Molecular Basis of Anti-fibrosis via Destruction of an Organ Self-repair System

通过破坏器官自我修复系统抗纤维化的分子基础

基本信息

批准号：
14207005
负责人：
NAKAMURA Toshikazu
金额：
$ 28.87万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2005
项目状态：
已结题

项目摘要

Myofibroblast formation and overproduction of extra-cellular matrix (ECM) are common events in the pathogenesis of tissue fibrosis under chronic injuries, such as liver cirrhosis, pulmonary fibrosis and cardiomyopathy. In the present study, we found that HGF directly targeted the interstitial myofibroblasts and reduced ECM accumulation using the animal model of pulmonary fibrosis, liver cirrhosis and dilated cardiomyopathy.1) Regression of pulmonary fibrosis by HGE :We used bleomycin-injected mice as a model of lung fibrosis and found that HGF elicited apoptotic changes in the myofibroblast cell population in vivo. Furthermore, we obtained in vitro evidence that : (i) HGF degraded ECM proteins (i.e., cell anchorage) around the myofibroblasts, via induction of proteinases such as MMP-9/-1/-2 ; (ii) under such ECM-deficient conditions, the myofibroblasts lose the anchorage then anoikis-like apoptotic cell death occurred. Importantly, an MMP-inhibitor diminished HGF-mediated apoptotic cell death of myofibroblasts, in vitro as well as in vivo, thus indicating that HGF-induced anti-fibrotic effects largely depended on inductions of MMPs by HGF. We published these results in FASEB-Journal 19 : 580 (2005)2) Reduction of interstitial fibrosis in liver cirrhosis and cardiomyopathy by HGF :In the rat model of liver cirrhosis, HGF enhanced myofibroblast apoptosis and inhibited proliferation of interstitial myofibroblasts. These effects were associated with the reduction of ECM-accumulated areas. In vitro, HGF counteracted the PDGF-mediated proliferation of the lipocyte-derived myofibroblasts. In the hamster model of cardiomyopathy, HGF reduced TGF-beta production in the interstitial myofibroblasts, followed by the reduction of ECM as well as improvement in the cardiac functions. These outcomes were published in Am-J-Pathol 166 : 1017 (2005) and in Am-J-Physiol 288 : H2131 (2005), respectively.

肌成纤维细胞的形成和细胞外基质（ECM）的过量产生是慢性损伤下组织纤维化发病机制中的常见事件，例如肝硬化、肺纤维化和心肌病。在本研究中，我们通过肺纤维化、肝硬化和扩张型心肌病的动物模型发现HGF直接靶向间质肌成纤维细胞并减少ECM积累。1) HGE对肺纤维化的消退：我们使用注射博来霉素的小鼠作为模型肺纤维化的研究发现，HGF 引起体内肌成纤维细胞群的凋亡变化。此外，我们获得的体外证据表明：(i) HGF 通过诱导 MMP-9/-1/-2 等蛋白酶，降解肌成纤维细胞周围的 ECM 蛋白（即细胞锚定）； (ii)在这种ECM缺陷的条件下，肌成纤维细胞失去锚定，然后发生失巢凋亡样细胞凋亡。重要的是，MMP 抑制剂在体外和体内均可减少 HGF 介导的肌成纤维细胞凋亡细胞死亡，因此表明 HGF 诱导的抗纤维化作用很大程度上取决于 HGF 对 MMP 的诱导。我们将这些结果发表在 FASEB-Journal 19 : 580 (2005)2) HGF 减少肝硬化和心肌病中的间质纤维化：在肝硬化大鼠模型中，HGF 增强肌成纤维细胞凋亡并抑制间质肌成纤维细胞增殖。这些影响与 ECM 累积面积的减少有关。在体外，HGF 抵消了 PDGF 介导的脂肪细胞来源的肌成纤维细胞的增殖。在仓鼠心肌病模型中，HGF 减少间质肌成纤维细胞中 TGF-β 的产生，随后减少 ECM 并改善心脏功能。这些结果分别发表在 Am-J-Pathol 166 : 1017 (2005) 和 Am-J-Physiol 288 : H2131 (2005) 中。

项目成果

期刊论文数量（395）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Adenoviral gene transduction of hepatocyte growth factor elicits inhibitory effects for hepatoma.

肝细胞生长因子的腺病毒基因转导可引起肝癌的抑制作用。

DOI：
发表时间：
2005
期刊：
Int J Oncol 27
影响因子：
0
作者：
Okunishi;K. et al.;Shigemura N. et al.;Fujiwara H. et al.;Futamatsu H. et al.;Murakami M. et al.;Shigemura N. et al.;Ito W.et al.;Isogawa K. et al.;Kashiwakura Y. et al.;Imai Y.et al.;Ishihara N. et al.;Chiyonobu T. et al.;Yuge K.et al.
通讯作者：
Yuge K.et al.

船越洋, 中村敏一: "脳と神経"医学書院. 5 (2003)

船越浩、中村俊一：《大脑与神经》医学书院 5 (2003)。