Allergen-induced inflammation and airway epithelial and smooth muscle cell proliferation: role of Jun N-terminal kinase.
Chronic cellular inflammation and airway wall remodelling with subepithelial fibrosis and airway smooth muscle (ASM) cell hyperplasia are features of chronic asthma. Jun N-terminal kinase (JNK) may be implicated in these processes by regulating the transcriptional activity of activator protein (AP)-1. We examined the effects of an inhibitor of JNK, SP600125 (anthra [1,9-cd] pyrazole-6 (2 H)-one), in a model of chronic allergic inflammation in the rat. Rats sensitised to ovalbumin (OA) were exposed to OA-aerosol every third day on six occasions and were treated with SP600125 (30 mg kg-1 b.i.d; 360 mg in total) for 12 days, starting after the second through to the sixth OA exposure. We measured eosinophilic and T-cell inflammation in the airways, proliferation of ASM cells and epithelial cells by incorporation of bromodeoxyuridine (BrdU), and bronchial responsiveness to acetylcholine. SP600125 significantly reduced the number of eosinophils (P<0.05) and lymphocytes (P<0.05) in bronchoalveolar lavage fluid, suppressed eosinophilic (P<0.05) and CD2+ T-cell (P<0.05) infiltration within the bronchial submucosa, and the increased DNA incorporation in ASM (P<0.05) and epithelial cell incorporation (P<0.05). SP600125 did not alter bronchial hyper-responsiveness observed after chronic allergen exposure. Pathways regulated by JNK positively regulate ASM cell proliferation and allergic cellular inflammation following chronic allergen exposure.
Eynott
Paul R
PR
National Heart & Lung Institute, Imperial College School of Medicine, Dovehouse St, London SW3 6LY.
Nath
Puneeta
P
Leung
Sum-Yee
SY
Adcock
Ian M
IM
Bennett
Brydon L
BL
Chung
K Fan
KF
D000199:Actins / Q000378:metabolism; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002908:Chronic Disease; D004804:Eosinophils / Q000187:drug effects / Q000473:pathology; D006967:Hypersensitivity / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D010047:Ovalbumin / Q000276:immunology; D051381:Rats; D011914:Rats, Inbred BN; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
D000199:Actins; D000873:Anthracenes; C432165:pyrazolanthrone; D010047:Ovalbumin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases