Hepatobiliary physiology and disease are intimately related to eicosanoid metabolism. The production of cholecystitis occurring in the presence and absence of gallstones is associated with increased prostanoid formation. In experimental models of cholecystitis, cyclooxygenase inhibitors decrease gallbladder inflammation. Acute acalculous cholecystitis occurring in humans may be mediated by prostanoids, and recent information suggests that systemic factors associated with shock such as platelet activating factors are capable of inducing cholecystitis through a prostanoid mediated process. The distention of the gallbladder associated with acute cholecystitis may be related to epithelial cell water secretion produced by afferent nerve stimulation through a prostanoid mediated process. The prostanoids are involved in painful gallbladder contraction and cyclooxygenase inhibitors are the analgesic agents of choice in treating bilary tract pain. Experiments will be performed utilizing an in vivo tonometer to evaluate gallbladder contraction to determine the eicosanoids and specific antagonists which would be expected to relieve gallbladder pain. In cholecystitis, water absorption is eliminated and mucosal mucus and protein secretion occurs. Utilizing feline and human gallbladder explants in tissue culture, it is intended to separate out the various eicosanoids which mediate and which inhibitors prevent these three processes. The relationship of the possible changes in gallbladder blood flow to alterations in fluid transport and mucin and protein secretion will be evaluated by determining the effect of the vasoactive eicosanoids on gallbladder blood flow. These studies will produce correlative information concerning the role that gallbladder blood flow changes play in the functional changes found associated with experimental cholecystitis. Lysophospholipids and eicosanoids contribute to gallstone formation and cholecystitis. A common factor in the control of lysophosphatidylcholine and eicosanoid formation is the activity of the mucosal enzyme, phospholipase A2. We will evaluate the role of this enzyme in the production of gallstones and the development of cholecystitis. Promising therapeutic modalities to treat gallbladder diseases are likely to become available through continued pursuit of a better understanding of eicosanoid metabolism in gallbladder tissue.
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