RGS1通过PLC/IP3/Ca2+信号调控炎性肺泡巨噬细胞表型差异介导COPD发病机制的研究

慢阻肺（COPD）是我国的常见病和高发病，带来巨大经济和社会负担，但发病机制未明。我们报道了肺泡巨噬细胞（AM）Ly6C-、Ly6Chi-和Ly6Clow亚群分别具有抗炎、促炎和组织损伤异质性，可能参与COPD发病。肺部感染小鼠存活率取决于Flt3+和Tie2+AMs是否平衡及RGS1基因在这两种AMs中的表达是否持续下调；RGS1敲除小鼠较WT小鼠更易发生烟雾暴露相关肺损伤，且PLC相关信号通路可能参与其中。因此提出假设RGS1可能通过调控AMs炎症化表型介导COPD发病的关键基因。拟用免疫表征不同的RGS1Tie2/RGS1Flt3小鼠，予烟雾暴露，观测小鼠促/抗炎因子、肺损伤指标等变化，使用敲除或过表达RGS1及PLC信号通路抑制剂干预等手段，分别在动物和细胞层面探索RGS1基因在COPD发病中的机制，有助于揭示RGS1在巨噬细胞参与的肺脏免疫防御机制中的作用和寻找COPD干预靶点。

Chronic obstructive pulmonary disease (COPD) is a common and high incidence disease in China, which brings huge economic and social burdens, but the pathogenesis is unknown. We report that the Ly6C-, Ly6Chi- and Ly6Clow subgroups of alveolar macrophages (AM) have anti-inflammatory, pro-inflammatory and tissue damage heterogeneity, respectively, and may be involved in the pathogenesis of COPD. The survival rate of mice with lung infection depends on whether Flt3+ and Tie2+ AMs are balanced and whether the expression of RGS1 gene in these two AMs continues to be down-regulated; RGS1 knockout mice are more likely to develop smoke exposure-related lung injury than WT mice, and PLC Related signal pathways may be involved. Therefore, it is hypothesized that RGS1 may mediate the key genes in the pathogenesis of COPD by regulating the inflammatory phenotype of AMs. It is planned to use immunological characterization of different RGS1Tie2/RGS1Flt3 mice, expose them to smoke, observe changes in mouse pro-/anti-inflammatory factors, lung injury indicators, etc., and use methods such as knockout or overexpression of RGS1 and PLC signaling pathway inhibitor intervention, respectively. Exploring the mechanism of RGS1 gene in the pathogenesis of COPD at the animal and cellular level will help to reveal the role of RGS1 in the lung immune defense mechanism involved in macrophages and to find targets for COPD intervention.