Effect of the p38 kinase inhibitor, SB 203580, on allergic airway inflammation in the rat.
Tumour necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta) have been implicated in the pathogenesis of asthma. The p38 kinase inhibitor, SB 203580 inhibits TNF-alpha and IL-1beta production in vitro and in vivo. In this study the effect of SB 203580 on allergen-induced airway TNF-alpha production and inflammatory cell recruitment was investigated in sensitized Brown Norway rats. The allergen-induced increase in bronchoalveolar lavage (BAL) TNF-alpha was inhibited by SB 203580 at every dose tested (10 - 100 mg kg(-1), p.o.). In contrast, neither ovalbumin-induced eosinophilia or neutrophilia were inhibited by SB 203580 (10 - 100 mg kg(-1), p.o.). In conclusion, SB 203580 inhibits BAL TNF-alpha production by 95% without inhibiting either antigen-induced airway eosinophilia or neutrophilia. This data suggests that either the residual TNF-alpha is sufficient to drive allergen-induced inflammatory cell recruitment into the lung or that TNF-alpha is not involved in allergen-induced inflammatory cell recruitment.
Escott
K J
KJ
Department of Pharmacology, Aventis Pharmaceuticals, Rainham Road South, Dagenham, Essex, RM10 7XS. jane.escott@astrazeneca.com
Belvisi
M G
MG
Birrell
M A
MA
Webber
S E
SE
Foster
M L
ML
Sargent
C A
CA
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy*; D001985:Bronchial Provocation Tests; D018893:Bronchoalveolar Lavage; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006967:Hypersensitivity / Q000188:drug therapy*; D007093:Imidazoles / Q000627:therapeutic use*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D010047:Ovalbumin; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D010047:Ovalbumin; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580