Aerobic Exercise Attenuates Acute Lung Injury Through NET Inhibition.

Yue Shi,Tingting Liu,Yanqiu Cui,Hui Shi,Peijie Chen,Fei Li,Luyu Yang,David C Nieman

doi:10.3389/fimmu.2020.00409

Abstract

Introduction: Aerobic exercise improves lung inflammation in acute lung injury (ALI), but its mechanism remains unknown. Neutrophil extracellular traps (NETs) play an important role in LPS-induced ALI, and a positive correlation exists between NET formation and proinflammatory macrophage polarization. This study investigated whether aerobic exercise reduces the pro-inflammatory polarization of alveolar macrophages (AMs) by inhibiting the excessive release of NETs and then alleviating the inflammatory response of ALI.Methods: C57BL/6 male mice were randomly divided into four groups: sedentary group (CON), sedentary and extra-pulmonary LPS injection group (LPS), 5-weeks aerobic training intervention and LPS injection group (EXE+LPS), and DNase I plus LPS injection group (DNase+LPS). Twenty-four hours after drug injection, bronchoalveolar lavage fluid (BALF), AM, and lung tissues were obtained to detect inflammatory responses, NET formation, macrophage polarization, and protein activation. In the in vitro study, a murine AM cell line, designated MH-S, was stimulated with LPS, purified NETs, and NETs plus DNase I.Results: EXE+LPS and DNase+LPS mice exhibited reduced neutrophil infiltration, decreased NET release, and lower pro-inflammatory polarization of AM compared with LPS mice. Subsequently, Western blot showed inhibition of the phosphorylation of MAPK and NF-κB proteins of AMs in EXE+LPS and DNase+LPS mice compared with LPS mice. Lastly, stimulation of MH-S cells by NETs revealed a trend for pro-inflammatory cell polarization, with NF-κB protein activation at 8 h and ERK1/2 activation at 1, 2, and 8 h.Conclusions: Aerobic exercise alleviated ALI through NET-induced AM pro-inflammatory polarization involving ERK1/2 and NF-κB signaling.

Highlights

Aerobic exercise improves lung inflammation in acute lung injury (ALI), but its mechanism remains unknown
In this study with ALI mice, we demonstrated that 5 weeks of aerobic treadmill exercise reduced LPS-induced lung inflammation and inhibited Neutrophil extracellular traps (NETs) formation, similar to DNase I treatment
Response Twenty-four hours after the last training bout, LPS and EXE+LPS mice received the same dose of LPS intraperitoneally to establish an extra-pulmonary model of ALI, while CON mice received intraperitoneal phosphate-buffered saline (PBS)

Summary

Introduction

Aerobic exercise improves lung inflammation in acute lung injury (ALI), but its mechanism remains unknown. Acute lung injury (ALI) is a common clinical respiratory illness characterized by acute and progressive respiratory insufficiency caused by a variety of causes. Excessive airway inflammatory response is Exercise Attenuates Acute Lung Injury regarded as the underlying cause of ALI and, when uncontrolled, leads to acute respiratory distress syndrome (ARDS) and even respiratory failure [2]. Aerobic exercise training for 5 weeks may inhibit extra-pulmonary LPS-induced lung inflammation by attenuating inflammatory cytokines and oxidative stress markers via IL-10 production [4]. The underlying molecular and signaling mechanisms of how aerobic exercise training may counter the ALI inflammation response is not well-understood

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Results

Conclusion