Korean J Med.
2006 Dec;71(6):609-619.
Gene therapy via adenovirus vector carrying matrix metalloproteinase-3 (MMP-3) in a rat model of liver cirrhosis
- Affiliations
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- 1WHO Collaborating Center of Viral Hepatitis, Seoul, Korea.
- 2Department of Internal Medicine, The Catholic University of Korea Colleage of Medicine, Seoul, Korea. yoonsk@catholic.ac.kr
- 3School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
Abstract
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BACKGROUND: Liver cirrhosis is characterized by fibrous scarring and hepatocellular regeneration. Matrix metalloproteinases (MMPs) comprise a family of zinc-dependent enzymes that degrade the extracellular matrix (ECM) components. This study examined whether or not gene delivery of human MMP-3 can attenuate established liver cirrhosis in a rat.
METHODS
Rat liver cirrhosis was induced by an intraperitoneal injection of dimethylnitrosamine (DMN) three times a week for 8 weeks. The rats were infected once with either a recombinant adenovirus, AdMMP3.GFP, or a control adenovirus, Ad.GFP, into a portal vein and followed up for 3 weeks. In the rat liver tissues, the collagen content, histopathology and immunohistochemical staining were measured.
RESULTS
Liver fibrosis in the DMN induced cirrhotic rat was attenuated along with a diminished hydroxyproline content and increased dried liver weight after the gene delivery of AdMMP3.GFP. In addition, the number of activated hepatic stellate cells was lower whereas the proliferation of hepatocytes, which was confirmed by immunohistochemical staining using anti-proliferating cell nuclear antigen (PCNA) antibody, was observed in the AdMMP3.GFP infected rats, suggesting that human MMP-3 stimulated hepatocyte proliferation.
CONCLUSIONS
These results suggest that the gene transfer of human MMP-3 in the liver attenuates established fibrosis and induces hepatocyte proliferation. Therefore, gene therapy using MMP-3 in liver cirrhosis might be a promising therapeutic option in the future.
MeSH Terms
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Adenoviridae*
Animals
Cicatrix
Collagen
Dimethylnitrosamine
Extracellular Matrix
Fibrosis
Genetic Therapy*
Hepatic Stellate Cells
Hepatocytes
Humans
Hydroxyproline
Injections, Intraperitoneal
Liver Cirrhosis*
Liver*
Matrix Metalloproteinases
Models, Animal*
Portal Vein
Rats*
Regeneration
Collagen
Dimethylnitrosamine
Hydroxyproline
Matrix Metalloproteinases
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