We propose to assess the role of reactive oxygen metabolites (ROM) in mediating mucosal injury using an experimental model of ulcerative colitis in rats. Although the sources of superoxide radical, hydrogen peroxide and hydroxyl radical in the colon have not been identified, certain mucosal oxidases as well as resident and inflammatory phagocytic leukocytes (macrophages, neutrophils, eosinophils) are primary candidates. We suggest that active episodes of ulcerative colitis are associated with enhanced production of FOM that may injure the mucosa directly and/or may recruit inflammatory leukocytes into the tissue, where phagocyte-derived oxidants mediate and/or exacerbate mucosal injury. In order to test this hypothesis we intend to: 1) characterize the various oxidases (xanthine oxidase, aldehyde oxidase, lipoxygenase, prostaglandin synthetase) known to occur in high concentrations in the colonic mucosa, 2) determine the role of these oxidases in producing reactive oxygen metabolites in normal and inflamed colons, 3) determine the role of endogenous iron-containing compounds in catalyzing the formation of cytotoxic oxidants in vivo, 4) investigate the role of neutrophils in mediating and/or exacerbating mucosal injury, 5) quantitate the antioxidant defenses in both normal and inflamed colons, and 6) investigate the effect of exogenously administered antioxidant enzymes and scavengers on mucosal damage produced during active episodes of colitis. Information obtained from these studies may provide a better understanding of the biochemical mechanisms involved in mucosal injury in ulcerative colitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DK039168-03
Application #
3463069
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1988-05-01
Project End
1993-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
3
Fiscal Year
1990
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
Yamada, T; Sartor, R B; Marshall, S et al. (1993) Mucosal injury and inflammation in a model of chronic granulomatous colitis in rats. Gastroenterology 104:759-71
Grisham, M B; Ware, K; Marshall, S et al. (1992) Prooxidant properties of 5-aminosalicylic acid. Possible mechanism for its adverse side effects. Dig Dis Sci 37:1383-9
Arndt, H; Kubes, P; Grisham, M B et al. (1992) Granulocyte turnover in the feline intestine. Inflammation 16:549-59
Yamada, T; Fujimoto, K; Tso, P et al. (1992) Misoprostol accelerates colonic mucosal repair in acetic acid-induced colitis. J Pharmacol Exp Ther 260:313-8
Yamada, Y; Marshall, S; Specian, R D et al. (1992) A comparative analysis of two models of colitis in rats. Gastroenterology 102:1524-34
Harris, M L; Schiller, H J; Reilly, P M et al. (1992) Free radicals and other reactive oxygen metabolites in inflammatory bowel disease: cause, consequence or epiphenomenon? Pharmacol Ther 53:375-408
Grisham, M B; Ware, K; Gilleland Jr, H E et al. (1992) Neutrophil-mediated nitrosamine formation: role of nitric oxide in rats. Gastroenterology 103:1260-6
Grisham, M B; Yamada, T (1992) Neutrophils, nitrogen oxides, and inflammatory bowel disease. Ann N Y Acad Sci 664:103-15
Grisham, M B; Volkmer, C; Tso, P et al. (1991) Metabolism of trinitrobenzene sulfonic acid by the rat colon produces reactive oxygen species. Gastroenterology 101:540-7
Yamada, T; Grisham, M B (1991) Role of neutrophil-derived oxidants in the pathogenesis of intestinal inflammation. Klin Wochenschr 69:988-94

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