Disorders of gallbladder function are important health concerns, since marked gallbladder motor dysfunction is seen in both acute and chronic cholecystitis. This proposal will utilize common bile duct ligation in the guinea pig (as a model of acute acalculous cholecystitis) to examine the hypothesis that the effects of local inflammatory mediators during early cholecystitis alter gallbladder muscarinic receptor subtype expression and the downstream signal transduction mechanisms responsible for gallbladder contraction. The initial focus of this proposal is to determine the role of muscarinic receptor subtypes and their signal transduction pathways on normal gallbladder contraction. The second major focus of this proposal is to delineate the effects of acute inflammation and inflammatory mediators (eicosanoids, cytokines) on gallbladder muscarinic receptor subtypes and the transduction of external signals. This proposal will provide insight into both the pathophysiology of acute cholecystitis and the general mechanisms involved in decreasing gallbladder contractility during initiation of acute gallbladder inflammation. The results from the proposed studies will identify future studies on ways to prevent the motor dysfunction that occurs with gallbladder inflammation.
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