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

Gene Ther. 2006 Jul;13(13):1000-9. doi: 10.1038/sj.gt.3302744. Epub 2006 Mar 2.

Abstract

Hepatic fibrosis represents a process of healing and scarring in response to chronic liver injury. alpha-Melanocyte-stimulating hormone (alpha-MSH) is a 13-amino-acid peptide with potent anti-inflammatory effects. We have previously demonstrated that alpha-MSH gene therapy protects against thioacetamide (TAA)-induced acute liver failure. Therefore, the aim of this study is to investigate whether alpha-MSH gene therapy possesses antihepatic fibrogenic effect. Liver fibrosis was induced by long-term TAA administration in mice. alpha-Melanocyte-stimulating hormone expression plasmid was delivered via electroporation after liver fibrosis was established. Our results showed that alpha-MSH gene therapy attenuated liver fibrosis in TAA-treated mice. Reverse transcription polymerase chain reaction revealed that alpha-MSH gene therapy attenuated the liver transforming growth factor-beta1, collagen alpha1 and cell adhesion molecule mRNA upregulation. Following gene transfer, the expression of alpha-smooth muscle actin and cyclooxygenase-2 were both significantly attenuated. Further, alpha-MSH significantly increased matrix metalloproteinase (MMP), while tissue inhibitors of matrix metalloproteinase (TIMPs) were inactivated. In summary, alpha-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, alpha-MSH gene therapy may be an effective therapeutic modality against liver fibrosis with potential clinical use.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Animals
  • Cell Adhesion Molecules / genetics
  • Collagen Type I / analysis
  • Collagen Type I / genetics
  • Cyclooxygenase 2 / genetics
  • Electrophoresis, Polyacrylamide Gel / methods
  • Electroporation / methods*
  • Fibrosis
  • Genetic Therapy / methods*
  • Immunohistochemistry / methods
  • Liver / chemistry
  • Liver / metabolism
  • Liver Cirrhosis, Experimental / metabolism
  • Liver Cirrhosis, Experimental / pathology
  • Liver Cirrhosis, Experimental / therapy*
  • Male
  • Matrix Metalloproteinases / metabolism
  • Mice
  • Mice, Inbred ICR
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thioacetamide
  • Tissue Inhibitor of Metalloproteinases / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta1
  • Up-Regulation
  • alpha-MSH / blood
  • alpha-MSH / genetics*

Substances

  • Actins
  • Cell Adhesion Molecules
  • Collagen Type I
  • Tgfb1 protein, mouse
  • Tissue Inhibitor of Metalloproteinases
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Thioacetamide
  • alpha-MSH
  • Cyclooxygenase 2
  • Matrix Metalloproteinases