トランスジェニックマウスを用いたTissue inhibitor of metalloproteinase-1(TIMP-1)の肝線維化過程における役割の解析

Abstract

Tissue inhibitor of metalloproteinase-1 (TIMP-1) has been shown to be increased in liver fibrosis development, however, the direct role of TIMP-1 has not been defined. To elucidate the role of TIMP-1 in liver fibrogenesis, we developed liver-targeted TIMP-1 transgenic mice under the control of albumin promoter/enhancer. A model of CCl^4 -induced hepatic fibrosis was used to assess the extent of fibrosis develtpment in TIMP-1 transgenic (TIMP-Tg) mice and control hybrid (Cont) mice. Without any treatment, overexpression of TIMP-1 in the liver did not induce liver fibrosis. After four-week treatment with CCl^4, however, TIMP-Tg-mice revealed a seven-fold increase in liver fibrosis compared to the Cont--mice by densitometric analysis. The hepatic collagen and hydroxyproline content and serum fibrosis markers, such as 7S-collagen, P-Ⅲ-N-P, were also significantly increased in the TIMP-Tg-mice. Furthermore, immunohistochemical analysis showed that collagen-Ⅰ and collagen-Ⅳ accumulations were markedly increased along the sinusoidal lining in the liver of the TIMP-Tg-mice with a pattern similar to that of α-smooth muscle actin (α-SMA) positive cells. Activated hepatic stellate cells (HSC) from TIMP-Tg-mice displayed markedly increased RNA expression of pro-collagen-Ⅰ and collagen-Ⅳ in response to exogenous recombinant TIMP-1 (rTIMP-1). These results suggest that TIMP-1 does not by itself result in liver fibrogeneis, but strongly promotes liver fibrosis development through HSC stimulation.