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

肌成纤维细胞的形成和细胞外基质（ECM）的过度产生是慢性损伤下组织纤维化的发病机制中的常见事件，如肝硬化、肺纤维化和心肌病。在本研究中，我们发现HGF直接靶向间质肌成纤维细胞，并减少ECM积累使用肺纤维化，肝硬化和扩张型心肌病的动物模型。1）通过HGE的肺纤维化的消退：我们使用博莱霉素注射小鼠作为肺纤维化模型，并发现HGF在体内引起肌成纤维细胞群的凋亡变化。此外，我们获得了体外证据：（i）HGF降解ECM蛋白（即，细胞锚定）;（ii）在这种ECM缺陷条件下，肌成纤维细胞失去锚定，然后发生失巢凋亡样凋亡细胞死亡。重要的是，MMP-抑制剂减少了HGF介导的肌成纤维细胞的凋亡性细胞死亡，在体外以及在体内，从而表明HGF诱导的抗纤维化作用在很大程度上依赖于由HGF诱导的MMP。我们将这些结果发表在FASEB-Journal 19：580（2005）中。2）通过HGF减少肝硬化和心肌病中的间质纤维化：在肝硬化的大鼠模型中，HGF增强肌成纤维细胞凋亡并抑制间质肌成纤维细胞的增殖。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。在心肌病仓鼠模型中，HGF减少间质肌成纤维细胞中TGF-β的产生，随后减少ECM以及改善心脏功能。这些结果分别发表在Am-J-Pathol 166：1017（2005）和Am-J-Physiol 288：H2131（2005）中。

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.