TNF-alpha induces the late-phase airway hyperresponsiveness and airway inflammation through cytosolic phospholipase A(2) activation.
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).
Choi
Il-Whan
IW
Department of Microbiology, Inje University College of Medicine, Busan, Korea.
Sun-Kim
Kim
Young-Suk
YS
Ko
Hyun-Mi
HM
Im
Suhn-Young
SY
Kim
Jae-Hong
JH
You
Hye-Jin
HJ
Lee
Yong-Chul
YC
Lee
Jae-Hoon
JH
Park
Young-Min
YM
Lee
Hern-Ku
HK
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*
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