Adipose-derived exosomes protect the pulmonary endothelial barrier in ventilator-induced lung injury by inhibiting the TRPV4/Ca2+ signaling pathway
Adipose-derived exosomes protect the pulmonary endothelial barrier in ventilator-induced lung injury by inhibiting the TRPV4/Ca2+ signaling pathway
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脂肪源性外泌体通过抑制 TRPV4/Ca2 信号通路保护呼吸机所致肺损伤中的肺内皮屏障
DOI：
10.1152/ajplung.00255.2019
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发表时间：
2020-04-01
影响因子：
4.9
通讯作者：
Zhu, Tao
中科院分区：
文献类型：
--
作者：
Yu, Qian;Wang, Daoxin;Zhu, Tao
机械通气（MV）是急性呼吸窘迫综合征（ARDS）的主要支持治疗方法，但它可能导致呼吸机诱导的肺损伤（VILI）。大型流行病学研究发现，在急性肺损伤的机械通气患者中，肥胖与较低的死亡率有关，这被称为“肥胖悖论”。然而，肥胖对VILI的影响尚不清楚。本研究通过高脂肪饮食（HFD）和高潮气量通气，研究肥胖对体内VILI的影响，并在体外对肺微血管内皮细胞（PMVECs）进行18%循环拉伸（CS），进一步研究其潜在机制。我们发现HFD通过减轻小鼠肺内皮屏障损伤和炎症反应来保护小鼠免受VILI。脂肪来源的外泌体可以作为一种新的脂肪因子调节远端组织，为细胞间相互作用提供了一种新的机制。我们提取了三种脂肪源性外泌体，包括HFD小鼠血清外泌体（S-Exo）、脂肪组织外泌体（AT-Exo）和脂肪源性干细胞外泌体（ADSC-Exo），并在体内和体外进一步探讨了它们对MV或18% cs诱导的VILI的影响。三种外泌体通过抑制肺内皮屏障高通透性，修复粘附连接的表达，减轻体内和体外炎症反应，同时伴有瞬时受体电位香草样蛋白4 (TRPV4)/Ca2+途径抑制，来保护VILI。总之，这些数据表明，hfd诱导的肥胖通过脂肪来源的外泌体减轻肺内皮屏障损伤和炎症反应，至少部分地通过抑制TRPV4/Ca2+途径，在VILI中发挥保护作用。
Mechanical ventilation (MV) is the main supportive treatment of acute respiratory distress syndrome (ARDS), but it may lead to ventilator-induced lung injury (VILI). Large epidemiological studies have found that obesity was associated with lower mortality in mechanically ventilated patients with acute lung injury, which is known as “obesity paradox.” However, the effects of obesity on VILI are unknown. In the present study, wild-type mice were fed a high-fat diet (HFD) and ventilated with high tidal volume to investigate the effects of obesity on VILI in vivo, and pulmonary microvascular endothelial cells (PMVECs) were subjected to 18% cyclic stretching (CS) to further investigate its underlying mechanism in vitro. We found that HFD protects mice from VILI by alleviating the pulmonary endothelial barrier injury and inflammatory responses in mice. Adipose-derived exosomes can regulate distant tissues as novel adipokines, providing a new mechanism for cell-cell interactions. We extracted three adipose-derived exosomes, including HFD mouse serum exosome (S-Exo), adipose tissue exosome (AT-Exo), and adipose-derived stem cell exosome (ADSC-Exo), and further explored their effects on MV or 18% CS-induced VILI in vivo and in vitro. Administration of three exosomes protected against VILI by suppressing pulmonary endothelial barrier hyperpermeability, repairing the expression of adherens junctions, and alleviating inflammatory response in vivo and in vitro, accompanied by transient receptor potential vanilloid 4 (TRPV4)/Ca2+ pathway inhibition. Collectively, these data indicated that HFD-induced obesity plays a protective role in VILI by alleviating the pulmonary endothelial barrier injury and inflammatory response via adipose-derived exosomes, at least partially, through inhibiting the TRPV4/Ca2+ pathway.