Dynamic changes in the expression of matrix metalloproteinases and their inhibitors, TIMPs, during hepatic fibrosis induced by alcohol in rats.
OBJECTIVE
To determine the dynamic changes in the expression of matrix metalloproteinases (MMPs) and the endogenous tissue inhibitors of MMPs inhibitors (TIMPs) during hepatic fibrosis induced by alcohol.


METHODS
Male Sprague-Dawley rats were randomly divided into normal, 4 d, 2 wk, 4 wk, 9 wk and 11 wk groups, and the model rats were fed with a mixture of alcohol by gastric infusion at the designed time, respectively, then decollated and their livers were harvested for the examination of MMP-2, MMP-3, MMP-9, MMP-13, TIMP-1 and TIMP-2 by immunohistochemistry, zymograghy and Western blotting, respectively.


RESULTS
Normal rats had moderate expression of MMP-2, which was decreased in the model rats except in the 11 wk group, where MMP-2 expression slightly increased. MMP-3 had the similar changing pattern to MMP-2 despite weaker expression. MMP-9 expression decreased in the 4 d and 2 wk groups, rose in the 4 wk group, decreased again in the 9 wk group and returned to normal levels in the 11 wk group. MMP-13 expression decreased in the 4 d and 2 wk groups, and returned to normal levels in the 4 wk, 9 wk and 11 wk groups. TIMP-1 expression decreased in the 4 d and 2 wk groups, but sharply increased in the 4 wk group and sustained at a high level even after modeling was stopped for 2 wk. In normal rats TIMP-2 expression was strong. However, it decreased as soon as modeling began, and then gradually rose, but remained to a level lower than that in normal rats even after modeling was stopped for 2 wk.


CONCLUSIONS
MMP-2 may not always expresses at a high level during hepatic fibrosis. MMP-13 and MMP-3 are acutely affected by TIMP-1. In this model TIMP-1 is the most powerful factor imposed on capillarization and peri-sinusoidal fibrosis. TIMP-2 is the most effective regulator on the metabolism of type IV collagen located in the basement of sinus.
Xu
Guang-Fu
GF
Department of Infectious Diseases, 1st Affiliated Dongzhimen Hospital, Beijing University of Traditional Chinese Medicine, Beijing 100700, China. guangfuxu@hotmail.com
Li
Peng-Tao
PT
Wang
Xin-Yue
XY
Jia
Xu
X
Tian
De-Lu
DL
Jiang
Liang-Duo
LD
Yang
Jin-Xiang
JX
D000818:Animals; D017364:Collagenases / Q000378:metabolism; D004195:Disease Models, Animal; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000473:pathology; D008297:Male; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*
D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; C507083:Mmp13 protein, rat; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9