MECHANISMS OF NITRIC OXIDE PROTECTION IN REPERFUSION INJURY

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Much of the microvascular dysfunction observed in ischemia and reperfusion (L/R) of the small intestine has been attributed to activated polymorphonuclear leukocytes (PMNs) that adhere in postcapillary venules and subsequently emigrate into the intestinal interstitium. Intravenous administration of certain enzymatic antioxidants (e.g. SOD, catalase) or monoclonal antibodies directed against the adhesion glycoproteins on PMNS or endothelial cells attenuates adhesion of PMNs to the venular endothelium and consequently attenuates the increase in microvascular permeability induced by I/R. These data suggest that leukocyte and/or endothelial cell- derived reactive oxygen species play a role in promoting adhesion of PMNs to venular endothelium which increases vascular permeability. Recent studies from several laboratories, including our own, have demonstrated that nitric oxide (NO) releasing compounds dramatically inhibit this I/R- induced PMN adhesion and microvascular dysfunction. Hypothesis: We propose that NO attenuates adhesion of PMNs to the post-ischemic endothelium by inhibiting superoxide (O2)-and/or hydrogen peroxide (H2O2)- dependent, iron-catalyzed reactions that promote the synthesis of proinflammatory mediators and increase the expression of adhesion molecules. In order to test this hypothesis, we propose the following specific aims; 1) Characterize the biochemical interactions among O2, H2O2 and NO in the absence or presence of redox-active iron complexes, 2) Determine the mechanism(s) by which NO attenuates anoxia/reoxygenation (A/R)induced oxidant production by venular endothelial cells, PMNs and /or platelets, 3) Determine the mechanisms by which NO attenuates A/R-induced PMN adhesion to endothelial cells in the absence or presence of platelets and 4) Identify the mechanisms by which NO attenuates A/R-induced increases in endothelial cell permeability int eh absence or presence of PMNs and/or platlets. The proposed studies will increase our understanding of the biochemical and cellular mechanisms that underlie the protective effects of NO in ischemia and reperfusion-induced injury in the intestine. Because of the growing interest in the use of No-releasing compounds as a potential therapeutic agents for ischemic disorders, such as occlusive vascular disease and organ transplantation, data obtained from these studies may prove useful in the design of new therapeutic agents for the treatment of these disorders.