We propose to further assess the role of oxygen-derived free radicals in ischemia/reperfusion injury to the small intestine. The proposed studies will focus on the contribution of neutrophils to ischemia/reperfusion (I/R)-induced tissue injury. Our working hypothesis is that ischemia triggers the conversion of xanthine dehydrogenase to the oxy-radical producing xanthine oxidase. Concomitantly, cellular ATP is catabolized under the hypoxic condition to hypoxanthine. Upon reperfusion (reoxygenation) a burst of superoxide, hydrogen peroxide, and hydroxyl radical results from the oxidation of hypoxanthine by xanthine oxidase. The oxy-radicals formed by xanthine oxidase mediate tissue injury via two mechanisms: 1) by directly reacting with cellular and interstitial components to initiate lipid peroxidation and other processes that lead to cellular necrosis, and 2) by triggering the infiltration of neutrophils, which, in turn, mediate injury by both oxidative and non-oxidative (e.g., proteases) processes. The proposed studies will utilize microvascular permeability and mucosal lesion development as indices of tissue injury and intravital microscopic techniques to monitor neutrophil- endothelial cell interactions in vivo. We plan to determine whether: 1) xanthine oxidase inhibition or inactivation modifies ischemia-induced neutrophil infiltration, 2) superoxide-dependent chemoattractants initiate neutrophil infiltration, 3) depletion of circulating neutrophils (with antineutrophil serum) ameliorates I/R-induced tissue injury and 4) neutrophil adherence to microvascular endothelium plays a role in I/R-induced tissue injury. We also propose to develop a model that will allow for assessment of neutrophil-mediated injury in the absence of ischemia. The proposed studies should improve our understanding of the role of oxidants as mediators of cell injury in the gastro- intestinal tract.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033594-07
Application #
3232008
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1984-04-01
Project End
1992-11-30
Budget Start
1990-12-20
Budget End
1991-11-30
Support Year
7
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Type
Schools of Medicine
DUNS #
City
Shreveport
State
LA
Country
United States
Zip Code
71103
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Benoit, J N; Grisham, M B; Mesh, C L et al. (1992) Hepatic oxidant and antioxidant systems in portacaval-shunted rats. J Hepatol 14:253-8

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