The goal of this project is to better define the chemical mediators of inflammation in intestinal inflammation and especially in inflammatory bowel disease. Of particular interest are the lipoxygenase products, a group of arachidonate metabolites formed by neutrophils and other cell types and known to have proinflammatroy properties. Preliminary data indicate that inflamed mucosa from inflammatory bowel disease patients converts exogenous arachidonate to leukotriene B4, a lipoxygenase product which is chemotactic for neutrophils. One of the specific aims of this project is the comparison of the metabolism of endogenous and exogenous arachidonate by normal and inflamed colonic mucosa from humans (inflammatroy bowel disease and normals) and animal models of inflammation.
Other aims i nclude the characterization of the effects of lipoxygenase products on intestinal histology a microvascular permeability and the definition of the contribution of lipoxygenase products to intestinal inflammation in inflammatory bowel disease and animal models of inflammation. Total chemotactic activity in inflamed mucosa will be measured and the contribution of lipoxygenase products to the chemotactic activity determined. The effects of drugs on the production of lipoxygenase products in inflamed mucosa will be determined. Information derived from this study should contribute to our understanding of how the inflammatory response is amplified and modulated in inflammatory bowel disease and give new insight into the mechanisms of action of the drugs used to treat infalammatory bowel disease. This study may also suggest new approaches to the pharmacologic manipulation of the inflammatory response in this disease.
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