慢性间歇低氧对上气道扩张肌内质网应激损伤的影响及脂联素的干预机制

Obstructive sleep apnea hypopnea syndrome (OSAHS), characterized by chronic intermittent hypoxia (CIH), is closely correlated to genioglossus dysfunction. Chronic intermittent hypoxia (CIH) has been identified to mediate mitochondrial damage in genioglossus. Our previous studies have implicated that CIH could to hypoadiponectinemia, as well as mitochondrial and microstructral dysfunction in genioglossus. It has been reported that endoplasmic reticulum stress (ERS) could be induced by outcomes of mitochondrial dysfunction. Similar to CIH, ischemia/reperfusion could induce ERS in cardiac myocytes which further lead to mitochondrial dysfunction and cellular damage. Our preliminaries also implied that CIH may arouse the signaling pathways of ERS in genioglossus. Thereby, we speculate that the CIH-induced mitochondrial and microstructure dysfunction in genioglossus are probably associated with ERS. Aiming to investigate the role of ERS in CIH-induced genioglossus injury, as well as the possible intervention effect of adiponectin (Ad) supplement, this study will be helpful to illuminate the pathogenesis of OSAS and to innovate novel medications for OSAHS.

颏舌肌是最重要的上气道扩张肌，其功能障碍可导致阻塞性睡眠呼吸暂停低通气综合征（OSAHS）。慢性间歇低氧（CIH）可降低血清脂联素水平、破坏线粒体结构并干扰其功能，引起颏舌肌收缩障碍；补充脂联素可显著改善上述病理损伤。但具体机制仍未完全阐明。细胞的内质网对蛋白合成及维持细胞稳态至关重要。内质网应激（ERS）可介导组织损伤。缺氧可干扰二硫键生成而激发ERS；在与CIH相似的缺血—再灌注过程中也存在由ERS介导的损伤。我们前期研究发现：CIH可在颏舌肌组织中激活ERS的启动分子；可能诱导心肌细胞发生ERS。因此猜想：CIH通过诱发ERS介导颏舌肌组织损伤和功能障碍。通过本课题研究进一步探讨内质网应激与CIH所致颏舌肌损伤的关联，以及脂联素干预作用的潜在机理，为彻底阐明OSAHS的发病机制及设计新型治疗药物提供线索。

颏舌肌是最重要的上气道扩张肌，其功能障碍可导致阻塞性睡眠呼吸暂停低通气综合征（OSAHS）。慢性间歇低氧（CIH）可降低血清脂联素水平、破坏线粒体结构并干扰其功能，引起颏舌肌收缩障碍；补充脂联素可显著改善上述病理损伤。但具体机制仍未完全阐明。本研究建立大鼠的间歇性缺氧模型，发现该条件下大鼠肺组织存在结构破坏、炎症因子增多以及氧化应激加强，予以关防己治疗的间歇性缺氧大鼠上述损害相对减轻。本研究还通过观察间歇性缺氧条件下培养的成人心肌细胞，发现其存在活性降低、细胞膜不稳定、凋亡比例增加、炎症因子增多、氧化应激加强等损伤表现，予以脂联素治疗的同类细胞则具有一定的缓解作用，并且呈现剂量相关性。本研究因此得出结论，间歇性缺氧可通过结构破坏、诱发炎症和诱导氧化应激等途径损伤肺组织、心肌细胞，脂联素和关防己在这种病理因素中具有一定的治疗效果。