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Aerobic Exercise Attenuates Acute Lung Injury Through NET Inhibition.

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-?B 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-?B 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-?B signaling.

SUBMITTER: Shi Y

PROVIDER: S-EPMC7096358 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Aerobic Exercise Attenuates Acute Lung Injury Through NET Inhibition.

Shi Yue Y Liu Tingting T Nieman David C DC Cui Yanqiu Y Li Fei F Yang Luyu L Shi Hui H Chen Peijie P

Frontiers in immunology 20200319

<b>Introduction:</b> 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 ...[more]

PMID: 32265910

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Project description:ObjectivesExtracellular adenosine has tissue-protective potential in several conditions. Adenosine levels are regulated by a close interplay between nucleoside transporters and adenosine kinase. On the basis of the evidence of the role of adenosine kinase in regulating adenosine levels during hypoxia, we evaluated the effect of adenosine kinase on lung injury. Furthermore, we tested the influence of a pharmacologic approach to blocking adenosine kinase on the extent of lung injury.DesignProspective experimental animal study.SettingUniversity-based research laboratory.SubjectsIn vitro cell lines, wild-type and adenosine kinase+/- mice.InterventionsWe tested the expression of adenosine kinase during inflammatory stimulation in vitro and in a model of lipopolysaccharide inhalation in vivo. Studies using the adenosine kinase promoter were performed in vitro. Wild-type and adenosine kinase+/- mice were subjected to lipopolysaccharide inhalation. Pharmacologic inhibition of adenosine kinase was performed in vitro, and its effect on adenosine uptake was evaluated. The pharmacologic inhibition was also performed in vivo, and the effect on lung injury was assessed.Measurements and main resultsWe observed the repression of adenosine kinase by proinflammatory cytokines and found a significant influence of nuclear factor kappa-light-chain-enhancer of activated B-cells on regulation of the adenosine kinase promoter. Mice with endogenous adenosine kinase repression (adenosine kinase+/-) showed reduced infiltration of leukocytes into the alveolar space, decreased total protein and myeloperoxidase levels, and lower cytokine levels in the alveolar lavage fluid. The inhibition of adenosine kinase by 5-iodotubercidin increased the extracellular adenosine levels in vitro, diminished the transmigration of neutrophils, and improved the epithelial barrier function. The inhibition of adenosine kinase in vivo showed protective properties, reducing the extent of pulmonary inflammation during lung injury.ConclusionsTaken together, these data show that adenosine kinase is a valuable target for reducing the inflammatory changes associated with lung injury and should be pursued as a therapeutic option.

Project description:BackgroundVentilator-induced lung injury (VILI) is caused by stretch stimulation and other factors related to mechanical ventilation (MV). NOD-like receptor protein 3 (NLRP3), an important innate immune component, is strongly associated with VILI. This study aimed to investigate the effect and mechanisms of aerobic exercise (EX) on VILI.MethodsTo test the effects of the PKC inhibitor bisindolylmaleimide I on PKC and NLRP3, male C57BL/6 mice (7 weeks old, 19 ~ 23 g) were randomly divided into four groups: control group(C), bisindolylmaleimide I-pretreated group(B), MV group, and bisindolylmaleimide I-pretreated + MV (B + MV) group. The mice were pretreated with bisindolylmaleimide I through intraperitoneal injection (0.02 mg/kg) 1 h before MV. MV was performed at a high tidal volume (30 ml/kg). To explore the ameliorative effect of EX on VILI, the mice were randomly divided into C group, MV group, EX group and EX + MV group and subjected to either MV or 5 weeks of EX training. After ventilation, haematoxylin-eosin (HE) staining and wet/dry weight ratio was used to assess lung pathophysiological changes. PKCɑ, P-PKCɑ, ASC, procaspase-1, caspase-1, pro-IL-1β, IL-1β, NLRP3 and occludin (tight junction protein) expression in lung tissues was determined by Western blotting. The level of IL-6 in alveolar lavage fluid was determined by ELISA.ResultsNLRP3, P-PKCɑ, and PKCɑ levels were inceased in MV group, but bisindolylmaleimide I treatment reversed these changes. Inhibition of PKC production prevented NLRP3 activation. Moreover, MV increased ASC, procaspase-1, caspase-1, pro-IL-1β, and IL1β levels and decreased occludin levels, but EX alleviated these changes. HE staining and lung injury scoring confirmed an absence of obvious lung injury in C group and EX group. Lung injury was most severe in MV group but was improved in EX + MV group. Overall, these findings suggest that MV activates the NLRP3 inflammasome by activating PKCɑ and inducing occludin degradation, while Exercise attenuates NLRP3 inflammasome and PKCɑ activation. Besides, exercise improves cyclic stretch-induced degradation of occludin.ConclusionPKC activation can increase the level of NLRP3, which can lead to lung injury. Exercise can reduce lung injury by inhibiting PKCɑ and NLRP3 activation. Exercise maybe a potential measure for clinical prevention of VILI.

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Aerobic Exercise Attenuates Acute Lung Injury Through NET Inhibition.

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Aerobic Exercise Attenuates Acute Lung Injury Through NET Inhibition.

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