PDF(Pubmed)
Abstract：
Fibrosis can occur in almost all tissues and organs and affects normal physiological function, which may have serious consequences, such as organ failure. However, there are currently no effective, broad-spectrum drugs suitable for clinical application. Revealing the process of fibrosis is an important prerequisite for the development of new therapeutic targets and drugs. Studies have shown that the limiting of myofibroblast activation or the promoting of their elimination can ameliorate fibrosis. However, it has not been reported whether a direct decrease in cell contraction can inhibit fibrosis in vivo. Here, we have shown that (-)-blebbistatin (Ble), a non-muscle myosin Ⅱ inhibitor, displayed significant inhibition of liver fibrosis in different chronic injury mouse models in vivo. We found that Ble reduced the stiffness of fibrotic tissues from the early stage, which reduced the extent of myofibroblast activation induced by a stiffer extracellular matrix (ECM). Moreover, Ble also reduced the activation of myofibroblasts induced by TGF-β1, which is the most potent pro-fibrotic cytokine. Mechanistically, Ble reduced mechanical contraction, which inhibited the assembly of stress fibers, decreased the F/G-actin ratio, and led to the exnucleation of YAP1 and MRTF-A. Finally, we verified its broad-spectrum antifibrotic effect in multiple models of organ fibrosis. Our results highlighted the important role of mechanical contraction in myofibroblast activation and maintenance, rather than just a characteristic of activation, suggesting that it may be a potential target to explore broad-spectrum drugs for the treatment of fibrotic diseases.
摘要：
纤维化可以发生在几乎所有的组织和器官，并影响正常的生理功能，这可能会有严重的后果，如器官衰竭。然而,目前没有有效的，适合临床应用的广谱药物。揭示纤维化的过程是开发新的治疗靶点和药物的重要前提。研究表明，限制肌成纤维细胞的活化或促进其消除可以改善纤维化。然而,目前还没有报道直接减少细胞收缩是否可以抑制体内纤维化。这里,我们已经证明了(-)-blebbistatin(Ble)，一种非肌肉肌球蛋白Ⅱ抑制剂，在体内不同慢性损伤小鼠模型中表现出明显的肝纤维化抑制作用。我们发现Ble从早期就降低了纤维化组织的硬度，这降低了由更硬的细胞外基质（ECM）诱导的肌成纤维细胞活化的程度。此外，Ble还降低了由TGF-β1诱导的肌成纤维细胞的激活，TGF-β1是最有效的促纤维化细胞因子。机械上,Ble减少了机械收缩，抑制应力纤维的组装，降低了F/G-肌动蛋白比，并导致YAP1和MRTF-A的去核。最后,我们在多个器官纤维化模型中验证了其广谱抗纤维化作用.我们的结果强调了机械收缩在肌成纤维细胞活化和维持中的重要作用，而不仅仅是激活的特征，这表明它可能是探索用于治疗纤维化疾病的广谱药物的潜在靶标。
