Disruption of gallbladder smooth muscle function is an early feature in the development of cholesterol gallstone disease

Authors


  • Current addresses: B. Nausch, University of Calgary, Calgary, AB, Canada.
    O. B. Balemba, University of Idaho, Moscow, ID, USA.
    A. C. Bartoo, Medtronics, Minneapolis, MN, USA.

Address for Correspondence
G. M. Mawe, Department of Anatomy and Neurobiology, University of Vermont College of Medicine, 89 Beaumont Ave., Burlington, VT 05405, USA.
Tel: 802 656 8257; fax: 802 656 8704;
e-mail: gary.mawe @uvm.edu

Abstract

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 Ca2+ 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 Ca2+ flashes, and their frequency is increased by carbachol (3 μm). After 1 week, lithogenic diet-fed mice exhibited disrupted Ca2+ flash activity, manifesting as clustered flashes, asynchronous flashes, or prolonged quiescent periods. These changes could lead to a depletion of intracellular Ca2+ stores, which are required for agonist-induced contraction, and diminished basal tone of the organ. Responsiveness of Ca2+ 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.

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