title: Inflammatory role of AMP-activated protein kinase signaling in an experimental model of toxic smoke inhalation injury.
abstract: OBJECTIVE
  The molecular mechanisms underlying lung inflammation in toxic smoke inhalation injury are unknown. We investigated the signaling pathway responsible for the induction of interleukin 8 by wood smoke extract in lung epithelial cells and lung inflammation induced by wood smoke exposure in mice.
  
  
  METHODS
  A randomized, controlled study.
  
  
  METHODS
  A research laboratory.
  
  
  RESULTS
  Exposure of primary human bronchial epithelial cells to wood smoke extract sequentially activated NADPH oxidase and increased intracellular reactive oxygen species level; activated AMP-activated protein kinase, extracellular signal-regulated kinase and Jun N-terminal kinase (two mitogen-activated protein kinases), and nuclear factor-κB and signal transducer and activator of transcription protein 3 (two transcription factors); and induced interleukin-8. Inhibition of NADPH oxidase activation with apocynin or siRNA targeting p47(phox ) (a subunit of NADPH oxidase) attenuated the increased intracellular reactive oxygen species level, AMP-activated protein kinase activation, and interleukin-8 induction. Removal of intracellular reactive oxygen species by N-acetyl-cysteine reduced the activation of AMP-activated protein kinase, extracellular signal-regulated kinase and Jun N-terminal kinase, and interleukin-8 induction. Prevention of AMP-activated protein kinase activation by Compound C or AMP-activated protein kinase siRNA lessened the activation of Jun N-terminal kinase, extracellular signal-regulated kinase, nuclear factor-κB, signal transducer and activator of transcription protein 3 and interleukin-8 induction. Inhibition of Jun N-terminal kinase and extracellular signal-regulated kinase activation by inhibitors reduced the activation of nuclear factor-κB and signal transducer and activator of transcription protein 3 and interleukin-8 induction. Abrogation of nuclear factor-κB and signal transducer and activator of transcription protein 3 activation by inhibitors attenuated the interleukin-8 induction. Additionally, acute exposure of mice to wood smoke promoted AMP-activated protein kinase phosphorylation and expression of macrophage inflammatory protein 2 (an interleukin-8 homolog) in lung epithelial cells and lungs and lung inflammation, all of which were reduced by Compound C treatment.
  
  
  CONCLUSIONS
  Interleukin-8 induction by wood smoke extract in lung epithelial cells is mediated by novel NADPH oxidase-dependent, reactive oxygen species-sensitive AMP-activated protein kinase signaling with Jun N-terminal kinase and extracellular signal-regulated kinase as the downstream kinases and nuclear factor-κB and signal transducer and activator of transcription protein 3 as the downstream transcription factors. This AMP-activated protein kinase signaling is likely important for inducing lung inflammation with toxic smoke exposure in mice.
authors.affiliation: Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Diahn-Warng
authors.initials: DW
authors.lastname: Perng
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Chang
authors.forename: Jen-Ying
authors.initials: JY
authors.lastname: Wang
authors.forename: Chih-Chieh
authors.initials: CC
authors.lastname: Lee
authors.forename: Shing-Hwa
authors.initials: SH
authors.lastname: Lu
authors.forename: Song-Kun
authors.initials: SK
authors.lastname: Shyue
authors.forename: Tzong-Shyuan
authors.initials: TS
authors.lastname: Lee
authors.forename: Yu Ru
authors.initials: YR
authors.lastname: Kou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D016209:Interleukin-8 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology; D015208:Smoke Inhalation Injury / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology
chemical_list: D016209:Interleukin-8; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D055372:AMP-Activated Protein Kinases