Abstract
BackgroundVascular 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.MethodsUsing 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.ResultsThe 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.ConclusionsEMPs 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.Graphic abstract8k8MRpqBub_wL9wmZ4ez89Video
Highlights
Vascular leakage is an important pathophysiological process of critical conditions such as shock and ischemia–reperfusion (I/R)-induced lung injury
MPs play an important role in pulmonary vascular leakage and lung injury after I/R To explore the relationship between MPs and vascular permeability, I/R and hemorrhage-transfusion (Hemo/ Trans) rats were utilized, and flow cytometry was used to analyze MP concentrations in blood
The results showed that H/R induced MP production (Additional file 2: Fig. S1C) and caused the increase of monolayer pulmonary Vascular endothelial cells (VEC) permeability with the decrease of trans-endothelial resistance (TER) of monolayer pulmonary VECs (Additional file 2: Fig. S1D)
Summary
Vascular leakage is an important pathophysiological process of critical conditions such as shock and ischemia–reperfusion (I/R)-induced lung injury. 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. Ischemia/reperfusion (I/R)-induced lung injury, which further leads to respiratory failure and even death, is commonly seen in cardiopulmonary resuscitation, lung transplantation and shock-resuscitation. Vascular leakage is a key pathophysiological process of I/R-induced. Zhang et al Cell Commun Signal (2020) 18:184 lung injury. The mechanism mainly includes para-cellular pathway and trans-cellular pathway. The para-cellular pathway is mainly related to the destruction of tight junctions and adhesion junctions and the degradation of their major constituent proteins, such as ZO-1, claudin-5 and VE-Cadherin (VE-Cad). The trans-cellular pathway is mainly related to the activation of cavealin-1 (Cav-1). Many treatments based on current mechanisms can not effectively improve the vascular leakage [1, 2], suggesting that the mechanism underlying vascular leakage is not entirely understood
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