EMP 与 PMP 对缺血/再灌注后肺血管渗漏和肺损伤的协同作用。
Synergistic effects of EMPs and PMPs on pulmonary vascular leakage and lung injury after ischemia/reperfusion.
机构信息
State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Army Medical University, Daping, Chongqing, 400042, People's Republic of China.
出版信息
Cell Commun Signal. 2020 Nov 23;18(1):184. doi: 10.1186/s12964-020-00672-0.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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. Video Abstract.
背景
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下的重要病理生理过程。微粒（MPs），包括内皮细胞衍生的微粒（EMP）、血小板衍生的微粒（PMP）和白细胞衍生的微粒（LMP），已被证明参与许多疾病。这些 MPs 中的哪些以及哪些 MPs 参与了 I/R 后的肺血管渗漏和肺损伤，以及这些 MPs 是否具有协同作用及其潜在机制尚不清楚。
方法
使用出血/输血（Hemo/Trans）和腹主动脉结扎诱导的 I/R 大鼠模型，观察 EMP、PMP 和 LMP 的作用及其在肺血管渗漏和肺损伤中的机制。
结果
I/R 后 EMPs、PMPs 和 LMPs 的浓度显著增加。静脉给予 EMP 和 PMP 而非 LMP 可诱导肺血管渗漏和肺损伤。此外，EMP 诱导血小板在肺中的隔离，并促进更多的 PMP 产生，并在肺血管渗漏中发挥协同作用。缺氧/复氧（H/R）后 EMPs 中的 miR-1、miR-155 和 miR-542 以及 PMPs 中的 miR-126 和 miR-29 显著增加。其中，抑制 EMPs 中的 miR-155 和 PMPs 中的 miR-126 可减轻 EMPs 和 PMPs 对血管屏障功能和肺损伤的有害影响。在 EMPs 中转染 miR-155 过表达可下调紧密连接相关蛋白如 ZO-1 和 Claudin-5 的表达，而在 PMPs 中转染 miR-126 过表达可上调 Cav-1（Cav-1）的表达，即 Cav-1 相关的细胞间转运蛋白。用 blebbistatin（BLE）和阿米替林（AMI）抑制 EMPs 和 PMPs 的产生可减轻 I/R 诱导的肺血管渗漏和肺损伤。
结论
EMP 和 PMPs 有助于 I/R 后肺血管渗漏和肺损伤。EMP 介导血小板在肺中的隔离，产生更多的 PMP 发挥协同作用。从机制上讲，携带 miR-155 的 EMP 通过下调 ZO-1 和 Claudin-5，携带 miR-126 的 PMP 通过上调 Cav-1，协同介导 I/R 后的肺血管渗漏和肺损伤。视频摘要。
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