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Edith Hintermann, Selina Christen, Monika Bayer and Urs Christen?>
Periportal fibrosis is one of the defining parameters of autoimmune hepatitis. Only little is known about the mechanisms involved in the development of fibrosis during this severe human autoimmune disease. 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 well established CCl4-induced fibrosis model. CYP2D6 transgenic mice express the human Cytochrome P450 2D6 under its own promotor in the liver and do not develop liver damage unless infected with an Adenovirus-CYP2D6 vector. We found that in the CYP2D6 model fibrosis, as detected by Sirius Red and anti-Collagen I IgG staining, was mostly subcapsular resulting in the fusion of individual lobules. After 10-12 weeks post-infection, weak periportal fibrosis became apparent. In contrast, in CCl4-treated mice the kinetics of extracellular matrix deposition were much quicker resulting in periportal fibrosis already 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. However, subcapsular fibrosis was not as dominant in CCl4-treated mice. Activation of HSCs could be detected by staining for a-smooth muscle actin (aSMA) in tissue 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 aSMA expression) in CCl4-treated mice and virus-infected CYP2D6 mice. Our data indicate that Adenovius-CYP2D6-infected CYP2D6 mice display subcapsular and periportal fibrosis that correlates with an activation of HSCs similar to CCl4-induced fibrosis. Thus, the CYP2D6 mouse will be a good model system to further investigate the molecular mechanisms involve in fibrotic events during autoimmune hepatitis.