BMP信号调节系统性红斑狼疮相关肺动脉高压中内皮细胞损伤的机制研究

Pulmonary arterial hypertension (PAH) is a serious complication of systemic lupus erythematosus (SLE). At present, the related factors affecting PAH penetrance in SLE patients and the relationship between inflammation and bone morphogenetic protein (BMP) pathway in this disease have not been clearly clarified. In this project, we will focus on the damage of pulmonary vascular endothelial cells (EC) and the activation mechanism of innate immune cells in SLE-PAH: at first，we would try to analyze the "inside factor" -BMP-related autoantibodies and "outside factor" -endotoxin from the external environment to elucidate their effects on inhibiting BMP signaling，upregulating pro-inflammatory factors expression in EC and the mechanism of EC damage; besides, mass cytometry was used to compare the inflammatory cells in peripheral blood of patients with SLE-PAH before and after treatment, so as to identify the specific type(s) of innate immune cells involving in the development of SLE-PAH. We would also study the interaction of damaged EC and the specific innate immune cell(s), to explore the mechanism of BMP signaling regulating innate immune system. In addition, a SLE-PAH mouse model would be established using pristane and hypoxic conditions to elucidate the regulatory effect of BMP upregulator BUR1 on inflammation and to analyze the potential therapeutic effects on SLE-PAH. This study is expected to clarify the association between impaired BMP signaling and PAH penetrance in patients with SLE, and provide a novel target for the SLE-PAH treatment in the future.

肺动脉高压(PAH)是系统性红斑狼疮(SLE)的一种严重并发症。目前对SLE患者发生PAH的影响因素及该疾病中炎症与骨形成蛋白（BMP）通路之间的关系未有明确阐释。本课题针对SLE-PAH中肺血管内皮细胞(EC)受损和天然免疫细胞的活化机制进行探讨：通过对“内”—BMP相关自身抗体和“外”—外源的内毒素两方面因素的分析，阐明其降低BMP信号、上调促炎因子表达进而导致EC损伤的机制；利用质谱流式技术分析SLE-PAH患者治疗前后外周血中免疫细胞变化，明确参与SLE-PAH疾病过程的天然免疫细胞，分析其与受损EC的相互作用机制，探究BMP信号对天然免疫的调控机理。利用降植烷及低氧条件建立SLE-PAH小鼠模型，阐明BMP上调剂BUR1对炎症的调节作用和对SLE-PAH潜在的治疗作用。本课题预期阐明受损BMP信号与SLE患者并发PAH的关联，为今后开发SLE-PAH相关治疗药物提供新的理论靶点。

肺动脉高压(PAH)是系统性红斑狼疮(SLE)的一种严重并发症。对SLE患者发生PAH的影响因素及该疾病中炎症与骨形成蛋白（BMP）通路之间的关系未详细阐明。本课题针对SLE-PAH中肺血管内皮细胞(EC)细胞焦亡和中性粒细胞的活化机制进行探讨：发现了“内”—BMP相关自身抗体和“外”—外源的内毒素两方面因素对SLE患者继发PAH的诱导作用，阐明了其降低BMP信号、上调促炎因子表达进而导致EC焦亡的机制；利用质谱流式技术分析SLE-PAH患者治疗前后外周血中免疫细胞变化，发现中性粒细胞在肺组织的浸润参与SLE-PAH疾病过程。利用降植烷及低氧条件建立SLE-PAH小鼠模型，并建立了AAV诱导的BMPR2内皮敲除小鼠模型，阐明抑制BMP信号会导致SLE-PAH发病更为严重，并且明确了BMP上调剂BUR1对炎症的调节作用和对SLE-PAH潜在的治疗作用。本课题阐明受损BMP信号与LPS共同促进肺血管内皮细胞焦亡导致SLE患者并发PAH，为今后开发BMP自身抗体作为SLE-PAH早期诊断标志物以及焦亡抑制分子作为SLE-PAH相关治疗药物提供新的诊疗策略。