细胞外基质刚度通过调控miR-21/Yap1-自噬轴抑制肺成纤维细胞凋亡：肺纤维化新机制

The irreversible aggravation of pulmonary fibrosis is the main cause of the difficulty of treatment in patients with Idiopathic Pulmonary Fibrosis (IPF), but its pathophysiological mechanism is still unclear. Literatures have revealed the tissue stiffness of fibrous lesions in IPF patients and bleomycin-treated rats was significantly higher than that in non-lesion areas, and matrix stiffness was confirmed to play an important role in activating pulmonary fibroblasts, indicating the positive feedback regulation to promote each other between matrix stiffness and pulmonary renin-angiotensin system (RAS). In addition, angiotensin II type 1 receptor (AT1R) was demonstrated as the main effector of RAS, which promoted the process of autophagy and fibrosis, inhibiting apoptosis in fibroblasts, as well as one of the essential transducers of mechanical signal. Simultaneously, Yap1 was verified to be at the core of three mechanisms: mechanical conduction of stiffness, pulmonary fibrosis induced by RAS and regulation of autophagy. Thus, in this study, we aimed to prove the regulatory network among RAS-matrix stiffness-pulmonary fibrosis-autophagy via in vivo and in vitro experiments, and verify the scientific hypothesis: extracellular matrix stiffness promoted the proliferation and activation of fibroblasts by interacting with AT1R to produce a mutually reinforcing "cascade amplification" effect, resulting in progressive exacerbation of pulmonary fibrosis. Finally, our study would provide a new molecular target and theoretical basis for the pathophysiological mechanism of idiopathic pulmonary fibrosis.

肺纤维化持续性进展是特发性肺纤维化（IPF）病人治疗困难的重要原因，但其病理生理机制仍不清楚。研究发现IPF病人及博来霉素处理大鼠肺组织中纤维病灶区域的组织刚度显著高于非病变区，而新近报道证实细胞外基质刚度可持续活化肺成纤维细胞，提示基质刚度与肺纤维化之间存在相互促进的正反馈作用。血管紧张素II 1型受体是肾素-血管紧张素系统（RAS）的主要效应器，介导血管紧张素II对成纤维细胞的促自噬、抑凋亡及促纤维化作用，同时也是重要的机械信号转导分子。结合我们既往已证实的结果，Yap1处于基质刚度机械力传导、RAS诱导肺纤维化及调节自噬三种机制的核心位置，本研究拟通过体内外实验证实RAS-基质刚度-自噬-纤维化调控的网络关系，验证科学假说：细胞外基质刚度通过与AT1R相互作用产生“级联放大”效应促进成纤维细胞持续活化，导致肺纤维化进行性加重，为特发性肺纤维化治疗提供新的靶点及治疗策略。

肺纤维化持续性进展是特发性肺纤维化（IPF）病人治疗困难的重要原因，但其病理生理机制仍不清楚。新近研究证实细胞外基质刚度可持续活化肺成纤维细胞，基质刚度与肺纤维化存在相互存进的正反馈作用。肺脏RAS是肺纤维化研究热点，然二者联系未见报道。本课题通过体内外实验探究肺脏RAS系统与细胞外基质刚度之间的关系及分子机制，发现血管紧张素II促进肺成纤维细胞活化，上调局部基质刚度；基质刚度反过来促进AT1R，上调miR-21/Yap1复合体，激活自噬抑制肺成纤维细胞凋亡，促进肺成纤维细胞持续合成I型胶原蛋白，最终促进肺纤维化持续进展。研究结果将有助于完善肺纤维化持续进展调控过程中的信号传导通路理论，为明确肺纤维化发病机制及Hippo-Yap1信号通路作为新的治疗靶标的确立提供实验数据。