Activated neutrophils impair gastric cytoprotection - Role of neutrophil elastase

Neutrophil elastase decreases production of PGI(2) by cultured endothelial cells. Thus, neutrophil elastase may play an important role in gastric muco sal injury by decreasing he tissue level of PGI(2), an important gastric cy toprotective substance. We examined whether activated neutrophils inhibit g astric PGI(2) production in rats subjected to water-immersion restraint str ess. Gastric 6-keto-PGF(1 alpha) levels were determined by enzyme immunoass ay. Gastric mucosal blood how was determined by laser-Doppler flowmeter, Ga stric microvascular permeability was determined by Evans blue leakage. Gast ric levels of 6-keto-PGF(1 alpha) were transiently increased 0.5 hr after t he stress, followed by a decrease to below baseline at 6 hr, when mucosal b lood flow fell to 60% of baseline. Gastric levels of 6-keto-PGF(1 alpha) we re significantly higher in animals with nitrogen mustard-induced leukocytop enia than in controls 1 and 6 hr after the stress. In leukocytopenic animal s, levels 6 hr after stress were not lower than those preceding stress, Leu kocytopenia markedly limited both the decrease in mucosal blood flow and th e increase in gastric microvascular permeability. The level of gastric muco sal injury observed 6 hr after the stress was markedly attenuated by leukoc ytopenia. Pretreatment with neutrophil elastase inhibitors (ONO-5046 and Eg lin C) or an anti-P-selectin monoclonal antibody produced effects similar t o leukocytopenia. Neutrophil elastase is involved in the stress-induced gas tric mucosal injury by decreasing gastric production of PGI(2). Thus, pharm acologic inhibition of neutrophil elastase should help to prevent stress-in duced gastric mucosal injury.