Cyr61在结缔组织病相关肺动脉高压发病机制中作用的研究

Pulmonary arterial hypertension（PAH）is a severe complication of connective tissue disease. Proliferation and inflammation have been confirmed to be involved in the pathogenesis of connective tissue disease associated PAH. Cysteine-rich 61（Cyr61）is important in promoting angiogenesis, cell proliferation, and inflammatory processes. It has been proved that Cyr61 plays a povital role in varieties of biological processes. Our preliminary study demonstrated that expression of Cyr61 was significantly elevated in the plasma of systemic lupus erythematosus and systemic sclerosis associated PAH and in the wall of pulmonary artery in monocrotaline rat models of PAH, indicating Cyr61 may play an important role in the pathogenesis of connective tissue disease associated PAH, therefore, we hypothesize that Cyr61 is involved in the pathogenesis of connective tissue disease associated PAH by stimulating vascular proliferation and promoting inflammation in lung. To test this hypotheses, we will set out to look at the impact of Cyr61 on the cell proliferation and inflammation of pulmonary vessels, and try to further investigate the possible mechanism in this study. Our study will help to further understand the pathogenesis of CTD-PAH, and also may provide important clues to finding potential therapeutic targets in the future. The study on Cyr61 in the pathogenesis of connective tissue disease asssociated PAH has never been reported worldwide.

肺动脉高压（Pulmonary arterial hypertension, PAH）是结缔组织病的严重并发症，血管过度增殖和炎症是主要发病机制。高半胱氨酸蛋白61（Cysteine rich 61 ,Cyr61) 是重要的血管刺激因子，可促进炎症反应、细胞增殖，并在多种疾病的发病中起关键作用。我们的前期研究发现系统性红斑狼疮及系统性硬化相关PAH患者血浆及野百合碱诱导的PAH大鼠模型肺动脉壁Cyr61表达均增加，提示Cyr61可能在参与结缔组织病相关PAH的发病。我们推测，Cyr61通过促进血管增殖和肺组织炎症参与了结缔组织病相关PAH的发病。因此，我们将针对Cyr61对野百合碱诱导的PAH大鼠肺血管平滑肌细胞增殖以及炎症过程的影响进行研究，并探讨其作用机制。目前此研究在国内外尚属首次，希望能够通过此研究进一步加深对于结缔组织病相关PAH发病机制的理解,为寻找新的治疗靶点提供重要线索。

肺动脉高压是结缔组织病常见且极为严重的并发症，病情进展快、死亡率高。目前其具体发病机制仍不清楚，但越来越多研究显示异常免疫炎症反应及其所致的血管重塑是其基本病理改变。因此，我们一直在积极寻找参与PAH发病过程中的新型免疫调节分子和/或免疫细胞及相关调控机制。基于我们前期工作基础，本课题组通过临床结合基础研究首次提出并证实新型免疫调节分子Cyr61在CTD-PAH患者和动物模型中表达明显升高。随后在多中心SLE-PAH队列研究中进一步分析，发现Cyr61高水平不仅可作为SLE患者合并PAH的独立预测因素，还与SLE-PAH患者长期预后有关，具有潜在的临床应用价值。此外，巨噬细胞在PAH发病机制中发挥关键作用。我们团队探索并发现PAH发生发展过程中出现肺组织局部区域M1、M2型巨噬细胞动态演变现象，在疾病早期以CD68+NOS2+ M1型巨噬细胞增多为主，而在中晚期以CD68+CD206+ M2型巨噬细胞增多为主。体外实验显示M1型巨噬细胞可诱导血管内皮细胞凋亡增加、抑制增殖，导致血管内皮损伤及炎症反应加重；而M2巨噬细胞可明显促进血管平滑肌细胞增殖，参与血管中膜增厚过程。通过对Cyr61 5ug/ml刺激24h后的M0型巨噬细胞进行转录组学RNA-seq检测发现：Cyr61可诱导巨噬细胞M1型极化，分泌大量趋化因子及细胞因子，高表达M1型巨噬细胞极化相关表面marker，其中转录因子KLF4及转录调节因子SOCS3被证实参与此过程。因此，本研究首次揭示Cyr61参与结缔组织病相关肺动脉高压发病过程及其致病机制，同时提出并证实PAH发生发展过程中肺组织局部区域存在M1和M2型巨噬细胞动态改变现象，为进一步完善CTD-PAH的发病机制及对新药物靶点的开发提供全新思路及理论依据。