Inhibition of p38 MAPK Mitigates Lung Ischemia Reperfusion Injury by Reducing Blood-Air Barrier Hyperpermeability.
Inhibition of p38 MAPK Mitigates Lung Ischemia Reperfusion Injury by Reducing Blood-Air Barrier Hyperpermeability.
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抑制 p38 MAPK 通过降低血液-空气屏障通透性过高减轻肺缺血再灌注损伤
DOI：
10.3389/fphar.2020.569251
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发表时间：
2020
影响因子：
5.6
通讯作者：
Lin F
中科院分区：
文献类型：
--
作者：
Wang T;Liu C;Pan LH;Liu Z;Li CL;Lin JY;He Y;Xiao JY;Wu S;Qin Y;Li Z;Lin F
背景：肺缺血再灌注损伤（LIRI）是由肺移植和急性肺损伤激活的复杂病理生理过程。 p38 丝裂原激活蛋白激酶 (MAPK) 参与 LIRI 期间内皮屏障的破坏，但其机制仍不清楚。因此，我们在体内和体外研究了 p38 MAPK 在 LIRI 中的功能。 方法：Sprague-Dawley 大鼠在使用或不使用 p38 MAPK 抑制剂预处理的情况下进行缺血再灌注。使用苏木精和伊红染色评估肺损伤，并使用伊文思蓝染色评估肺血气屏障通透性。大鼠肺微血管内皮细胞系用表达靶向 p38 MAPK 的短发夹 (sh)RNA 的慢病毒感染，然后对细胞进行缺氧/葡萄糖剥夺和复氧 (OGD/R)。通过蛋白质印迹和免疫荧光测量内皮破坏的标志物。 结果：体内 LIRI 模型显示出表明肺损伤和血气屏障渗透性过高的结构变化。抑制 p38 MAPK 可减轻这些影响。缺氧/葡萄糖剥夺和复氧可促进体外内皮屏障的通透性过高，但 p38 MAPK 的敲低可减轻细胞损伤；维持内皮屏障完整性；部分逆转损伤诱导的通透性蛋白 AQP1、内皮保护蛋白 eNOS、连接蛋白 ZO-1 和 VE-钙粘蛋白的下调，同时下调 ICAM-1（一种参与破坏内皮屏障的蛋白质）和 ET-1（一种参与内皮功能障碍的蛋白质）。 结论：抑制 p38 MAPK 通过降低血液-空气通透性来减轻 LIRI。阻断 p38 MAPK 可能是治疗急性肺损伤的有效方法。
Background: Lung ischemia reperfusion injury (LIRI) is a complex pathophysiological process activated by lung transplantation and acute lung injury. The p38 mitogen-activated protein kinase (MAPK) is involved in breakdown of the endothelial barrier during LIRI, but the mechanism is still unclear. Therefore, we investigated the function of p38 MAPK in LIRI in vivo and in vitro. Methods: Sprague–Dawley rats were subjected to ischemia reperfusion with or without pretreatment with a p38 MAPK inhibitor. Lung injury was assessed using hematoxylin and eosin staining, and pulmonary blood–air barrier permeability was evaluated using Evans blue staining. A rat pulmonary microvascular endothelial cell line was infected with lentiviral expressing short hairpin (sh)RNA targeting p38 MAPK and then cells were subjected to oxygen/glucose deprivation and reoxygenation (OGD/R). Markers of endothelial destruction were measured by western blot and immunofluorescence. Results: In vivo LIRI models showed structural changes indicative of lung injury and hyperpermeability of the blood–air barrier. Inhibiting p38 MAPK mitigated these effects. Oxygen/glucose deprivation and reoxygenation promoted hyperpermeability of the endothelial barrier in vitro, but knockdown of p38 MAPK attenuated cell injury; maintained endothelial barrier integrity; and partially reversed injury-induced downregulation of permeability protein AQP1, endothelial protective protein eNOS, and junction proteins ZO-1 and VE-cadherin while downregulating ICAM-1, a protein involved in destroying the endothelial barrier, and ET-1, a protein involved in endothelial dysfunction. Conclusion: Inhibition of p38 MAPK alleviates LIRI by decreasing blood–air hyperpermeability. Blocking p38 MAPK may be an effective treatment against acute lung injury.
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