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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.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Iimuro Y,Nishio T,Morimoto T,Nitta T,Stefanovic B,Choi SK,Brenner DA,Yamaoka Y

doi

10.1053/gast.2003.50063

keywords:

subject

Has Abstract

pub_date

2003-02-01 00:00:00

pages

445-58

issue

eissn

0016-5085

issn

1528-0012

pii

S0016508502159142

journal_volume

124

pub_type

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