期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 182, 期 5, 页码 1607-1616出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2013.01.036
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资金
- National Natural Science Foundation of China [81000172, 81100287, 30972602]
- Basic-Clinic Cooperation project of Capital Medical University [09JL-L02]
- Municipal Key Laboratory of Beijing for Regulation of Liver Protection and Regeneration [NCET-09-0008]
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.
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