of prostacyclin by interacting with cell surface glycosaminoglycans in vivo. Trp49-modified AT III, which lacks affinity for heparin, did not prevent LPS-induced pulmonary vascular injury. Plasma levels of 6-keto-prostaglandin F1alpha were markedly increased in rats after the administration of LPS and significantly decreased in the LPS-treated rats administered Trp49-modified AT III, but not altered in those LPS-treated rats receiving AT III. Preventive effects of AT III were not observed in rats pretreated with indomethacin, which inhibits prostacyclin biosynthesis. Prostacyclin prevents LPS-induced pulmonary vascular injury by inhibiting leukocyte accumulation in the lungs. These observations strongly suggest that AT III prevents pulmonary vascular injury induced by LPS by promoting the endothelial release of prostacyclin, a potent inhibitor of leukocyte activation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anticoagulants; Antithrombin III; Blood Coagulation Disorders; Drug Evaluation, Preclinical; Endothelium, Vascular; Leukocyte Elastase; Leukocytes; Leukopenia; Lipopolysaccharides; Lung; Male; Mechlorethamine; Rats; Rats, Wistar; Serine Proteinase Inhibitors

This study was designed to examine haemodynamic and haematologic effects of the crown-of-thorns starfish venom (Acanthaster planci venom: APV) in dogs. Severe systemic hypotension, thrombocytopenia and leukopenia were induced by APV (1.0 mg protein/kg i.v.), followed by gradual return to the baseline level within 60 min. Hypotension was presumably caused by two factors: an early decrease in systemic vascular resistance and the large reduction in cardiac output due to reduced ventricular filling. Indomethacin, a cyclooxygenase inhibitor, remarkably suppressed systemic hypotension induced by APV. The peak reduction in systemic pressure was associated with concomitant rise of plasma 6-keto-PGF1 alpha, a major stable metabolite of prostacyclin. Thus, the hypotensive effect of APV may be caused primarily by prostacyclin and/or some vasodilating prostaglandins. In contrast, thrombocytopenia and leukopenia were not affected by cyclooxygenase inhibitor, 5-lipoxygenase inhibitor or platelet activating factor (PAF) receptor antagonist. When APV was administered repeatedly, tachyphylaxis was developed in haemodynamic effects, but not in haematologic effects. These findings suggest that APV-induced hypotensive effects may occur mainly through endogenous production of vasodilating prostaglandins including prostacyclin, although APV-induced thrombocytopenia and leukopenia may be caused by other mechanism(s) unrelated to arachidonate metabolites and/or PAF.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Cells; Blood Pressure; Cardiac Output; Cyclooxygenase Inhibitors; Dogs; Dose-Response Relationship, Drug; Female; Hemodynamics; Hypotension; Indomethacin; Injections, Intravenous; Leukopenia; Lipoxygenase Inhibitors; Male; Platelet Activating Factor; Starfish; Tachyphylaxis; Thrombocytopenia; Vascular Resistance; Venoms

Because certain inflammatory processes are dependent on the fatty acid composition of the cellular membrane, dietary manipulations that replace omega-6 fatty acids with omega-3 fatty acids may modify inflammatory responses. We investigated the effect of supplemental dietary linseed oil, containing the omega-3 fatty acid, alpha-linolenic acid, on in vivo responses of horses to endotoxin. One group of horses (n = 6) was fed a control pelleted ration (0% linseed oil), and another group of horses (n = 6) was fed an 8% linseed oil pelleted ration. After 8 weeks of consuming these rations, all horses were given 0.03 micrograms of Escherichia coli 055:B5 endotoxin/kg of body weight, infused over 30 minutes. Horses were monitored over 24 hours. Compared with baseline values within each ration group, endotoxin infusion caused significant (P less than 0.05) increase in rectal temperature, heart rate, and plasma concentration of thromboxane B2, 6-keto-prostaglandin F1 alpha, and fibrinogen and significant (P less than 0.05) decrease in total WBC count. Compared with baseline values within each ration group, endotoxin infusion failed to cause significant changes in prothrombin, activated partial thromboplastin, thrombin, or whole blood recalcification times, serum concentration of fibrin degradation products, PCV, or plasma total protein concentration. Before and after endotoxin infusion, horses given the linseed oil ration had longer mean whole blood recalcification time and activated partial thromboplastin time than did horses fed the control ration.

