Increased Circulating Endothelial Microparticles Associated with PAK4 Play a Key Role in Ventilation-Induced Lung Injury Process.

Shuming Pan,Chengjin Gao,Lihong Jing,Aihua Fei,Xiangyu Zhang

doi:10.1155/2017/4902084

Abstract

Inappropriate mechanical ventilation (MV) can result in ventilator-induced lung injury (VILI). Probing mechanisms of VILI and searching for effective methods are current areas of research focus on VILI. The present study aimed to probe into mechanisms of endothelial microparticles (EMPs) in VILI and the protective effects of Tetramethylpyrazine (TMP) against VILI. In this study, C57BL/6 and TLR4KO mouse MV models were used to explore the function of EMPs associated with p21 activated kinases-4 (PAK-4) in VILI. Both the C57BL/6 and TLR4 KO groups were subdivided into a mechanical ventilation (MV) group, a TMP + MV group, and a control group. After four hours of high tidal volume (20 ml/kg) MV, the degree of lung injury and the protective effects of TMP were assessed. VILI inhibited the cytoskeleton-regulating protein of PAK4 and was accompanied by an increased circulating EMP level. The intercellular junction protein of β-catenin was also decreased accompanied by a thickening alveolar wall, increased lung W/D values, and neutrophil infiltration. TMP alleviated VILI via decreasing circulating EMPs, stabilizing intercellular junctions, and alleviating neutrophil infiltration.

Highlights

ventilator-induced lung injury (VILI) is associated with increasing vascular permeability and alveolar edema and increases the expression of proinflammatory cytokines [1, 2]
Each group was subdivided into three experimental subgroups: a mechanical ventilation (MV) group (n = 24), in which the mice were ventilated with high tidal volume (VT = 20 ml/kg) for 4 hours; a ligustrazine (Tetramethylpyrazine (TMP)) + MV group (n = 24), in which the mice were intraperitoneally injected with 80 mg/kg TMP 30 minutes before the mechanical ventilation with high tidal volume (VT = 20 ml/kg) for 4 hours; and a control group (n = 6), in which the mice underwent tracheotomy and were ventilated with low tidal volume (VT = 6 ml/kg) for 4 hours
There was no difference in alveolar wall thickness between the C57BL/6 control mice and the TLR4KO control mice (0.94 ± 0.05 μm versus 0.92 ± 0.05 μm)

Summary

Introduction

VILI is associated with increasing vascular permeability and alveolar edema and increases the expression of proinflammatory cytokines [1, 2]. Disruptions of vascular endothelial barriers are a consequence of lung inflammation and the loss of integrity of endothelial cellular barriers via intimate involvement with the cytoskeletons. Activation of the cytoskeletal apparatus results in a loss of barrier integrity and the amplification of inflammatory processes, with increased infiltration of inflammatory cells [3]. Our previous studies focusing on lung injury indicated that disorders of cytoskeletons damaged the integrity of the pulmonary endothelial barrier, subsequently resulting in pulmonary edema and amplification of inflammation [4]. Endothelial membrane microparticles (EMPs) are shed by endothelial cells associated with cytoskeletal disorders [5]. We previously investigated Rho-kinase-regulated EMPs released by altering cytoskeletons [4, 7], while the detailed regulatory mechanisms were not illustrated

Methods

Results

Conclusion