We propose to assess the involvement of oxygen derived free radicals in ischemic injury to the intestines. Particular emphasis will be placed on the role of oxygen radicals in causing the increased vascular permeability and mucosal lesions associated with reperfusion of the ischemic intestine. Our hypothesis is that ischemia triggers the conversion of xanthine dehydrogenase to the superoxide radical producing xanthine oxidase via a calcium regulated protease. Concomitantly, cellular ATP is catabolized under hypoxic conditions to hypoxanthine. Upon reperfusion and reoxygenation, a burst of superoxide production results from the oxidation of accumulated hypoxanthine by xanthine oxidase. We propose to determine: 1) whether leukocytes are a source of oxygen radicals in the ischemic bowel, 2) what proportion of ischemic injury occurs during the ischemic period and following reperfusion, 3) whether reperfusion injury can be attenuated by limiting the availability of oxygen to the parenchyma at the time of reperfusion, 4) whether the superoxide anion per se, hydrogen peroxide, or hydroxyl radicals are the primary mediators of the tissue injury induced by ischemia, 5) whether protease inhibitors or calcium blockers prevent or attenuate ischemic injury to the small bowel, and 6) whether aldehyde oxidase, another superoxide producing enzymes, plays a role in ischemic injury to the colon. The proposed studies should improve our understanding of the role of oxygen derived free radicals in the pathogenesis of ischemic injury to the intestines.
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