Electroporative alpha-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation.
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.
Wang
C-H
CH
Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan.
Lee
T-H
TH
Lu
C-N
CN
Chou
W-Y
WY
Hung
K-S
KS
Concejero
A M
AM
Jawan
B
B
D000199:Actins / Q000235:genetics; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics; D024042:Collagen Type I / Q000032:analysis / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D018274:Electroporation / Q000379:methods*; D005355:Fibrosis; D015316:Genetic Therapy / Q000379:methods*; D007150:Immunohistochemistry / Q000379:methods; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013853:Thioacetamide; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation; D000521:alpha-MSH / Q000097:blood / Q000235:genetics*
D000199:Actins; D015815:Cell Adhesion Molecules; D024042:Collagen Type I; C508961:Tgfb1 protein, mouse; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D013853:Thioacetamide; D000521:alpha-MSH; D051546:Cyclooxygenase 2; D020782:Matrix Metalloproteinases