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Electroporative α-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation

Gene Therapy volume 13, pages 1000–1009 (2006)Cite this article

Abstract

Hepatic fibrosis represents a process of healing and scarring in response to chronic liver injury. α-Melanocyte-stimulating hormone (α-MSH) is a 13-amino-acid peptide with potent anti-inflammatory effects. We have previously demonstrated that α-MSH gene therapy protects against thioacetamide (TAA)-induced acute liver failure. Therefore, the aim of this study is to investigate whether α-MSH gene therapy possesses antihepatic fibrogenic effect. Liver fibrosis was induced by long-term TAA administration in mice. α-Melanocyte-stimulating hormone expression plasmid was delivered via electroporation after liver fibrosis was established. Our results showed that α-MSH gene therapy attenuated liver fibrosis in TAA-treated mice. Reverse transcription polymerase chain reaction revealed that α-MSH gene therapy attenuated the liver transforming growth factor-β1, collagen α1 and cell adhesion molecule mRNA upregulation. Following gene transfer, the expression of α-smooth muscle actin and cyclooxygenase-2 were both significantly attenuated. Further, α-MSH significantly increased matrix metalloproteinase (MMP), while tissue inhibitors of matrix metalloproteinase (TIMPs) were inactivated. In summary, α-MSH gene therapy reversed established liver fibrosis in mice and prevented the upregulated fibrogenic and pro-inflammatory gene responses after TAA administration. Its collagenolytic effect might be attributed to MMP and TIMP modulation. Hence, α-MSH gene therapy may be an effective therapeutic modality against liver fibrosis with potential clinical use.

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Acknowledgements

This work was supported by Chang Gung Memorial Hospital Research Grant No. 840451 (CMRPG-840451). We thank Dr Hedley for providing us the recombinant α-MSH expression plasmid used in this study.

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Authors and Affiliations

  1. Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan

    C-H Wang, T-H Lee, W-Y Chou & B Jawan

  2. Department of Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan

    C-N Lu

  3. Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan

    K-S Hung & A M Concejero

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  1. C-H Wang
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Correspondence to B Jawan.

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Wang, CH., Lee, TH., Lu, CN. et al. Electroporative α-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation. Gene Ther 13, 1000–1009 (2006). https://doi.org/10.1038/sj.gt.3302744

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