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 Ca2+ transients were imaged in intact gallbladder. Key Results Lipid composition of bile was altered lithogenically as early as one 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 (3μM). After one 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.

Telocytes: new insight into the pathogenesis of gallstone disease

“…A study by Lavoie et al . proved that excess cholesterol in the smooth muscle of the gallbladder attenuates the ability of the muscle to contract as a result of changes in signal transduction and ion channel activity, decoupled membrane receptor–ligand interactions and disturbances in contractile protein activity. Moreover, in a subsequent study on guinea pigs fed a lithogenic diet, Lavoie et al .…”

“…A study by Xu and Shaffer [9] reported that gallbladder hypomotility was impaired by the increased bile cholesterol level. A study by Lavoie et al [63] proved that excess cholesterol in the smooth muscle of the gallbladder attenuates the ability of the muscle to contract as a result of changes in signal transduction and ion channel activity, decoupled membrane receptor-ligand interactions and disturbances in contractile protein activity. Moreover, in a subsequent study on guinea pigs fed a lithogenic diet, Lavoie et al [48] reported cholesterol accumulation in gallbladder smooth muscles in the plasma membrane, especially membrane caveolae, leading to a decrease in membrane fluidity and a subsequent change in rhythmic electric activity.…”

The inflammatory inception of gallbladder cancer

“…In another study using the same model, morphological changes including epithelial hyperplasia, muscularis hypertrophy and increased wall thickness were observed as early as four weeks after the mice began the lithogenic diet. These changes were accompanied by inflammatory infiltrate composed of eosinophils, macrophages, neutrophils and lymphocytes within the lamina propia [67]. Moderate granulocyte infiltrate was also observed in the gallbladder with progressive impairment of gallbladder emptying [68].…”

Evidence of interstitial Cajal-like cells in human gallbladder

“…Indeed, there is growing evidence that the gallbladder's ICLCs are responsible for these processes and that their function may be influenced by numerous pathological factors (e.g. cholesterol in gallstone disease) www.fhc.viamedica.pl [23]. Elucidation of the role of interstitial Cajal-like cells in the human gallbladder may contribute to new treatment options for gallbladder motility disorders, present in gallstone disease, for example.…”