Delivery of matrix metalloproteinase-1 attenuates established liver fibrosis in the rat.

Abstract

BACKGROUND & AIMS:

During hepatic fibrogenesis, the hepatic extracellular matrix changes to fibrillar collagens types I and III, and cirrhosis is believed to produce an irreversible scar. In this study, we investigated whether gene delivery of human matrix metalloproteinase-1, which degrades collagens types I and type III, would attenuate established hepatic fibrosis in the rat, induced by either thioacetamide or bile duct ligation.

METHODS:

Hepatic fibrosis induced by thioacetamide for 7 weeks was persistent for at least 2 months, even after discontinuation of the treatment. The rats were infected once with a recombinant adenovirus, Ad5MMP-1, into which human pro-human matrix metalloproteinase-1 complementary DNA was packaged, or with a control adenovirus, Ad5LacZ.

RESULTS:

In Ad5MMP-1-infected, but not in Ad5LacZ-infected, rats, the fibrosis was dramatically attenuated at 2 weeks after the infection. It is interesting to note that the number of activated hepatic stellate cells was also decreased in Ad5MMP-1-infected rats. Moreover, disorganization of the hepatic trabecula, heterogeneity in the size of hepatocytes, and increased dried liver weight were observed only in Ad5MMP-1-treated rats, suggesting that human matrix metalloproteinase-1 stimulated hepatocyte proliferation, which was confirmed by bromodeoxyuridine staining. After 4 weeks, the proliferative effect of human matrix metalloproteinase-1 almost disappeared, but the hepatic fibrosis remained attenuated, whereas the fibrosis in Ad5LacZ-treated rats persisted. Furthermore, the administration of Ad5MMP-1, but not Ad5LacZ, decreased type I collagen and generated a small collagen fragment in hepatic fibrosis induced by bile duct ligation.

CONCLUSIONS:

Our findings show that transient human matrix metalloproteinase-1 overexpression in the liver effectively attenuates established fibrosis and induces hepatocyte proliferation.

• Authors: Yuji Iimuro, Toshihiro Nishio, Taisuke Morimoto, Takashi Nitta, Branko Stefanovic, Sung Kyu Choi, David A Brenner, Yoshio Yamaoka
• Journal: Gastroenterology (Gastroenterology) Vol. 124 Issue 2 Pg. 445-58 (Feb 2003) ISSN: 0016-5085 [Print] United States
• PMID: 12557150 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Prodrugs
• Thioacetamide
• Matrix Metalloproteinase 1

Topics

• Adenoviridae (genetics)
• Animals
• Cell Division (physiology)
• Genetic Therapy
• Genetic Vectors
• Hepatocytes (metabolism, pathology)
• Humans
• Liver (metabolism, pathology)
• Liver Cirrhosis (chemically induced, pathology, therapy)
• Male
• Matrix Metalloproteinase 1 (genetics)
• Prodrugs (metabolism)
• Rats
• Rats, Sprague-Dawley
• Recombination, Genetic
• Thioacetamide
• Time Factors