Many factors probably contribute to inflammatory bowel disease (IBD). Intestinal epithelial dells interact with the outside environment as well as with gut immune cells and neurons. This epithelia merits attention both as a source of and target for inflammatory mediators. Among the mediators which are increased in IBD are eicosanoids (metabolites of arachidonic acid). These compounds not only possess potent direct effects but are also implicated in the activities of PAF, interleukin 1 and neuropeptides. Preliminary data shows that pure populations of cultured colonic epithelial cells respond to the inflammatory mediators BK and fMLP by releasing eicosanoids. The objectives of this study are to exploit these previously unavailable purified populations of cultured intestinal epithelial cells and extend these findings to other intrinsic and foreign inflammatory mediators. The specific goals of this proposal are to evaluate the effects on eicosanoid synthesis of purified, exogenously added agents known to be products of luminal bacteria, mucosal mast cells, lymphocytes or intestinal neuropeptides, or other mediators known to be increased in IBD. The effects of these agents will be assessed first upon the colonic epithelial cell eicosanoid release by radioimmunoassay, radiochromatographic and bioassay measurements. The effects will be further characterized as to dose dependency (to confirm their potential for a more than pharmacological effect), the time course of the reaction, and the profile of eicosanoid products released (some eicosanoids are potentially """"""""cytoprotective"""""""" while others may contribute more the inflammation). These findings will be extended to other mucosal cells including fibroblasts (a frequent contaminant of unpurified mucosal preparations) and immune cells of the lamina propria. Because of their potential usefulness for functional studies, intestinal epithelial cell lines will also be assessed. Identifying mediators from different cell sources which affect the epithelial eicosanoid response will aid in delineating the cellular interactions which contribute to the pathophysiology of chronic inflammatory diseases such as IBD>

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Los Angeles County Harbor-UCLA Medical Center
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LeDuc, L E; McRoberts, J A; Vidrich, A (1994) Eicosanoid production by a differentiated canine colonic epithelial cell line, VNCC. Gastroenterology 106:297-305
LeDuc, L E; Su, K C; Guth, E et al. (1993) Effects of cyclooxygenase and lipoxygenase inhibition on eicosanoids and healing of acetic acid colitis in rats. Dig Dis Sci 38:289-94