Delivery of matrix metalloproteinase-1 attenuates established liver fibrosis in the rat.
OBJECTIVE
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.
Iimuro
Yuji
Y
Department of Gastroenterological Surgery, Kyoto University Graduate School of Medicine, Japan. siimuro@hyo-med.ac.jp
Nishio
Toshihiro
T
Morimoto
Taisuke
T
Nitta
Takashi
T
Stefanovic
Branko
B
Choi
Sung Kyu
SK
Brenner
David A
DA
Yamaoka
Yoshio
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002455:Cell Division / Q000502:physiology; D015316:Genetic Therapy; D005822:Genetic Vectors; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D011355:Prodrugs / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011995:Recombination, Genetic; D013853:Thioacetamide; D013997:Time Factors
D011355:Prodrugs; D013853:Thioacetamide; D020781:Matrix Metalloproteinase 1