Abstract
The non-selectivity of tyrosine kinase inhibitors is the leading cause of drug withdrawals, and limits their application in anti-fibrosis. The role of Src tyrosine kinase Lyn in hepatic fibrosis remains elusive. In this study, we aimed to elucidate the role of Lyn kinase in the pathogenesis of hepatic fibrosis. Through examining Lyn-transgenic (Lyn TG) mice treated with CCl4 (carbon tetrachloride), we determined whether Lyn kinase is involved in the pathogenesis of hepatic fibrosis. On top of that, we also investigated the role of Lyn in the activation of hepatic stellate cells (HSCs) in vitro. Here, we showed that Lyn kinase was highly expressed in liver fibrosis upon CCl4 treatment. Meanwhile, Lyn TG mice showed that perivascular infiltration of mononuclear cells, and the markers of liver injury and hepatocytes apoptosis were significantly increased in liver tissue after CCl4 treatment. In comparison with wild-type (WT) mice after CCl4 treatment, we found that the fibrotic score in liver tissues of Lyn TG mice with the same treatment went up dramatically, so did the gene expression of fibrotic markers. In addition, over-expression of Lyn kinase drastically promoted the expression of HSCs activation markers in vivo or in vitro. Additionally, the Src-specific inhibitor PP2 significantly suppressed the increased expression of integrin αvβ3 in TGF-β1-induced HSCs, and PP2 further induced HSC apoptosis in TGF-β1-treated cells. These results collectively indicated that Lyn kinase is implicated in the pathogenesis of hepatic fibrosis through the modulating of HSC activation.