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.
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