title: TNF-alpha induces the late-phase airway hyperresponsiveness and airway inflammation through cytosolic phospholipase A(2) activation.
abstract: BACKGROUND
  Late-phase airway hyperresponsiveness (AHR) in asthma is considered the event leading to persistent inflammation in the lungs, but the molecular mechanisms involved in this process are poorly understood.
  
  
  OBJECTIVE
  To examine the role of TNF-alpha in the development of a late AHR and airway inflammation in asthma.
  
  
  METHODS
  We established a murine model of asthma with not only biphasic AHR to methacholine but also airway eosinophilia. The effect of TNF-alpha blockade was determined by using anti-TNF-alpha antibody and TNF-alpha knockout mice. Cytosolic phospholipase A(2) (cPLA(2)) mRNA expression and activity were assessed by using RT-PCR and 1-stearoyl-2-[1-(14)C] arachidonyl-sn-glycero-3-phosphocholine as the substrate, respectively.
  
  
  RESULTS
  TNF-alpha blockade resulted in significant inhibition of the late AHR without affecting the early AHR, and reduction in airway eosinophilia and inflammation. cPLA(2) activity was increased in asthmatic lungs in a TNF-alpha-dependent way, and cPLA(2) inhibitor blocked late AHR and airway eosinophilia. TNF-alpha also stimulated the synthesis of cPLA(2) metabolites such as leukotriene B(4) and platelet-activating factor in the airway. Specific inhibitors of cPLA(2) metabolites inhibited the late AHR and airway eosinophilia.
  
  
  CONCLUSIONS
  TNF-alpha is the proximal key cytokine capable of developing late-phase AHR and subsequent airway inflammation through expression/activation of cPLA(2).
authors.affiliation: Department of Microbiology, Inje University College of Medicine, Busan, Korea.
authors.forename: Il-Whan
authors.initials: IW
authors.lastname: Choi
authors.lastname: Sun-Kim
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Kim
authors.forename: Hyun-Mi
authors.initials: HM
authors.lastname: Ko
authors.forename: Suhn-Young
authors.initials: SY
authors.lastname: Im
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Kim
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: You
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Lee
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Lee
authors.forename: Young-Min
authors.initials: YM
authors.lastname: Park
authors.forename: Hern-Ku
authors.initials: HK
authors.lastname: Lee
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D006632:Histamine / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D007975:Leukotriene B4 / Q000276:immunology / Q000378:metabolism; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010741:Phospholipases A / Q000276:immunology / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000276:immunology / Q000378:metabolism; D011657:Pulmonary Eosinophilia / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D016085:Bronchoconstrictor Agents; D010972:Platelet Activating Factor; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride; D007975:Leukotriene B4; D006632:Histamine; D010741:Phospholipases A