and/or aims): Ethanol ingestion is known to produce gastric mucosal injury which appears to involve, as an initial event, engorgement and disruption of the microvasculature. Although the mechanisms by which luminal ethanol produces gastric mucosal injury are unclear, several factors have been implicated: products of arachidonate metabolism, oxygen derived free radicals, and mast cell secretions. Since all of these factors are involved in the inflammatory response, the main objective of this proposal is to fully characterize the role of neutrophils in the ethanol-induced injury to the gastric mucosa. To this end, an in vivo model of ethanol-induced gastritis has been developed which involves perfusing the gastric lumen with ethanol at concentrations that mimic those observed in man during acute intoxication. The leakage of chromium-51 ethylenediaminotetraacetate (51Cr-EDTA) from the circulation into the gastric lumen will be used to quantitate mucosal integrity. Using this model, the role of neutrophils in ethanol injury will be assessed by determining whether: 1) mucosal neutrophil infiltration occurs during ethanol perfusion and 2) antineutrophil serum offers protection against ethanol-induced injury. In addition, the effects of ethanol on neutrophil adherence to gastric microvascular endothelial cells, as well as their ability to injure the endothelial cell, will be assessed in vitro using isolated neutrophils and endothelial cells in culture. Neutrophil adherence and endothelial cell injury will be quantitated using 51Cr-labelled neutrophils and endothelial cell monolayers, respectively. The mechanisms of neutrophil-mediated injury will be studied in vivo and in vitro using scavengers of oxygen-derived metabolites and inhibitors of neutrophil-derived proteases. The studies outlined in this proposal will allow a more comprehensive model of the role of neutrophils in the pathogenesis of ethanol-induced gastritis. The information obtained is expected to provide a basis for potential therapeutic intervention in preventing or ameliorating the gastric mucosal injury caused by ethanol ingestion.
