Vascular leakage is an important pathophysiological process of critical conditions such as shock and ischemia–reperfusion (I/R)-induced lung injury. Microparticles (MPs), including endothelial cell-derived microparticles (EMPs), platelet-derived microparticles (PMPs) and leukocyte-derived microparticles (LMPs), have been shown to participate in many diseases. Whether and which of these MPs take part in pulmonary vascular leakage and lung injury after I/R and whether these MPs have synergistic effect and the underlying mechanism are not known. Using hemorrhage/transfusion (Hemo/Trans) and aorta abdominalis occlusion-induced I/R rat models, the role of EMPs, PMPs and LMPs and the mechanisms in pulmonary vascular leakage and lung injury were observed. The concentrations of EMPs, PMPs and LMPs were significantly increased after I/R. Intravenous administration of EMPs and PMPs but not LMPs induced pulmonary vascular leakage and lung injury. Furthermore, EMPs induced pulmonary sequestration of platelets and promoted more PMPs production, and played a synergistic effect on pulmonary vascular leakage. MiR-1, miR-155 and miR-542 in EMPs, and miR-126 and miR-29 in PMPs, were significantly increased after hypoxia/reoxygenation (H/R). Of which, inhibition of miR-155 in EMPs and miR-126 in PMPs alleviated the detrimental effects of EMPs and PMPs on vascular barrier function and lung injury. Overexpression of miR-155 in EMPs down-regulated the expression of tight junction related proteins such as ZO-1 and claudin-5, while overexpression of miR-126 up-regulated the expression of caveolin-1 (Cav-1), the trans-cellular transportation related protein such as caveolin-1 (Cav-1). Inhibiting EMPs and PMPs production with blebbistatin (BLE) and amitriptyline (AMI) alleviated I/R induced pulmonary vascular leakage and lung injury. EMPs and PMPs contribute to the pulmonary vascular leakage and lung injury after I/R. EMPs mediate pulmonary sequestration of platelets, producing more PMPs to play synergistic effect. Mechanically, EMPs carrying miR-155 that down-regulates ZO-1 and claudin-5 and PMPs carrying miR-126 that up-regulates Cav-1, synergistically mediate pulmonary vascular leakage and lung injury after I/R.

中文翻译：

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EMPs和PMPs对缺血/再灌注后肺血管渗漏和肺损伤的协同作用

血管渗漏是休克和缺血再灌注 (I/R) 诱导的肺损伤等危急情况的重要病理生理过程。微粒 (MP)，包括内皮细胞衍生微粒 (EMP)、血小板衍生微粒 (PMP) 和白细胞衍生微粒 (LMP)，已被证明参与许多疾病。这些MPs是否和哪些参与I/R后肺血管渗漏和肺损伤，这些MPs是否具有协同作用及其潜在机制尚不清楚。采用出血/输血（Hemo/Trans）和腹主动脉闭塞诱导的I/R大鼠模型，观察EMPs、PMPs和LMPs的作用及其在肺血管渗漏和肺损伤中的作用机制。I/R 后 EMPs、PMPs 和 LMPs 的浓度显着增加。静脉注射 EMPs 和 PMPs 而不是 LMPs 会导致肺血管渗漏和肺损伤。此外，EMPs诱导血小板肺隔离，促进更多PMPs产生，对肺血管渗漏起到协同作用。缺氧/复氧 (H/R) 后，EMP 中的 MiR-1、miR-155 和 miR-542 以及 PMP 中的 miR-126 和 miR-29 显着增加。其中，抑制 EMPs 中的 miR-155 和 PMPs 中的 miR-126 减轻了 EMPs 和 PMPs 对血管屏障功能和肺损伤的不利影响。EMPs中miR-155的过表达下调了紧密连接相关蛋白如ZO-1和claudin-5的表达，而miR-126的过表达上调了caveolin-1（Cav-1）的表达，反式-细胞运输相关蛋白，如caveolin-1 (Cav-1)。用blebbistatin (BLE) 和阿米替林(AMI) 抑制EMPs 和PMPs 的产生减轻了I/R 诱导的肺血管渗漏和肺损伤。EMPs 和 PMPs 导致 I/R 后肺血管渗漏和肺损伤。EMPs介导血小板的肺隔离，产生更多的PMPs发挥协同作用。在机械上，携带 miR-155 下调 ZO-1 和 claudin-5 的 EMP 和携带上调 Cav-1 的 miR-126 的 PMP 协同介导 I/R 后肺血管渗漏和肺损伤。产生更多的PMP，发挥协同效应。在机械上，携带 miR-155 下调 ZO-1 和 claudin-5 的 EMP 和携带上调 Cav-1 的 miR-126 的 PMP 协同介导 I/R 后肺血管渗漏和肺损伤。产生更多的PMP，发挥协同效应。在机械上，携带 miR-155 下调 ZO-1 和 claudin-5 的 EMP 和携带上调 Cav-1 的 miR-126 的 PMP 协同介导 I/R 后肺血管渗漏和肺损伤。