重叠综合征模式低氧致血管内皮损伤中性粒细胞与内皮细胞交互作用机制研究

OSA and COPD are independent risk factors of cardiovascular events, and respiratory overlap syndrome( OS ) with coexistence of intermittent hypoxia (IH) and continuous hypoxia (CH) probably increases this risk. Endothelial dysfunction is the basis of cardiovascular disease. However, the cellular mechanism of endothelial dysfunction in OS is unclear. We have explored the cell interaction mechanism of endothelial dysfunction in IH with the support of Natural Science Fundation of China. In this study, we will continue to explore the mechanism of endothelial dysfunction associated with the crosstalk between polymorphonuclear neutrophils (PMN) and endothelium in hypoxia with OS. IH, CH and nomoxia exposure are control groups, the mechanism of crosstalk between PMN and endothelial cells and abnormal apoptosis will be studied in three levels including OS patients, mice with intermittent with continuous hypoxia exposure, and PMN from healthy person and endothelium with intermittent with continuous hypoxia exposure. We will mainly discuss the effect of changing abnormal apoptosis of PMN in protecting endothelium and ameliorating endothelial dysfunction. Pharmacological and pathophysiological insight will be provided for ameliorating endothelial dysfunction and reducing the occurrence of cardiovascular complication.

OSA与COPD均为心血管疾病主要危险因素，两者并存的呼吸重叠综合征(OS)同时存在间歇低氧和持续低氧，心血管损害会更为严重。血管内皮损伤是心血管疾病发生的基础，目前关于OS内皮损伤细胞水平发病机理尚不清楚。本课题在前一个基金间歇低氧内皮损伤细胞交互机制研究的基础上，进一步探讨OS模式低氧导致内皮损伤的中性粒细胞与血管内皮细胞间的交互作用机制。研究以间歇低氧、持续低氧与正常氧暴露为对照组，分别对OS患者与间歇伴持续低氧暴露动物，以及正常人PMN和血管内皮细胞进行间歇伴持续低氧暴露三个层次进行PMN和内皮细胞交互作用及异常凋亡机制研究，重点探讨PMN凋亡延迟对内皮细胞损伤的机制，进而观察改变PMN异常凋亡对保护内皮细胞和功能的作用。为揭示OS患者并发心血管疾病的可能发病机制与可行干预措施提供必要理论和实验依据。

呼吸重叠综合征（respiratory overlap syndrome, OS）是指OSA与COPD并存，同时存在间歇低氧和持续低氧。研究发现，其心血管损害会更为严重，死亡率也会更高。心血管疾病的发生和血管内皮的损伤明显相关，而以中性粒细胞（PMN）为代表的炎症细胞与血管内皮细胞间的交互作用成为内皮细胞损伤的关键环节。目前关于OS病理机制方面的研究较少。在本课题组前期研究基础上，本研究成功建立间歇低氧伴持续低氧动物和细胞模型，模拟OS间歇伴持续低氧模式。分别对OS患者与间歇伴持续低氧暴露动物，以及正常人PMN和血管内皮细胞进行间歇伴持续低氧暴露三个层次进行PMN和内皮细胞交互作用及异常凋亡机制研究。发现OS组较间歇低氧或熏烟组存在更为明显的PMN凋亡延迟，更为明显的内皮细胞凋亡和损伤，抗氧化剂Tempol或炎症信号通路阻断剂PDTC干预后可减少PMN凋亡延迟并可延缓内皮细胞凋亡和损伤。OS组存在更为明显的炎症和氧化应激反应，通过Tempol或PDTC干预可减轻炎症和氧化应激反应。OS模式下PMN促凋亡、抗凋亡基因表达失衡，血管和细胞粘附作用增强，进而导致更为严重的血管内皮功能障碍。本研究可为进一步揭示OS合并心血管疾病的发病机制及未来治疗的靶点提供相关的实验依据，有重要的临床意义。