Synergistic effects of EMPs and PMPs on pulmonary vascular leakage and lung injury after ischemia/reperfusion
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Synergistic effects of EMPs and PMPs on pulmonary vascular leakage and lung injury after ischemia/reperfusion Jie Zhang, Yu Zhu, Yue Wu, Qing‑Guang Yan, Xiao‑Yong Peng, Xin‑Ming Xiang, Ming‑Ying Xue, Qing‑Hui Li, Liang‑Ming Liu*† and Tao Li*†
Abstract 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 par‑ ticipate 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 adminis‑ tration 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 sig‑ nificantly 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. Keywords: Emps, Pmps, Pulmonary vascular permeability
*Correspondence: [email protected]; [email protected] † Liang-Ming Liu and Tao Li have contributed equally to this work 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
Background Ischemia/reperfusion (I/R)-induced lung injury, which further le
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