ACE2-Ang(1-7)-MAS轴在肌成纤维细胞致哮喘气道重塑中的作用及机制

The effect and mechanism of myofibroblast in the asthma-induced airway remodeling has become a hot spot in the field of asthma. The ACE-Ang II-AT1 receptor axis in local renin-angiotensin system (RAS) plays a pivotal role in collagen production in asthma. As evidenced, ACE2-Ang(1-7)-Mas axis, as the new branch of RAS, has the antagonism against ACE-Ang II-AT1 receptor axis. However, effect and mechanism of this new branch in the airway remodel by myofibroblast still remains unclear. We recently have studied the effect of ACE2-Ang(1-7)-Mas axis in lung cancer and pulmonary hypertension and published some relevant articles. Our results convincingly demonstrated that AngⅡ induced the local RAS imbalance in the process of Fibroblasts-Myofibroblasts transition. We also established human fetal lung fibroblast subline with overexpressed ACE2. Based on previous studies, we in this study aim to investigate the role and mechanism of ACE2-Ang(1-7)-Mas axis in the process of Fibroblasts-Myofibroblasts transition and asthma-induced airway remodeling. For practical reasons, we hope that this study will provide the basis for a novel strategy to treat asthma-induced airway remodeling.

近年来肌成纤维细胞(MF)在哮喘气道重塑中的作用及机制逐渐成为哮喘的研究热点。局部肾素血管紧张素系统(RAS)中ACE-AngⅡ-AT1受体轴可促进哮喘胶原蛋白形成增加。而与该轴对抗的RAS新分支ACE2-Ang(1-7)-Mas轴是否抑制成纤维细胞(FB)向MF转化，减轻哮喘气道重塑，是通过何种机制发挥作用还尚未有报道。我们近几年来一直致力于该RAS新分支在肺癌及肺动脉高压中作用的研究，发表多篇相关文章。最近我们研究发现AngⅡ在促进FB向MF转化过程中出现局部RAS系统表达失衡，胶原蛋白产生增加，同时我们构建了过表达ACE2的大鼠成纤维细胞。本研究拟在现有基础上，通过探讨该新分支在FB向MF转化及其在气道重塑中的作用，寻找相关的作用通路，结合动物模型研究，从分子、细胞及动物整体水平上揭示该新分支与MF致气道重塑的关系，为进一步研究哮喘气道重塑的机制，减轻气道重塑提供新的方向。

近年来肌成纤维细胞(MF)在哮喘气道重塑中的作用及机制逐渐成为哮喘的研究.热点。局部肾素血管紧张素系统(RAS)中 ACE-AngⅡ-AT1 受体轴可促进哮喘胶原蛋白形成增加。而与该轴对抗的 RAS 新分支 ACE2-Ang(1-7)-Mas 轴是否抑制成纤维细胞(FB)向 MF 转化，减轻哮喘气道重塑，是通过何种机制发挥作用还尚未有报道。我们近几年来一直致力于该 RAS新分支在肺癌及肺动脉高压中作用的研究，发表多篇相关文章。我们此项研究发现AngⅡ在促进 FB 向 MF 转化过程中出现局部 RAS 系统表达失衡，胶原蛋白产生增加，α-SMA, TGF-β1表达增加。血管紧张素-(1-7) 通过TGF-β1/Smad2/3通路降低胶原蛋白I表达，从而可抑制肺成纤维细胞向肌成纤维细胞转化，逆转哮喘的气道重塑。过表达ACE2通过MAPK及Smad通路抑制胶原蛋白I表达，抑制哮喘气道重塑。本研究拟在现有基础上，通过探讨该新分支在 FB 向MF转化及其在气道重塑中的作用，寻找相关的作用通路，结合动物模型研究，从分子、细胞及动物整体水平上揭示该新分支与 MF 致气道重塑的关系，为进一步研究哮喘气道重塑的机制，减轻气道重塑提供新的方向。