Involvement of TNF-alpha in Intestinal Inflammation in a Model of Colitis

$0S06FY2001GMNIH

Ponce School Of Medicine, Ponce PR

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Abstract

Description (provided by applicant): Ailments of the gastrointestinal tract are often very debilitating yet despite decades of research, the basic pathogenic mechanisms involved in inflammatory bowel diseases (IBD) are unknown with no cure for diseases such as Crohn?s and Ulcerative Colitis. Until now the lack of a clinically relevant animal model which mimics the periods of remission and relapse seen in the human condition has limited our understanding of the disease pathogenesis. The recent development of a "reactivated" model of colitis represents a more realistic model for the study of colitis-induced inflammation and ulceration. Previous investigations have shown significantly increased levels of inflammatory mediators in inflammatory bowel disease (IBD). This has led to the suggestion that cytokines, prostaglandins and leukotrienes may play an important role in the pathogenesis of IBD. Recent data suggest that the proinflammatory mediator tumor necrosis factor alpha (TNF-alpha) may be a key player in thc inflammatory process. Three sets of experiments will test this central hypothesis: (1) Absolute levels of TNF-alpha will be measured in a reactivated animal model of colitis and the possible cellular source will be investigated (hypothesis: TNF-alpha levels are increased in periods of relapse and inflammation in inflammatory bowel disease). (2) The underlying mechanism of action of TNF-alpha will be characterized by the administration of various inhibitors, drugs or antibodies (hypothesis: involvement of TNF-alpha in this reactivated model of colitis is an essential step in the inflammatory process and resultant ulceration; moreover this is regulated by the nuclear transcription factor kappa beta, NF-kB). (3) The effect of TNF-alpha on ion transport will be investigated using Ussing chambers (hypothesis: TNF-alpha contributes to the pathogenesis of one of the major symptoms of IBD, diarrhea). This research will advance our understanding of the cytokine network and interactions involved in inflammatory bowel disease. It will provide new avenues for potential therapeutic intervention and, ultimately, offer a preferable alternative to the pharmacologic agents and surgical procedures currently employed.

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