iloprost 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

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

To investigate whether iloprost, a stable analog of prostacyclin, is useful for the prevention of posttraumatic spinal cord injury, we examined its effects on compression trauma-induced spinal cord injury in rats. Spinal cord injury was induced by applying a 20-g weight for 20 minutes to the spinal cord at the level of T-12, resulting in motor disturbances in the hindlimbs. These motor disturbances, evaluated using Tarlov's index, were markedly attenuated in rats with nitrogen mustard-induced leukocytopenia. Administration of iloprost also attenuated the motor deficits. Histological examination revealed that intramedullary hemorrhages observed 24 hours after trauma were significantly attenuated in leukocytopenic animals and in animals that received iloprost. The accumulation of leukocytes at the site of trauma, evaluated by measuring tissue myeloperoxidase activity, significantly increased with time following the trauma, peaking at 3 hours postinjury. Spinal cord myeloperoxidase activity in sham-operated animals did not increase postoperatively. Leukocyte depletion and administration of iloprost reduced the accumulation of leukocytes in the damaged spinal cord segment 3 hours posttrauma. These findings indicate that iloprost attenuates motor disturbances induced by spinal cord trauma and that its therapeutic efficacy can be partly explained by its inhibition of leukocyte accumulation at the traumatized site.

Topics: Animals; Epoprostenol; Iloprost; Leukopenia; Male; Mechlorethamine; Peroxidase; Rats; Rats, Wistar; Spinal Cord; Spinal Cord Injuries; Wounds, Nonpenetrating

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