Characterization of time-related changes after experimental bile duct ligation

Background: Although bile duct ligation (BDL) in mice is used to study cholestasis, a detailed description of this animal model is lacking. The aim of this study was to define specific phases of acute and chronic injury and repair in the different cellular compartments of the liver. Methods: C57BL/6 mice underwent BDL or sham laparotomy, and serum and liver tissue were analysed between 8 h and 6 weeks later. Results: Biliary infarcts and alanine aminotransferase levels revealed acute hepatocellular injury peaking at days 2-3, paralleled by enhanced transcription of pro-proliferative mediators and followed by a distinct peak of hepatocellular proliferation at day 5. Cholangiocellular proliferation occurred in large bile ducts on days 2-3 and in small bile ducts on day 5. Neutrophil infiltration occurred within 8 h, with neutrophils remaining the predominant immune cell type until day 3. Acute injury was followed by continuous tissue repair, lymphocyte and Kupffer cell infiltration, and accumulation of collagen during the second week. Thereafter, the number of alpha-smooth muscle actin-positive cells and the expression of transforming growth factor beta 1, tissue inhibitor of metalloproteinases 1 and procollagen (I) decreased, and liver fibrosis stabilized. Conclusion: BDL elicits dynamic changes in mouse liver. The chronological dissection and quantification of these events identified specific phases of acute and chronic cholestatic liver injury.