SURGICAL STUDIES ON GALLBLADDER INFLAMMATION

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Acute cholecystitis is a common disease that causes substantial morbidity and death. Current definitive treatment of acute cholecystitis continues to be surgical with medical treatment utilized only to stabilize patients prior to cholecystectomy. The overall long term objective of this proposal is to delineate the complex series of mechanisms that stimulate local gallbladder fibroblasts to increase eicosanoid release during the initiation of acute cholecystitis. Our long term goal is to establish medical treatment regimens that inhibit the specific eicosanoids released by the stimulated gallbladder fibroblasts to prevent or retard the initiation of acute cholecystitis. Rabbit common bile duct ligation (BDL, model of acute cholecystitis) will be utilized to examine the following specific aims: 1) To determine the trophic factors (altered biliary lipids, increased intra-gallbladder pressure) involved with the regulation of gallbladder eicosanoid synthesis during evolving acute inflammation; 2) To determine the molecular mechanisms regulating the increase synthesis and release of gallbladder eicosanoid following BDL; 3) To determine the intracellular pathways that contribute to the "up regulation" of the enzymes responsible for increased PGI2 in the 72-hour BDL cultures. The proposal will utilize several strategies to determine the role of gallbladder eicosanoids in the initiation of acute cholecystitis. The first strategy will examine the effects of increased intra-gallbladder pressure and altered biliary lipids on gallbladder mucosal histology and eicosanoid release. The second strategy will examine the molecular mechanisms responsible for increased gallbladder eicosanoid synthesis and release during the initiation of early cholecystitis. The third strategy will be to examine the role of intracellular second messengers on the regulation of the enzymes responsible for stimulated eicosanoid synthesis during the initiation and propagation of acute cholecystitis.