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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033594-03
Application #
3232005
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1984-04-01
Project End
1987-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of South Alabama
Department
Type
Schools of Medicine
DUNS #
City
Mobile
State
AL
Country
United States
Zip Code
36688
Asako, H; Wolf, R E; Granger, D N (1993) Leukocyte adherence in rat mesenteric venules: effects of adenosine and methotrexate. Gastroenterology 104:31-7
Arndt, H; Kubes, P; Grisham, M B et al. (1992) Granulocyte turnover in the feline intestine. Inflammation 16:549-59
Asako, H; Kubes, P; Baethge, B A et al. (1992) Reduction of leukocyte adherence and emigration by cyclosporine and L683,590 (FK506) in postcapillary venules. Transplantation 54:686-90
Kubes, P; Hunter, J; Granger, D N (1992) Ischemia/reperfusion-induced feline intestinal dysfunction: importance of granulocyte recruitment. Gastroenterology 103:807-12
Bienvenu, K; Hernandez, L; Granger, D N (1992) Leukocyte adhesion and emigration in inflammation. Ann N Y Acad Sci 664:388-99
Zimmerman, B J; Anderson, D C; Granger, D N (1992) Neuropeptides promote neutrophil adherence to endothelial cell monolayers. Am J Physiol 263:G678-82
Asako, H; Wolf, R E; Granger, D N et al. (1992) Phalloidin prevents leukocyte emigration induced by proinflammatory stimuli in rat mesentery. Am J Physiol 263:H1637-42
Asako, H; Kubes, P; Wallace, J et al. (1992) Modulation of leukocyte adhesion in rat mesenteric venules by aspirin and salicylate. Gastroenterology 103:146-52
Fujimoto, K; Imamura, I; Granger, D N et al. (1992) Histamine and histidine decarboxylase are correlated with mucosal repair in rat small intestine after ischemia-reperfusion. J Clin Invest 89:126-33
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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