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Disruption of gallbladder smooth muscle function is an early feature in the development of cholesterol gallstone disease
Author(s) -
Lavoie B.,
Nausch B.,
Zane E. A.,
Leonard M. R.,
Balemba O. B.,
Bartoo A. C.,
Wilcox R.,
Nelson M. T.,
Carey M. C.,
Mawe G. M.
Publication year - 2012
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/j.1365-2982.2012.01935.x
Subject(s) - contractility , medicine , endocrinology , gallbladder , carbachol , cholesterol , contraction (grammar) , inflammation , cholecystitis , agonist , bile duct , basal (medicine) , biology , receptor , diabetes mellitus
Background Decreased gallbladder smooth muscle (GBSM) contractility is a hallmark of cholesterol gallstone disease, but the interrelationship between lithogenicity, biliary stasis, and inflammation are poorly understood. We studied a mouse model of gallstone disease to evaluate the development of GBSM dysfunction relative to changes in bile composition and the onset of sterile cholecystitis. Methods BALB/cJ mice were fed a lithogenic diet for up to 8 weeks, and tension generated by gallbladder muscle strips was measured. Smooth muscle Ca 2+ transients were imaged in intact gallbladder. Key Results Lipid composition of bile was altered lithogenically as early as 1 week, with increased hydrophobicity and cholesterol saturation indexes; however, inflammation was not detectable until the fourth week. Agonist‐induced contractility was reduced from weeks 2 through 8. GBSM normally exhibits rhythmic synchronized Ca 2+ flashes, and their frequency is increased by carbachol (3 μ m ). After 1 week, lithogenic diet‐fed mice exhibited disrupted Ca 2+ flash activity, manifesting as clustered flashes, asynchronous flashes, or prolonged quiescent periods. These changes could lead to a depletion of intracellular Ca 2+ stores, which are required for agonist‐induced contraction, and diminished basal tone of the organ. Responsiveness of Ca 2+ transients to carbachol was reduced in mice on the lithogenic diet, particularly after 4–8 weeks, concomitant with appearance of mucosal inflammatory changes. Conclusions & Inferences These observations demonstrate that GBSM dysfunction is an early event in the progression of cholesterol gallstone disease and that it precedes mucosal inflammation.