Basic-liver, pancreas, and biliary tractRegurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice☆
Section snippets
Animals
Mdr2−/− knock-out and Mdr2+/+ wild-type mice (FVB/N background) were obtained from Jackson Laboratory (Jackson Laboratory, Bar Harbor, ME). Mice were housed with a 12-hour light-dark cycle and permitted ad libitum consumption of water and a standard mouse diet (Sniff, Soest, Germany). Livers from 2-, 4-, and 8-week-old male mice (n = 5–10 in each group owing to the small amounts of liver tissue in 2- and 4-week-old mice) were excised after cervical dislocation under general anesthesia (400 mg
Results
Severe bile duct epithelial cell (BEC) injury rarely is observed before week 4 in Mdr2−/−, 1 a time point when periductal inflammation and fibrosis, the hallmarks of the liver phenotype in this model, already are developed fully. Therefore, we established a detailed time course of the individual pathogenetic steps of sclerosing cholangitis in these animals.
Discussion
Because understanding of the pathogenesis of bile duct injury is a key prerequisite for the development of effective medical treatment for bile duct disorders including sclerosing cholangitis (e.g., primary sclerosing cholangitis [PSC]), we designed this study in Mdr2−/− as a model system to obtain novel insights into the pathogenetic principles of sclerosing cholangitis.1 We show that sclerosing cholangitis in Mdr2−/− is a multistep process initiated by leakage of bile acids from the bile
Acknowledgements
The authors thank Dr. Alan Hofmann (San Diego, California) for providing fluorescence-labeled bile acids; Dr. W. Erwa (Graz, Austria) and colleagues for performing liver function tests; and Judith Gumhold and Dagmar Silbert (Graz, Austria) for excellent technical assistance.
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Supported by grants P-15502 (to M.T.) and P-15783 (to H.T.) from the Austrian Science Foundation and a GEN-AU project grant from the Austrian Ministry for Science (to M.T.).