Cholesterol gallstone disease, a common problem in the United States, is characterized by the presence of lithogenic bile within the gallbladder lumen and biliary stasis. These are also critical factors in the pathogenesis of gallstones in the cholesterol fed prairie dog model. In this model, and perhaps in the human, there is a profound depression in contractility of the smooth muscle within the gallbladder wall. In prairie dogs, depressed contractility is seen as early as eight days after initiation of a 1.2% cholesterol diet, a time when cholesterol crystals but not stones are present in the bile. Contractility stays depressed during stone formation. It is likely that the depressed contractility is one of the factors responsible for bile stasis and stone formation. The depressed contractility is accompanied by, and perhaps due to, molecular and biochemical changes in the smooth muscle. There are shifts in the proportions of the alpha and gamma isoforms of actin, and decreases in the phosphorylation of the 20,000 dalton light chain of myosin. We propose to use molecular, biochemical, and functional techniques to further study changes that take place in gallbladder muscle from prairie dogs during development and during the resolution of stones. The attraction of mononuclear leukocytes into gallbladders of cholesterol-fed prairie dogs, and the depressed gallbladder muscle contractility induced by interleukin- 1beta suggest a role for cytokines in the gallbladder response. We propose to use molecular techniques to follow changes in the expression of interleukin-1, interleukin-6, and tumor necrosis factor during development and during the resolution of stones. We also propose to use similar techniques to study human gallbladders retrieved at cholecystectomy for symptomatic gallstones in order to determine by analogy to the prairie dog model the pathogenesis of human cholesterol gallstone disease. Understanding the role and the mechanism(s) of the decrease in gallbladder contractility may help to develop therapeutic strategies to prevent gallstone recurrence after treatment by non-surgical means, and to prevent stone occurrence in the first place in high risk patients. Also, study of the mechanisms of the depressed contractility in this model should add to our general understanding of gut smooth muscle physiology and pathophysiology.
