间充质干细胞治疗COPD与OSA重叠综合征的疗效及机制研究

The term “overlap syndrome” is commonly used to describe chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), when coexisting. Vascular endothelial injury could be the pivotal determinant in the development of cardiovascular pathology in overlap syndrome. Mesenchymal stem cells (MSCs) are undifferentiated cells, which can localize to the injured tissue and differentiate into vascular endothelial cells to repair vascular endothelial injury. In our preliminary study, we found that MSCs transplantation could alleviate emphysema of rats. Based on the result, in this study, overlap syndrome rat model will be established, and then we will estimate the vascular endothelial injury and determine mechanism of endothelial injury. After administration of MSCs, we will estimate the therapeutic effect of MSCs transplantation for the overlap syndrome by measuring survival rate, respiratory function, cardiac function, pulmonary vascular wall remodeling, atherosclerosis and vascular endothelial injury. We will identify repair mechanism after vascular endothelial injury by estimating the inflammation, oxidative stress and determining apoptosis of vascular endothelial cells and the engraftment and differentiation of MSCs in vascular wall. So as to find a new effective therapy for the overlap syndrome.

重叠综合征是由慢性阻塞性肺疾病（COPD）和阻塞性睡眠呼吸暂停（OSA）重叠构成的一种疾病。血管内皮损伤是重叠综合征并发心血管疾病的始动环节。间充质干细胞（MSCs）是未分化的细胞，能归巢到受损组织，分化为血管内皮细胞而修复血管内皮损伤。我们前期的研究发现MSCs移植可减轻大鼠肺气肿，本研究旨在此基础上建造重叠综合征大鼠模型，测定血管内皮损伤情况,明确损伤机制；予大鼠骨髓MSCs移植后通过观测存活率、呼吸功能、心功能、肺血管重塑、动脉粥样硬化及血管内皮损伤等指标评估MSCs的疗效；通过测定炎症水平及氧化应激水平，检测血管内皮细胞凋亡情况及MSCs向血管内皮细胞的分化情况，明确MSCs修复血管内皮损伤的机制。以寻求有效治疗重叠综合征的新方法。

重叠综合征（OS）由慢性阻塞性肺疾病（COPD）和阻塞性睡眠呼吸暂停（OSA）重叠构成的一种疾病，血管内皮损伤是重叠综合征并发心血管疾病最重要的病理生理基础，OS患者的病死率、住院率比单纯的 COPD或 OSA 高，OS患者更容易出现心血管疾病。目前治OS的主要方法是在药物治疗 COPD 的基础上正确使用无创呼吸机辅助通气，一方面COPD的药物治疗仅对症治疗，无法阻止疾病的进展；另一方面多数患者对无创呼吸机辅助通气的耐受性及依从性差，影响了治疗效果，故亟待需要寻找新的、有效治疗OS的方法。. 本研究采用熏烟联合间歇低氧的方法成功构建了OS大鼠模型，发现较单纯的肺气肿和OSA相比，OS存在更明显的血管内皮损伤情况，揭示熏烟联合间歇低氧通过氧化应激、减少血管内皮保护性因子、促血管生成因子生成等机制，协同加重OS血管内皮损伤。. 间充质干细胞（MSCs）是未分化的细胞，研究发现MSCs能从骨髓动员到其他器官，归巢到受损的组织，可分化为包括血管内皮细胞在内的多种细胞而发挥修复功能功能。本研究发现，BMSCs通过分化为肺泡壁内皮细胞、抑制内皮细胞损伤凋亡、促进内皮细胞增殖、抗氧化、抗炎症、调节血管损伤修复因子表达等多种机制，起到修复OS大鼠血管内皮损伤及治疗的作用。这为临床探索BMSCs移植治疗OS综合征奠定了坚实的理论基础和依据。