Potential role of c-Jun NH2-terminal kinase in allergic airway inflammation and remodelling: effects of SP600125.
Asthma is a chronic inflammatory disease of the airways associated with structural changes such as increased airway smooth muscle mass, which may contribute to impairment of lung function. To determine whether c-Jun NH2-terminal kinase (JNK) of the mitogen-activated protein kinase signalling pathway participated in these changes, the effects of an inhibitor, SP600125 (anthra [1, 9-cd] pyrazole-6 (2H)-one), were examined in a murine model of chronic airway inflammation and remodelling. Mice sensitised to ovalbumin were exposed to ovalbumin aerosol and were treated with SP600125 [30 mg kg(-1) intraperitoneal (i.p.)] on days of exposure. SP600125 significantly reduced eosinophil and lymphocyte numbers in bronchoalveolar lavage fluid, suppressed eosinophilic inflammation within the bronchial submucosa, inhibited goblet cell hyperplasia, and increased airway smooth muscle cell number in allergen-exposed mice. SP600125 also inhibited allergen-induced increase in bronchial responsiveness. SP600125 inhibited JNK activity in the challenged lungs. Although SP 600125 may also have other effects, we conclude that c-Jun NH2-terminal kinase may play a role in allergen-induced inflammation and remodelling associated with bronchial hyperresponsiveness.
Nath
Puneeta
P
National Heart and Lung Institute, Imperial College, Dovehouse St, London SW3 6LY, UK.
Eynott
Paul
P
Leung
Sum-Yee
SY
Adcock
Ian M
IM
Bennett
Brydon L
BL
Chung
Kian Fan
KF
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C
D000873:Anthracenes; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases