Reversine attenuates cholestatic ductular reaction in rats

Ductular reaction (DR) is usually observed in biliary disorders or various liver disorders, including nonalcoholic fatty liver disease. Few studies have focused on interrupting the DR process in the cholestatic environment. Here, we investigated the impact of reversine on DR in rats that had undergone bile duct ligation (BDL). Cholestatic injury was induced in rats 2 weeks following BDL. DR was assessed with biliary markers by immunohistochemistry. Biliary epithelial cells (BECs) were isolated for the analysis of proliferation and biliary factor gene expression. The effects of reversine on DR and fibrosis were analyzed in vivo via intraperitoneal injection in rats for 2 weeks. Chemically-induced BEC formation was used to investigate the biliary markers affected by reversine in vitro. DR with increased BEC expansion was identified in cholestatic liver injury, as indicated by CK7, CK19, and EpCAM expression around the portal vein in BDL rats. BDL-induced DR cells showed the increased expression of genes regulating cell proliferation (Ki67, Foxm1, and Pcna) and biliary markers (Krt7, Krt19, Epcam, Sox9, Cftr, and Asbt). Reversine attenuated cholestatic fibrosis and DR in rats. Reversine affected chemically-induced BEC formation, with the decreased expression of biliary Krt7, Cftr, and Ggt1 genes in vitro. BDL-induced Notch activation was attenuated upon reversine treatment in vivo, in part via the Notch/Sox9 pathway. In conclusion, reversine attenuated cholestatic ductular reaction and fibrosis in rats and reduced the bile duct formation associated with Dlk1/Notch/Sox9 signaling. Reversine may be regarded as a potential drug for cholangiopathies for preventing a ductular reaction.