The pathogenesis of cholesterol gallstone disease, a major public health concern in the United States, remains poorly understood in spite of several decades of intense study. Secretion of lithogenic bile by the liver, alterations in the bile salt pool, changes in the absorptive function of the gallbladder epithelium or an increase in mucus secretion and gallbladder stasis all have been suggested as etiologic factors. The experiments outlined in this proposal are directed at the last possibility: that gall bladder statsis plays a key and possibly initiating role in the process. These studies are designed to evaluate the changes that occur in gallbladder smooth muscle contractility during the development of cholesterol gallstones in the cholesterolfed prairie dog. The main HYPOTHESIS being tested is that a condition that predisposes to cholesterol gallstone formation (the feeding of a diet high in cholesterol) causes biochemical changes in gallbladder smooth muscle that lead to a decrease in contractility and are selective for the gallbladder.
The SPECIFIC AIMS directed at testing this hypothesis are: (1) to determine the nature and time course of the changes in contractility of the gallbladder smooth muscle, 2) to determine if the changes in contractility are specific to gallbladder smooth muscle, and 3) to determine the mechanism(s) of the changes in contractility induced by feeding a diet high in cholesterol. Gallbladder, intestinal, and vascular smooth muscle will be evaluated. Function will be determined in vitro by assessing the force of isometric contractions of muscle strips that are either intact or made permeable to calcium by treatment with detergent. The level of phosphorylation of the 20,000 dalton light chains of myosin in the smooth muscle will be measured to determine the biochemical mechanism of changes in contractility. The mechanisms responsible for changes in contractility will be assessed by diverting bile from the gallbladder and mechanically increasing resistance to bile flow. The role of inflammation will be monitored by measuring levels of peroxidase in the wall of the gallbladder. Functional and biochemical parameters will be correlated with changes in bile composition and the formation of gallstones in order to discern if changes in gallbladder contractility can be implicated in the pathogenesis of gallstone disease.
