血管紧张素1-7通过SIRT1调控老化相关的肺纤维化逆转功能失调的机制研究

特发性肺纤维化(IPF)的驱动因素—老化是近年来研究热点。肺纤维化常因机体老化而逆转障碍，但机制不明。前期工作发现，纤维化自发逆转过程中伴随脂肪酸β-氧化(FAO)升高，后者如被抑制则肺成纤维细胞由活化状态（aLF）向非活化状态（iLF）转化受抑；老化时FAO下降、脂肪酸合成增多，氧化应激增强，I型胶原交联重构增加，溶酶体功能下降，aLF向iLF转化及胶原清除障碍；受SIRT1调控的fPRDM16两种亚型（fPRDM16与sPRDM16）失衡与脂肪酸代谢异常相关；血管紧张素1-7(Ang(1-7))促进SIRT1表达及aLF向iLF转化。由此，我们设想：Ang(1-7)激活SIRT1，调节fPRDM16与sPRDM16平衡，改善脂肪酸代谢；同时增强溶酶体功能，最终促进aLF向iLF转化及胶原清除，对抗老化引起的肺纤维化逆转功能失调。本课题拟从体内外验证上述假说，为IPF的治疗提供新策略。

Aging, a hot topic in recent years，is a driving force of idiopathic pulmonary fibrosis (IPF). During aging, the specific mechanisms of pulmonary fibrosis reverse obstacle remain unclear. Our previous study found that the spontaneous reversal of fibrosis was accompanied by the increased capacity of fatty acid oxidation (FAO). Inhibited FAO resulted in decreased transformation of activated lung fibroblast (aLF) into inactivated state (iLF).During aging, FAO was inhibited, accompany with redox imbalance and extracellular collagen I remodeling induced by impaired fatty acid metabolism, and lysosomal degradability were also inhibited, which resulted in decreased transformation of aLF into iLF and reduced extracellular collagen I clearance. In addition, the imbalance of two subtypes of PRDM16 (fPRDM16 and sPRDM16) regulated by SIRT1 is a important contributor to impaired fatty acid metabolism，while angiotensinogen 1-7 (Ang 1-7) activated SIRT1, and subsequently promoted the transformation of aLF into iLF. Consequently, we hypothesize that Ang (1-7), mediated by SIRT1, modulated fatty acid metabolism by maintaining the balance of fPRDM16 and sPRDM16, meanwhile increased lysosomal degradability, leading to promote the transformation of aLF to iLF and clearance of extracellular collagen I, which promoted pulmonary fibrosis regression during aging.In this context, we will perform in vivo and in vitro experiments to verify the above hypothesis and provide a new strategy for the treatment of IPF.