Fibrosing cholestatic hepatitis in HBV transgenic mice after bone marrow transplantation

Abstract

Introduction: Chronic hepatitis B virus (HBV) infection is associated with acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Fibrosing cholestatic hepatitis (FCH) is a severe form of HBV infection, usually seen in immunocompromised patients, including liver and bone marrow transplant recipients. The aim of this study was to investigate the impact of bone marrow transplantation (BMT) on hepatic injury and fibrosis in transgenic mice that express HBV surface (HBs) proteins in the liver. Methods:12-week-old BALB/c transgenic mice that express HBs proteinsin the liver were lethally irradiated and whole bone marrow cells from BALB/c-GFP mice were transplanted by tail vein injection. 26- and 52-week-old transgenic mice (Tg-Tx) and their non-transgenic littermates (Lm-Tx) were sacrificed. The level of hepatic and bile duct injury was estimated by serum alanine transaminase (ALT) and alkaline phosphatise (AP) activity. Histological, immunohistochemical, microarray, and Western blot analyses were used to study liver pathology. Results: BMT resulted in strong increase of serum ALT and AP activity in 26-week-old Tg-Tx compared to Lm-Tx and non-transplanted mice. H&E and Sirius Red staining confirmed enhanced liver injury and development of biliary fibrosis in Tg-Tx. Furthermore, comparison of gene expression profile of 26-week-old Tg-Tx and Abcb4-/- mice, a well-established model for chronic cholestatic liver disease, supported the idea that major outcome of BMT is the development of FCH in HBV transgenic mice. Moreover, BMT induced senescence of liver cells, especially periportal hepatocytes and ductular reaction in Tg-Tx liver. Conclusion: BMT in transgenic mice expressing HBs proteins in the liver could be an attractive model for studies of FCH pathogenesis.