Topics: 6-Ketoprostaglandin F1 alpha; alpha-Linolenic Acid; Animal Feed; Animals; Blood Coagulation; Dietary Fats, Unsaturated; Endotoxins; Escherichia coli; Fatty Acids, Omega-3; Female; Horse Diseases; Horses; Leukopenia; Linolenic Acids; Linseed Oil; Male; Random Allocation; Thromboxane B2

Splanchnic artery occlusion shock was induced in anesthetized rats by clamping the splanchnic arteries for 45 min. The survival rate, plasma levels of thromboxane B2 (TxB2) and 6-keto-PGF1 alpha, serum and peritoneal levels of macrophage tumor necrosis factor (TNF alpha), the phagocytotic and killing activity of peritoneal macrophages and white blood cells count were evaluated. Shocked rats died within 2 h, while all sham-shocked rats survived more than 6 h. Plasma TxB2 and 6-keto-PGF1 alpha levels were increased in rats subjected to splanchnic artery occlusion shock compared to the levels in sham-shocked animals. Serum and peritoneal macrophage TNF alpha levels were undetectable in sham-shocked rats, whereas shocked rats exhibited increased levels of TNF alpha. Moreover, splanchnic artery occlusion shock reduced peritoneal macrophage phagocytotic and killing activity, and also produced severe leukopenia. A specific receptor antagonist of platelet activating factor (PAF), L-652, 731 (an i.v. bolus of 3.2 mg/kg 2 min after removal of the clamps followed, 5 min thereafter, by a continuous infusion of 0.16 mg/kg per min for 30 min) significantly increased the survival rate, lowered plasma TxB2 levels and reduced both serum and macrophage TNF alpha levels in shocked rats. In addition, L-652,731 completely restored macrophage phagocytosis, partially improved macrophage killing and significantly inhibited leukopenia. Finally, the administration of L-652,731 had beneficial effects on the cardiovascular changes induced by splanchnic artery occlusion shock. These findings are consistent with the involvement of PAF in splanchnic artery occlusion shock and indicate that PAF produces shock through direct and indirect (TxB2-mediated and TNF alpha-mediated) actions.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arterial Occlusive Diseases; Blood Pressure; Furans; Leukocyte Count; Leukopenia; Macrophages; Male; Phagocytosis; Platelet Activating Factor; Radioimmunoassay; Rats; Rats, Inbred Strains; Shock; Splanchnic Circulation; Thromboxane B2; Tumor Necrosis Factor-alpha

Diethylcarbamazine (DEC) is an inhibitor of lipoxygenase, with protective effects in several experimental models of anaphylaxis and lung dysfunction. The hypothesis of this study was that DEC would alter the pulmonary response to endotoxin infusion, especially the prolonged pulmonary hypertension, leukopenia, hypoxemia, and high flow of protein-rich lung lymph. We prepared sheep for chronic measurements of hemodynamics and collection of lung lymph. In paired studies we gave six sheep endotoxin (0.5 micrograms/kg iv) either with or without DEC. DEC was given (80-100 mg/kg iv) over 30 min followed by a continuous infusion at 1 mg X kg-1 X min-1. Endotoxin was given after the loading infusion of DEC, and variables were monitored for 4 h. The response to endotoxin was characterized by pulmonary hypertension, leukopenia, hypoxemia, and elevations of thromboxane B2 and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha). Lymph flow and protein content reflected hemodynamic and permeability changes in the pulmonary circulation. DEC did not significantly modify the response to endotoxin by any measured variable, including pulmonary arterial and left atrial pressures, cardiac output, lymph flow and protein content, alveolar-to-arterial PO2 difference, blood leukocyte count, and lymph thromboxane B2 and 6-keto-PGF1 alpha. We could not find evidence of release of leukotriene C4/D4 by radioimmunoassay in lung lymph after endotoxin infusion with or without DEC treatment. We conclude that lipoxygenase products of arachidonic acid may not be a major component of the pulmonary vascular response to endotoxin.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Diethylcarbamazine; Endotoxins; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Leukopenia; Lung; Lymph; Pulmonary Circulation; Sheep; SRS-A; Thromboxane B2