Synergistic Effects of EMPs and PMPs on Pulmonary Vascular Leakage and Lung Injury After Ischemia/Reperfusion

Abstract

Background Vascular leakage is an important process of critical conditions such as shock and I/R-induced lung injury. Microparticles (MPs), including endothelial cell-derived microparticles (EMPs), platelet-derived microparticles (PMPs) and neutrophil-derived microparticles (NMPs), have been shown to participate in many diseases. Whether these MPs take part in pulmonary vascular leakage and lung injury after ischemia/reperfusion (I/R) and have synergistic and the underlying mechanism are not known.Methods Using hemorrhage/transfusion (Hemo/Trans) and aorta abdominalis occlusion-induced ischemia/reperfusion (I/R) rat models, the role of EMPs, PMPs and NMPs and their relationship and the mechanisms in pulmonary vascular leakage and lung injury were studied.Results The concentrations of EMPs, PMPs and NMPs were significantly increased after I/R. Intravenous administration of EMPs and PMPs but not NMPs induced pulmonary vascular leakage and lung injury. Furthermore, EMPs could induce pulmonary sequestration of platelets and promote more PMP production, and synergistically exacerbate pulmonary vascular leakage. MiR-1, miR-155 and miR-542 in EMP, and miR-126 and miR-29 in PMP, 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 permeability and lung injury. Overexpression of miR-155 in EMPs down-regulated the expression of ZO-1 and claudin-5, the tight junction related proteins, while overexpression of miR-126 up-regulated the expression of caveolin-1 (Cav-1), the trans-cellular transportation related protein. Inhibiting EMP and PMP production with blebbistatin (BLE) and amitriptyline (AMI) respectively, protected pulmonary vascular permeability 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 targets ZO-1 and claudin-5 and PMPs carrying miR-126 that up-regulates Cav-1, synergistically regulate pulmonary vascular permeability and mediate the lung injury after I/R.