MEDIATORS OF INTESTINAL ISCHEMIA

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Intestinal ischemia due to vascular occlusion, vasospasm, or chronic inflammation is a major gastrointestinal disorder that results in significant morbidity and accounts for about 4% of deaths in this country. Although much work has been devoted to intestinal ischemic disorders, little is known about the underlying mechanisms involved in the pathogenesis of the disease. Furthermore, clinical diagnosis of intestinal ischemia may be missed or discovered at an irreversible stage of the disease resulting in massive resection of intestinal tissue. Since small intestinal allotransplantation could be a viable therapy in these settings and would require adequate preservation strategies, scientific investigation into intestinal ischemia and hypothermic intestinal preservation is warranted. This proposal investigates the role of local inflammatory mediators in intestinal ischemia and their effects on intestinal function through biochemical physiologic, and pharmacologic studies. Also, the production of lipid mediators by intestinal tissue subjected to hypothermic preservation and subsequent reperfusion (autotransplantation) is investigated. Close monitoring of intestinal function (nutrient absorption, blood flow, microcirculation) will allow elucidation of the functional derangements as well as possible benefits of pharmacologic intervention in intestinal tissue subjected to warm ischemia-reperfusion injury and cold ischemia-reperfusion injury (hypothermic preservation). A dog model of intestinal ischemia-reperfusion injury and intestinal organ preservation is used. Arachidonate metabolism and Platelet Activation Factor (PAF) production is elucidated (immunologic and GC/MS assays) in these models concurrent with intestinal functional studies (nutrient absorption and circulatory regulation) and compared to values obtained from normal intestinal tissue. The accumulation of toxic acyl-CoA esters during hypothermic and normothermic ischemia is monitored by HPLC. In-vitro determinations of mucosal metabolism (adenine, nucleotides, 02, glutathione) is determined during hypothermic ischemia with and without experimental preservation solutions and techniques. Intestinal neutrophil infiltration during normothermic and hypothermic . ischemia is monitored by tissue myeloperoxidase content. It is anticipated that dramatic alterations in eicosanoids, PAF, and other lipid metabolites by intestinal tissue during ischemia-reperfusion injury will correlate with functional decline. Also, rational pharmacologic intervention directed at arachidonate metabolism, PAF synthesis, oxygen free radicals, and lipid acyl-CoA esters should preserve intestinal function during warm and cold ischemia. This proposal is a broad investigation into the pathophysiologic mechanisms of severe intestinal ischemia and a study directed at exploring the local mechanisms of intestinal preservation-reperfusion injury.