Conclusion. These results provide molecular insights in anti-fibrogenic immunmodulatory action of PFD by counteracting ROS-induced pro-fibrogenic signalling, and by regulation of the biosynthesis of antioxidant proteins. This study indicates that activation of the antioxidant

system plays an essential role in the modulation of inflammatory and fibrogenic cytokines in HSC. Disclosures: The following people have nothing to disclose: Jose Macias-Barragan, Alessandra Caligiuri, Jose Vera-Cruz, Jesus Garcia-Banuelos, Silvia Lucano-Landeros, Adriana M. Salazar Montes, Margarita Montoya-Buelna, Belinda C. Gomez-Meda, Massimo Pinzani, Juan Armendáriz-Borunda We have shown previously that robust hepatic fibrin(ogen) deposition accompanies the development of chronic alpha-naph-thylisothiocyanate (ANIT)-induced cholestatic liver injury Enzalutamide concentration in mice. Similarly, hepatic fibrin deposition is evident in livers of patients with cholestatic liver disease. Despite being a conspicuous PI3K Inhibitor Library in vivo feature of chronic liver disease, the role of fibrin(ogen) deposition in liver injury and fibrosis is not completely understood. Of interest, we found that mice lacking circulating fib-rinogen (and hepatic fibrin deposits) developed increased liver injury when fed a diet containing

0.025% ANIT (ANIT diet), suggesting a hepatoprotective effect of fibrin in cholestatic liver injury. We tested the hypothesis that administration of the antifibrinolytic drug tranexamic acid would reduce ANIT diet-induced liver injury and fibrosis in mice. Compared to wild type C57Bl/6J mice fed control diet (AIN-93M), wild type mice fed ANIT diet developed liver injury characterized by multifocal hepatocellular necrosis, inflammation, biliary hyperplasia and peribiliary fibrosis. Liver inflammation and fibrosis Dichloromethane dehalogenase were more severe in mice fed the ANIT diet for 4 weeks compared to 2 weeks. Prophylactic administration of tranexamic

acid (1200 mg/kg, ip, bid) significantly reduced hepatocellular necrosis in mice fed ANIT diet for two weeks. Despite reducing necrosis, tranexamic acid did not impact hepatic expression of profibrogenic genes or peribiliary collagen deposition at this time. In mice fed the ANIT diet for 4 weeks, treatment with tranexamic acid for the last 14 days of the ANIT exposure increased hepatic fibrin deposition and suppressed profibrogenic gene induction in liver. Moreover, tranexamic acid treatment significantly reduced type 1 collagen deposition in mice fed ANIT diet for 4 weeks. This reduction in fibrosis occurred in the absence of an effect on integrin β6 mRNA expression, the latter a key component of the αVβ6 integrin, which activates latent TGF-β in this model. Taken together, the results suggest that inhibition of fibrinolysis and stabilization of hepatic fibrin reduces liver injury and fibrosis in mice fed ANIT diet.