title: Subanesthetic isoflurane relieves zymosan-induced neutrophil inflammatory response by targeting NMDA glutamate receptor and Toll-like receptor 2 signaling.
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.
authors.affiliation: Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan, China.|State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.|State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Jun-Tang
authors.initials: JT
authors.lastname: Li
authors.affiliation: State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Wei-Qi
authors.initials: WQ
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan, China.
authors.forename: Ning-Ning
authors.initials: NN
authors.lastname: Liu
authors.affiliation: Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan, China.
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Zhao
authors.affiliation: Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan, China.
authors.forename: Xiao-Shan
authors.initials: XS
authors.lastname: Zhu
authors.affiliation: Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan, China.
authors.forename: Qin-Qin
authors.initials: QQ
authors.lastname: Liu
authors.affiliation: Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan, China.
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: An-Gang
authors.initials: AG
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Lin-Tao
authors.initials: LT
authors.lastname: Jia
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007530:Isoflurane / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D034622:RNA Interference; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015054:Zymosan; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C121673:Gprin1 protein, mouse; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D015054:Zymosan; D007530:Isoflurane; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Immune response; Immunity; Immunology and Microbiology Section; NMDA receptor; TLR2; isoflurane; neutrophil; zymosan