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.
| Original language | English |
|---|---|
| Pages (from-to) | 1000-1009 |
| Number of pages | 10 |
| Journal | Gene Therapy |
| Volume | 13 |
| Issue number | 13 |
| DOIs | |
| Publication status | Published - Jul 2006 |
| Externally published | Yes |
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Keywords
- α-MSH
- Liver fibrosis
- Matrix metalloproteinase
- Thioacetamide
ASJC Scopus subject areas
- Genetics
Cite this
Electroporative α-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation. / Wang, C. H.; Lee, T. H.; Lu, C. N.; Chou, W. Y.; Hung, K. S.; Concejero, A. M.; Jawan, B.
In: Gene Therapy, Vol. 13, No. 13, 07.2006, p. 1000-1009.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Electroporative α-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation
AU - Wang, C. H.
AU - Lee, T. H.
AU - Lu, C. N.
AU - Chou, W. Y.
AU - Hung, K. S.
AU - Concejero, A. M.
AU - Jawan, B.
PY - 2006/7
Y1 - 2006/7
N2 - 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.
AB - 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.
KW - α-MSH
KW - Liver fibrosis
KW - Matrix metalloproteinase
KW - Thioacetamide
UR - http://www.scopus.com/inward/record.url?scp=33745220352&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33745220352&partnerID=8YFLogxK
U2 - 10.1038/sj.gt.3302744
DO - 10.1038/sj.gt.3302744
M3 - Article
VL - 13
SP - 1000
EP - 1009
JO - Gene Therapy
JF - Gene Therapy
SN - 0969-7128
IS - 13
ER -