Subanesthetic isoflurane relieves zymosan-induced neutrophil inflammatory response by targeting NMDA glutamate receptor and Toll-like receptor 2 signaling.

Jun-Tang Li,Lin-Tao Jia,Ya-Li Zhao,Chun-Fang Gao,Xiao-Shan Zhu,Wei-Qi Wang,An-Gang Yang,Ling Wang,Ning-Ning Liu,Qin-Qin Liu

doi:10.18632/oncotarget.9091

Jun-Tang Li, Lin-Tao Jia + Show 8 more

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https://doi.org/10.18632/oncotarget.9091

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Abstract

Neutrophil release of NO/ONOO− induces endothelial cell barrier dysfunction in inflammatory acute lung injury (ALI). Previous studies using zymosan-triggered inflammation and ALI model revealed that zymosan promotes inducible NO synthase (iNOS) expression in neutrophils, and that isoflurane inhibits zymosan-induced oxidative stress and iNOS biosynthesis. However, the underlying mechanisms remain largely unknown. We found here that in zymosan-primed neutrophils, iNOS is transcriptionally activated by NF-κB, whose nuclear translocation is triggered by excessive reactive oxygen species (ROS) and consequently activated p38 MAPK. ROS production is attributed to zymosan-initiated Toll-like receptor 2 (TLR2) signaling, in which the adaptor MyD88 recruits and activates c-Src, and c-Src activates NADPH oxidase to generate ROS. Subanesthetic isoflurane counteracts the aforementioned zymosan-induced signaling by targeting N-methyl-D-aspartic acid (NMDA) glutamate receptor and thereby suppressing calcium influx and c-Src activation. Whereas iNOS accelerates NO/ONOO− production in neutrophils which eventually promote protein leak from pulmonary microvascular endothelial cells (PMVEC), isoflurane reduced NO/ONOO− release from zymosan-treated neutrophils, and thus relieves trans- PMVEC protein leak. This study provides novel insights into the roles of neutrophils and the underlying mechanisms in zymosan-induced ALI, and has implications for the therapeutic potential of subanesthetic isoflurane in attenuating inflammatory responses causing lung endothelial cell damage.

Highlights

Acute lung injury (ALI) is a severe disorder that causes profound morbidity and 30-40% mortality, and exhibits high incidence of progressing into acute respiratory distress syndrome (ARDS) [1]
We found that zymosan initiates Tolllike receptor 2 (TLR2) signaling in neutrophils, which recruits and activates c-Src via the adaptor MyD88; c-Src triggers cytomembrane localization of the Nicotinamide adenine dinucleotidephosphate (NADPH) oxidase subunit, p47phox, leading to excessive reactive oxygen species (ROS) production and p38 MAPK activation [15]. p38 MAPK subsequently activates NF-κB to switch on inducible nitric oxide (NO) synthase (iNOS) expression, which promotes the synthesis and release of NO/ONOO- in neutrophils, and eventually causes the transmembrane protein leak from pulmonary microvascular endothelial cells (PMVEC)
These data suggest that zymosanprimed neutrophils cause trans-PMVEC protein leak by producing NO and ONOO, a process suppressed by www.impactjournals.com/oncotarget isoflurane treatment of neutrophils

Summary

Introduction

Acute lung injury (ALI) is a severe disorder that causes profound morbidity and 30-40% mortality, and exhibits high incidence of progressing into acute respiratory distress syndrome (ARDS) [1]. Zymosan-triggered inflammatory cascade leads to high-permeability pulmonary edema, largely through activation and injury of endothelial cells, the pulmonary microvascular endothelial cells (PMVECs) [6]. We and others have demonstrated that NO/ONOO- release from neutrophils underlies various pathophysiological events involved in ALI including pulmonary neutrophil infiltration, oxidant stress, and microvascular protein leak [7, 8]. NF-κB was reported to transcriptionally activate iNOS in several NO-producing cell types [9]; Nicotinamide adenine dinucleotidephosphate (NADPH) oxidase-derived ROS induce iNOS expression in neutrophils, leading to lung fibrosis [10]. How these signaling events are connected to switch on iNOS expression remains elusive

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