溶血磷脂胆碱在肺气肿中的作用及靶向干细胞治疗的机制研究

Chronic obstructive pulmonary disease and its featured pathological composition, lung emphysema, remain the primary threat to public health among the chronic diseases. Our preliminary study demonstrated that apoptosis causes emphysema, and the apoptotic cells can release certain proapoptotic substance that is simultaneously chemotactic. Using electrospray ionization mass spectrometry and flow cytometry, we identified the substance as lysophosphatidylcholine (LPC). Apoptosis and oxidative stress induced by this substance could be blocked either by inhibition of calcium-independent phospholipase A2 (to block the generation of LPC), or by inhibition of G2A, the receptor of LPC. Consistently, LPC concentration is remarkably elevated in either plasma or bronchoalveolar lavage fluid of emphysematous mice, while the expression of lysophosphatidylcholine acyltransferase 1 (LPCAT1) in the lung, which degrades LPC, is reduced. Here, using our unique real time in situ fluoresence microscopy for mouse lung, we aim to dissect the close interaction as well as temporal-spatial correlation among apoptosis, oxidative stress and proteolysis, and analyze their contributions to emphysema formation, thereby verifying our hypothesis that LPC released from apoptotic cells could in turn induce apoptosis of normal neighboring cells, chemotaxis of T cells, oxidative stress, proteolysis, and eventually lead to lung emphysema. Accordingly, targeted mesenchymal stem cell therapy by overexpression of its lpcat1 will be tested for safety and feasibility of potential clinical application. Our study may provide with a novel therapeutic strategy for this refractory disease.

慢性阻塞性肺病及其主要病理构成肺气肿是威胁人类健康最主要的慢性疾病。前期研究中，我们发现细胞凋亡能导致肺气肿发生，且肺凋亡细胞能释放出促凋亡、并具有趋化作用的物质，电喷雾质谱分析、流式细胞术等检测证实其为溶血磷脂胆碱(LPC)。该物质的促凋亡、增加氧化应激等作用能通过阻断钙离子非依赖性磷脂酶A2(抑制LPC生成)或阻断LPC受体G2A而得到缓解。结合肺气肿小鼠血液及肺灌洗液中LPC含量显著增加，而其肺组织中降解LPC的溶血磷脂胆碱酰基转移酶1(LPCAT1)表达下降的发现，本研究旨在使用国际特有的小鼠原位实时荧光显微镜技术精确剖析细胞凋亡、氧化应激和蛋白酶水解之间相互作用和时空关联对肺气肿的作用，验证关于凋亡肺细胞释放LPC导致正常细胞凋亡、T细胞趋化、氧化应激、蛋白酶水解，从而引起肺气肿的设想，并尝试使用过度表达 lpcat1基因的间充质干细胞治疗肺气肿，为治疗该疾病提供新的方法和依据

慢性阻塞性肺病及其主要病理构成肺气肿是威胁人类健康最主要的慢性疾病。前期研究中 ，我们发现细胞凋亡能导致肺气肿发生，且肺凋亡细胞能释放出促凋亡、并具有趋化作用的物质，电喷雾质谱分析、流式细胞术等检测证实其为溶血磷脂胆碱(LPC)。该物质的促凋亡、增加氧化应激等作用能通过阻断钙离子非依赖性磷脂酶A2(抑制LPC生成)或阻断LPC受体G2A而得到缓解。结合肺气肿小鼠血液及肺灌洗液中LPC含量显著增加，而其肺组织中降解LPC的溶血磷脂胆碱酰基转移酶1 (LPCAT1)表达下降的发现，本研究使用国际特有的小鼠原位实时荧光显微镜技术精确剖析细胞凋亡、氧化应激和蛋白酶水解之间相互作用和时空关联对肺气肿的作用，验证了关于凋亡肺细胞释放LPC导致正常细胞凋亡、T细胞趋化、氧化应激、蛋白酶水解，从而引起肺气肿的设想，并在动物模型中使用过度表达 lpcat1基因的间充质干细胞治疗肺气肿，为治疗该疾病提供新的方法和依据。