Endothelial Microvesicles Induce Pulmonary Vascular Leakage and Lung Injury During Sepsis.

Danyang Zheng,Lei Kuang,Yu Zhu,Liangming Liu,Yue Wu,Hongliang Zhao,Chenyang Duan,Tao Li,Mingying Xue,Zisen Zhang,Jie Zhang

doi:10.3389/fcell.2020.00643

Abstract

Sepsis is a prevalent severe syndrome in clinic. Vascular leakage and lung injury are important pathophysiological processes during sepsis, but the mechanism remains obscure. Microvesicles (MVs) play an essential role in many diseases, while whether MVs participate in vascular leakage and lung injury during sepsis is unknown. Using cecal ligation and puncture induced sepsis rats and lipopolysaccharide stimulated vascular endothelial cells (VECs), the role and the underlying mechanism of endothelial microvesicles (EMVs) in pulmonary vascular leakage and lung injury were observed. The role of MVs from sepsis patients was verified. The results showed that the concentration of MVs in blood was significantly increased after sepsis. MVs from sepsis rats and patients induced apparent pulmonary vascular leakage and lung injury, among which EMVs played the dominant role, in which miR-23b was the key inducing factor in vascular leakage. Furthermore, downregulation and upregulation of miR-23b in EMVs showed that miR-23b mainly targeted on ZO-1 to induce vascular leakage. MVs from sepsis patients induced pulmonary vascular leakage and lung injury in normal rats. Application of classic antidepressants amitriptyline reduced the secretion of EMVs, and alleviated vascular leakage and lung injury. The study suggests that EMVs play an important role in pulmonary vascular leakage and lung injury during sepsis by transferring functional miR-23b. Antagonizing the secretion of EMVs and the miR-23b might be a potential target for the treatment of severe sepsis.

Highlights

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, which leads to tissue damage and organ dysfunction even multiple organ dysfunction syndrome (MODS) with high mortality (Rhodes et al, 2017)
In order to investigate the role of MVs in pulmonary vascular leakage and lung injury after sepsis, MVs were purified from the blood of normal and cecal ligation and puncture (CLP) rats (CLP-MV) by ultracentrifugation, and the concentration of MVs, pulmonary vascular leakage and lung injury were observed
The present study showed that endothelial MVs (EMVs) played an important role in pulmonary vascular leakage and lung injury after sepsis, in this process, miR-23b played a critical role

Summary

Introduction

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, which leads to tissue damage and organ dysfunction even multiple organ dysfunction syndrome (MODS) with high mortality (Rhodes et al, 2017). The lung is usually one of the first failure organs during the development of multiple dysfunction after sepsis (Wu et al, 2007), and vascular leakage plays a fundamental role in lung injury, which is characterized by the endothelial. Endothelial Microvesicles Induce Vascular Leakage barrier dysfunction and vascular endothelial permeability increment, it is the crucial reason for the organ dysfunction in sepsis (Hou et al, 2017). Plenty of cells in circulation are stimulated during sepsis, such as platelets, vascular endothelial cells and leukocytes, and may secrete microvesicles (MVs) subsequently (Becker et al, 2016; Karpman et al, 2017; Todorova et al, 2017). Whether MVs play an important role in vascular leakage after sepsis remains unknown

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