Antifibrotic Effects of a Recombinant Adeno-Associated Virus Carrying Small Interfering RNA Targeting TIMP-1 in Rat Liver Fibrosis

被引：36

作者：

Cong, Min ^{[1
]}

Liu, Tianhui ^{[1
]}

Wang, Ping ^{[1
]}

Fan, Xu ^{[1
]}

Yang, Aiting ^{[1
]}

Bai, Yanfeng ^{[1
]}

Peng, Zhen ^{[1
]}

Wu, Peng ^{[1
]}

Tong, Xiaofei ^{[1
]}

Chen, Jing ^{[1
]}

Li, Hai ^{[1
]}

Cong, Rui ^{[1
]}

Tang, Shuzhen ^{[1
]}

Wang, Baoen ^{[1
]}

Jia, Jidong ^{[1
]}

You, Hong ^{[1
]}

机构：

[1] Capital Med Univ, Beijing Friendship Hosp, Liver Res Ctr, Beijing 100050, Peoples R China

来源：

AMERICAN JOURNAL OF PATHOLOGY | 2013年 / 182卷 / 05期

基金：

中国国家自然科学基金;

关键词：

HEPATIC STELLATE CELLS; MATRIX METALLOPROTEINASES; TISSUE INHIBITOR; EXPRESSION; MECHANISMS; APOPTOSIS; REVERSIBILITY; TGF-BETA-1; FIBROGENESIS; DEGRADATION;

D O I：

10.1016/j.ajpath.2013.01.036

中图分类号：

R36 [病理学];

学科分类号：

100103 [病原生物学];

摘要：

Elevated tissue inhibitor of metalloproteinase 1 (TIMP-1) expression contributes to excess production of extracellular matrix in liver fibrosis. Herein, we constructed a recombinant adeno-associated virus (rAAV) carrying siRNA of the TIMP-1 gene (rAAV/siRNA-TIMP-1) and investigated its effects on Liver fibrosis in rats. Two models of rat liver fibrosis, the carbon tetrachloride and bile duct ligation models, were treated with rAAV/siRNA-TIMP-1. In the carbon tetrachloride model, rAAV/siRNA-TIMP-1 administration attenuated fibrosis severity, as determined by histologic analysis of hepatic collagen accumulation, hydroxyproline content, and concentrations of types I and III collagen in Livers and sera. Levels of mRNA and active matrix metalloproteinase (MMP) 13 were elevated, whereas levels of mRNA and active MMP-2 were decreased. Moreover, a marked decrease was noted in the expression of alpha-smooth muscle actin, a biomarker of activated hepatic stellate cells (HSCs), and transforming growth factor-beta 1, critical for the development of Liver fibrosis. Similarly, rAAV/siRNA-TIMP-1 treatment significantly alleviated bile duct Ligation-induced liver fibrosis. Furthermore, this treatment dramatically suppressed TIMP-1 expression in HSCs from both model rats. These data indicate that the administration of rAAV/siRNA-TIMP-1 attenuated liver fibrosis by directly elevating the function of MMP-13 and diminishing activated HSCs. It also resulted in indirect decreased expression of type I collagen, MMP-2, and transforming growth factor-beta 1. In conclusion, rAAV/siRNA-TIMP-1 may be an effective antifibrotic gene therapy agent.

引用

页码：1607 / 1616

页数：10

共 41 条

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