Cholecystitis and colitis are inflammatory disorders which occur spontaneously and in response to a variety of stimuli. It is important to improve our understanding of why these epithelial inflammatory processes occur and to attempt to identify mechanisms to prevent and treat the disorders. Previous studies have demonstrated that cyclooxygenase inhibitors are specific drugs for the treatment of gallbladder disease. Gallbladder and colonic epithelial cells respond to inflammatory agents with specific alterations in production of prostanoids and platelet- activating factor, indicating that these cells have significant phospholipase A2 and cyclooxygenase activity. Stimulated by inflammatory agents, gallbladder epithelial cells produce 14 kDa phospholipase A2 and 72 kDa cyclooxygenase-2. ln-vivo exposure of animal gallbladders to various inflammatory stimuli results in mucosal cell necrosis. In-vitro, the inflammatory stimuli produce production of inflammatory mediators, however, these inflammatory stimuli and mediators in tissue culture media have no effect on cell integrity. The proposed research will be directed at evaluating the involvement of and interaction of epithelial cells, adhesion molecules, and leukocytes in mucosal cell necrosis. The relationships of mucosal cell inflammatory processes to eicosanoid formation is complex. Evaluation of the formation and control of the rate limiting enzymes cyclooxygenase- l, and cyclooxygenase-2 in these cell systems will increase our understanding of the role of the eicosanoids in cholecystitis and colitis. The production of the inflammatory mediator, platelet-activating factor by mucosal cells from the gallbladder and colon indicates that the cells have significant phospholipase A2 activity. Understanding of the mechanisms of epithelial cell inflammatory disorders will require improved understanding of the induction and expression of the secretory type II 14-kDa phospholipase A2 and 85-kDa arachidonyl selective type IV phospholipase A2. Protein production by mucosal cells occurs in response to inflammatory stimuli. We intend to evaluate the factors controlling protein production and to characterize the specific proteins produced. Epithelial inflammatory disorders may predispose the gallbladder mucosal cells and colonocytes to malignant transformation. We will evaluate the role of cyclooxygenase-2 in epithelial cell mitogenesis. The above described research will contribute to improved understanding of the mechanisms of the development of cholecystitis and colitis and provide information to assist in the development of preventative and therapeutic agents for these important clinical disorders.
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