Downregulation of R-Spondin1 Contributes to Mechanical Stretch-Induced Lung Injury
Downregulation of R-Spondin1 Contributes to Mechanical Stretch-Induced Lung Injury
复制标题
R-Spondin1 下调导致机械牵张引起的肺损伤
DOI：
10.1097/ccm.0000000000003767
复制
发表时间：
2019
影响因子：
8.8
通讯作者：
Jiang Lai
中科院分区：
文献类型：
--
作者：
Xu Chu-Fan;Liu Yu-Jian;Wang Yan;Mao Yan-Fei;Xu Dun-Feng;Dong Wen-Wen;Zhu Xiao-Yan;Jiang Lai
目的：R-Respondin家族通过紧致内皮和防止血管渗漏来减轻组织损伤。本研究旨在研究R-Spinins能否预防机械牵张引起的内皮功能障碍和肺损伤，并揭示其潜在的机制。设计：随机对照研究。地点：大学研究实验室。对象：计划接受机械通气支持手术的患者。成年雄性癌症研究所小鼠。原代培养小鼠肺血管内皮细胞。干预：患者接受机械通气支持3小时或更长时间的外科手术。小鼠给予机械通气量(6或30mL/kg)0.5~4h。另一组小鼠腹腔注射脂多糖1 mg/kg，12h后进行机械通气(10mL/kg)4h。对小鼠肺血管内皮细胞进行4小时的周期性拉伸。测量和主要结果：在手术患者和暴露于机械通气的实验动物中，R-Spin1的表达均下调。气管内滴注R-Spin1减弱，而敲除肺R-Spin1则加重呼吸机诱导的肺损伤和机械牵张诱导的肺血管内皮细胞凋亡。在周期性拉伸的小鼠肺血管内皮细胞中，R-Spindin1通过富含G蛋白偶联受体5的亮氨酸重复序列发挥抗细胞凋亡作用。我们发现P53-2是与富含G蛋白偶联受体5的亮氨酸重复序列相互作用的细胞内信号蛋白。R-Spin1处理减少了P53 2与P53的相互作用，而增加了P53 2与含有G蛋白偶联受体5的富亮氨酸重复序列的结合，从而使P53介导的促凋亡通路失活。在周期性拉伸的小鼠肺血管内皮细胞中，R-Spindin1可增强富含亮氨酸重复序列的G蛋白偶联受体5与P53 2的凋亡刺激蛋白的相互作用，从而抑制P53介导的促凋亡通路。R-Spindin1在减轻机械呼吸机所致肺损伤方面可能具有一定的临床意义。
Objectives:The R-spondin family attenuates tissue damage via tightening endothelium and preventing vascular leakage. This study aims to investigate whether R-spondins protect against mechanical stretch-induced endothelial dysfunction and lung injury and to reveal the underlying mechanisms.Design:Randomized controlled study.Setting:University research laboratory.Subjects:Patients scheduled to undergo surgery with mechanical ventilation support. Adult male Institute of Cancer Research mice. Primary cultured mouse lung vascular endothelial cells.Interventions:Patients underwent a surgical procedure with mechanical ventilation support of 3 hours or more. Mice were subjected to mechanical ventilation (6 or 30 mL/kg) for 0.5–4 hours. Another group of mice were intraperitoneally injected with 1 mg/kg lipopolysaccharide, and 12 hours later subjected to mechanical ventilation (10 mL/kg) for 4 hours. Mouse lung vascular endothelial cells were subjected to cyclic stretch for 4 hours.Measurements and Main Results:R-spondin1 were downregulated in both surgical patients and experimental animals exposed to mechanical ventilation. Intratracheal instillation of R-spondin1 attenuated, whereas knockdown of pulmonary R-spondin1 exacerbated ventilator-induced lung injury and mechanical stretch-induced lung vascular endothelial cell apoptosis. The antiapoptotic effect of R-spondin1 was mediated through the leucine-rich repeat containing G-protein coupled receptor 5 in cyclic stretched mouse lung vascular endothelial cells. We identified apoptosis-stimulating protein of p53 2 as the intracellular signaling protein interacted with leucine-rich repeat containing G-protein coupled receptor 5. R-spondin1 treatment decreased the interaction of apoptosis-stimulating protein of p53 2 with p53 while increased the binding of apoptosis-stimulating protein of p53 2 to leucine-rich repeat containing G-protein coupled receptor 5, therefore resulting in inactivation of p53-mediated proapoptotic pathway in cyclic stretched mouse lung vascular endothelial cells.Conclusions:Mechanical ventilation leads to down-regulation of R-spondin1. R-spondin1 may enhance the interaction of leucine-rich repeat containing G-protein coupled receptor 5 and apoptosis-stimulating protein of p53 2, thus inactivating p53-mediated proapoptotic pathway in cyclic stretched mouse lung vascular endothelial cells. R-spondin1 may have clinical benefit in alleviating mechanical ventilator-induced lung injury.