title: Disruption of gallbladder smooth muscle function is an early feature in the development of cholesterol gallstone disease.
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 Ca(2+) transients were imaged in intact gallbladder.
  
  
  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 μm). 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
  These observations demonstrate that GBSM dysfunction is an early event in the progression of cholesterol gallstone disease and that it precedes mucosal inflammation.
authors.affiliation: Department of Anatomy and Neurobiology, University of Vermont School of Medicine, Burlington, VT 05405, USA.
authors.forename: B
authors.initials: B
authors.lastname: Lavoie
authors.forename: B
authors.initials: B
authors.lastname: Nausch
authors.forename: E A
authors.initials: EA
authors.lastname: Zane
authors.forename: M R
authors.initials: MR
authors.lastname: Leonard
authors.forename: O B
authors.initials: OB
authors.lastname: Balemba
authors.forename: A C
authors.initials: AC
authors.lastname: Bartoo
authors.forename: R
authors.initials: R
authors.lastname: Wilcox
authors.forename: M T
authors.initials: MT
authors.lastname: Nelson
authors.forename: M C
authors.initials: MC
authors.lastname: Carey
authors.forename: G M
authors.initials: GM
authors.lastname: Mawe
mesh_terms: D000818:Animals; D001646:Bile / Q000737:chemistry*; D002764:Cholecystitis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D002769:Cholelithiasis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D002784:Cholesterol / Q000009:adverse effects*; D002791:Cholesterol, Dietary / Q000009:adverse effects; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D005704:Gallbladder / Q000473:pathology / Q000503:physiopathology; D042882:Gallstones / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D007150:Immunohistochemistry; D008055:Lipids; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000473:pathology / Q000503:physiopathology*
chemical_list: D002791:Cholesterol, Dietary; D008055:Lipids; D002784:Cholesterol