There have been major advances in defining the immunological events associated with fibrosis in various chronic liver diseases. We have taken advantage of this data to focus on the mechanisms of action of a unique multi-kinase inhibitor, coined sorafenib, on CCl4-induced murine liver fibrosis, including the effects of this agent in models of both acute and chronic CCl4-mediated pathology. Importantly, sorafenib significantly attenuated chronic liver injury-and fibrosis, including reduction in liver inflammation and histopathology as well as decreased expression of liver fibrosis-related genes, including alpha-smooth muscle actin, collagen, matrix metalloproteinases and the tissue inhibitor of metalloproteinase-1. Furthermore, sorafenib treatment resulted in translocation of cytoplasmic STAT3 to the nucleus in its active form. Based on this observation, we used hepatocyte-specific STAT3 knockout (STAT3(Hep-/-)) mice to demonstrate that hepatic STAT3 was critical for sorafenib-mediated protection against liver fibrosis, and that the upregulation of STAT3 phosphorylation was dependent on Kupffer cell-derived IL-6. In conclusion, these data reflect the clinical potential of the multi-kinase inhibitor sorafenib for the prevention of fibrosis as well as the treatment of established liver fibrosis and illustrate the immunological mechanisms that underlie the protective effects of sorafenib. (C) 2013 Elsevier Ltd. All rights reserved.
[1]Univ Sci & Technol China, Liver Immunol Lab, Inst Immunol, Hefei 230027, Peoples R China.
[2]Univ Sci & Technol China, Sch Life Sci, Hefei 230027, Peoples R China.
[3]Toyama Univ, Grad Sch Med & Pharmaceut Sci Res, Dept Diagnost Pathol, Toyama 9300194, Japan.
[4]Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Inst Liver Dis, Key Lab Liver & Kidney Dis,Minist Educ, Shanghai 201203, Peoples R China.
[5]Univ Calif Davis, Sch Med, Div Rheumatol Allergy & Clin Immunol, Davis, CA 95616 USA.
[6]Duke Univ, Med Ctr, Div Gastroenterol, Durham, NC 27710 USA.
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