Oncotarget

Research Papers: Immunology:

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

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

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Oncotarget. 2016; 7:31772-31789. https://doi.org/10.18632/oncotarget.9091

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Abstract

Jun-Tang Li1,2,3,*, Wei-Qi Wang4,5,6,*, Ling Wang7,*, Ning-Ning Liu1,*, Ya-Li Zhao1,*, Xiao-Shan Zhu1, Qin-Qin Liu1, Chun-Fang Gao1, An-Gang Yang2 and Lin-Tao Jia3

1 Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan, China

2 State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi’an, Shaanxi, China

3 State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, Shaanxi, China

4 State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi’an, China

5 National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi’an, China

6 Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi’an, China

7 Department of Anesthesiology, 150th Central Hospital of PLA, Luoyang, Henan, China

* These authors have contributed equally to this work

Correspondence to:

Jun-Tang Li, email:

An-Gang Yang, email:

Lin-Tao Jia, email:

Keywords: isoflurane, zymosan, neutrophil, NMDA receptor, TLR2, Immunology and Microbiology Section, Immune response, Immunity

Received: September 07, 2015 Accepted: April 18, 2016 Published: April 28, 2016

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.


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