Characterization of time-related changes after experimental bile duct ligation

TLDR

Bile duct ligation in mice is a common cholestasis model, yet its detailed temporal dynamics remain poorly described. This study aimed to delineate the distinct acute and chronic injury and repair phases across liver cellular compartments following BDL. C57BL/6 mice underwent BDL or sham surgery, with serial serum and liver tissue analyses performed from 8 h up to 6 weeks post‑ligation. BDL induces a dynamic sequence of liver injury and repair: hepatocellular damage peaks at days 2–3, followed by hepatocyte proliferation at day 5; cholangiocyte proliferation occurs in large ducts days 2–3 and small ducts day 5; neutrophils infiltrate within 8 h and dominate until day 3; subsequent weeks show lymphocyte/Kupffer infiltration, collagen deposition, then a decline in α‑smooth muscle actin, TGF‑β1, TIMP‑1, and procollagen‑I with fibrosis stabilization, delineating clear acute and chronic phases.

Abstract

Abstract 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 α-smooth muscle actin-positive cells and the expression of transforming growth factor β1, 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.