α‐Melanocyte‐stimulating hormone gene therapy reverses carbon tetrachloride induced liver fibrosis in mice

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Abstract
Background: Hepatic fibrosis represents a process of healing and scarring in response to chronic liver injury. Effective therapies are lacking. We have previously demonstrated that α‐melanocyte‐stimulating hormone (α‐MSH) gene therapy protects against thioacetamide‐induced acute liver failure in mice. Recent reports showed that collagen metabolism is a novel target of α‐MSH. Therefore, the aim of this study is to investigate whether α‐MSH gene therapy possesses anti‐hepatic fibrogenic effect in mice.Methods: Liver fibrosis was induced in mice by administering carbon tetrachloride (CCl4) continuously for 10 weeks. α‐MSH expression plasmid was delivered via electroporation after liver fibrosis had been established. Histopathology, reverse‐transcription polymerase chain reaction (RT‐PCR), immunoblotting, and gelatin zymography were used to investigate its possible mechanisms of action.Results: α‐MSH gene therapy reversed established liver fibrosis in CCl4‐treated mice. RT‐PCR revealed that α‐MSH gene therapy attenuated the liver TGF‐β1, collagen α1, and cell adhesion molecule mRNA upregulation. Following gene transfer, both the activation of α‐smooth muscle actin (α‐SMA) and cyclooxygenase‐2 (COX‐2) was significantly attenuated. Further, α‐MSH significantly increased matrix metalloproteinase (MMP) activity with tissue inhibitors of matrix metalloproteinase (TIMP) inactivation.Conclusions: We have demonstrated that α‐MSH gene therapy reversed established liver fibrosis in mice. It also prevented the upregulated fibrogenic and proinflammatory gene response after CCl4administration. Its collagenolytic effect may be attributed to MMP and TIMP modulation. In summary, α‐MSH gene therapy may be an effective therapeutic modality against liver fibrosis with potential clinical use. Copyright © 2006 John Wiley & Sons, Ltd.

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