Hepatitis C virus (HCV) protein expression enhances hepatic fibrosis in HCV transgenic mice exposed to a fibrogenic agent

作者：Chouteau Philippe; Defer Nicole; Florimond Alexandre; Calderaro Julien; Higgs Martin; Gaudin Aurore; Merour Emilie; Dhumeaux Daniel; Lerat Herve; Pawlotsky Jean Michel^*

来源：Journal of Hepatology, 2012, 57(3): 499-507.

• Hepatitis C virus
• Fibrosis
• Hepatocyte proliferation
• Reactive oxygen species
• Ductular reaction
• Hepatic progenitor cells

Background & Aims: During chronic HCV infection, activation of fibrogenesis appears to be principally related to local inflammation. However, the direct role of hepatic HCV protein expression in fibrogenesis remains unknown.
Methods: We used transgenic mice expressing the full length HCV open reading frame exposed to a 'second hit' of the fibrogenic agent carbon tetrachloride (CCl4). Both acute and chronic liver injuries were induced in these mice by CCl4 injections. Liver injury, expression of matrix re-modeling genes, reactive oxygen species (ROS), inflammation, hepatocyte proliferation, ductular reaction and hepatic progenitor cells (HPC) expansion were examined.
Results: After CCl4 treatment, HCV transgenic mice exhibited enhanced liver fibrosis, significant changes in matrix re-modeling genes and increased ROS production compared to wild type lit-termates despite no differences in the degree of local inflammation. This increase was accompanied by a decrease in hepatocyte proliferation, which appeared to be due to delayed hepatocyte entry into the S phase. A prominent ductular reaction and hepatic progenitor cell compartment expansion were observed in transgenic animals. These observations closely mirror those previously made in HCV-infected individuals.
Conclusions: Together, these results demonstrate that expression of the HCV proteins in hepatocytes contributes to the development of hepatic fibrosis in the presence of other fibrogenic agents. In the presence of CCl4, HCV transgenic mice display an intra-hepatic re-organization of several key cellular actors in the fibrogenic process.

• 出版日期2012-9