Pathophysiological preconditions promoting mixed 'black' pigment plus cholesterol gallstones in a DeltaF508 mouse model of cystic fibrosis
| Autor: | Folke Freudenberg, Martin C. Carey, Jonathan N. Glickman, Monika R. Leonard, Shou-An Liu |
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| Rok vydání: | 2010 |
| Předmět: |
Male
medicine.medical_specialty Pancreatic disease Cystic Fibrosis Physiology Gallstones Biology Cystic fibrosis Gastroenterology chemistry.chemical_compound Feces Mice Cholelithiasis Risk Factors Physiology (medical) Internal medicine Enterohepatic Circulation medicine Animals Bile Mice Inbred CFTR ΔF508 Hepatology Cholesterol Gallbladder Hepatobiliary disease Mucins Bilirubin Hydrogen-Ion Concentration medicine.disease Cystic fibrosis transmembrane conductance regulator Disease Models Animal Liver and Biliary Tract Endocrinology medicine.anatomical_structure chemistry biology.protein Female Hydrophobic and Hydrophilic Interactions |
| Zdroj: | American journal of physiology. Gastrointestinal and liver physiology. 299(1) |
| ISSN: | 1522-1547 |
| Popis: | Gallstones are frequent in patients with cystic fibrosis (CF). These stones are generally “black” pigment (i.e., Ca bilirubinate) with an appreciable cholesterol admixture. The pathophysiology and molecular mechanisms for this “mixed” gallstone in CF are unknown. Here we investigate in a CF mouse model with no overt liver or gallbladder disease whether pathophysiological changes in the physical chemistry of gallbladder bile might predict the occurrence of “mixed” cholelithiasis. Employing a ΔF508 mouse model with documented increased fecal bile acid loss and induced enterohepatic cycling of bilirubin ( Am J Physiol Gastrointest Liver Physiol 294: G1411–G1420, 2008), we assessed gallbladder bile chemistry, morphology, and microscopy in CF and wild-type mice, with focus on the concentrations and compositions of the common biliary lipids, bilirubins, Ca2+, and pH. Our results demonstrate that gallbladder bile of CF mice contains significantly higher levels of all bilirubin conjugates and unconjugated bilirubin with lower gallbladder bile pH values. Significant elevations in Ca bilirubinate ion products in bile of CF mice increase the likelihood of supersaturating bile and forming black pigment gallstones. The risk of potential pigment cholelithogenesis is coupled with higher cholesterol saturations and bile salt hydrophobicity indexes, consistent with a proclivity to cholesterol phase separation during pigment gallstone formation. This is an initial step toward unraveling the molecular basis of CF gallstone disease and constitutes a framework for investigating animal models of CF with more severe biliary disease, as well as the human disease. |
| Databáze: | OpenAIRE |
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