Activation of hepatic stellate cells during fibrosis: Comparison of the CYP2D6 model for autoimmune hepatits and CCl4 injection (130.2)

Abstract

Abstract Only little is known about the mechanisms of periportal fibrosis in the pathogenesis of human autoimmune hepatitis. We used the virus induced CYP2D6 model system to investigate the activation of hepatic stellate cells (HSC) and the kinetics of fibrosis in comparison with the CCl4-induced fibrosis model. CYP2D6 transgenic mice express the human Cytochrome P450 in the liver and develop liver damage upon Adenovirus-CYP2D6 infection. In the CYP2D6 model we found mostly subcapsular fibrosis resulting in the fusion of individual lobules (Sirius Red, Collagen I). At 10–12 weeks post-infection, weak periportal fibrosis became apparent. In contrast, in CCl4-treated mice the kinetic of extracellular matrix deposition was accelerated resulting in periportal fibrosis after 3–4 week of CCl4 administration. At later times, fibrosis was much more pronounced in CCl4-treated mice compared to virus-infected CYP2D6 mice but subcapsular fibrosis was not as dominat. Activation of HSCs could be detected by staining for α-smooth muscle actin (αSMA) in liver sections of both CCl4-treated mice and virus-infected CYP2D6 mice. In addition, isolation of HSCs revealed an enhanced activation status (decreased amount of oil droplets, de novo αSMA expression) in CCl4-treated mice and virus-infected CYP2D6 mice. Our data indicate that virus-infected CYP2D6 mice display subcapsular and periportal fibrosis that correlates with an activation of HSCs similar to CCl4-induced fibrosis. Thus, the CYP2D6 mouse is a good model system to further investigate the molecular mechanisms involved in fibrotic events during autoimmune hepatitis.