Effect of the p38 kinase inhibitor, SB 203580, on sephadex induced airway inflammation in the rat.
SB 203580 is a pyridinyl imidazole compound which inhibits the release of pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), in vitro and in vivo by inhibiting p38 mitogen-activated protein kinase (MAPK). The present study investigated the effects of SB 203580 in a model of airway inflammation induced by the topical administration of Sephadex into the rat airways. This inflammatory response is characterized by the development of lung oedema, airway tissue inflammatory cell recruitment and an increase in lung TNF-alpha and IL-1beta levels. Sephadex-induced lung oedema was accompanied by a significant increase in lung tissue TNF-alpha but not IL-1beta levels. There was also a significant increase in lung tissue macrophages and an increase in eosinophils which did not reach significance. SB 203580 administration significantly inhibited lung oedema (ED50=18 mg x kg(-1)) in a dose-related manner but was without significant effect on lung tissue cell recruitment or cytokine levels. These data suggest that the increase in tumour necrosis factor-alpha and lung oedema are separate processes which both contribute to Sephadex pathology. Furthermore, the inhibitory effect of SB 203580 on Sephadex-induced lung oedema suggests that p38 kinase inhibitors may be of use in pulmonary pathologies in which lung oedema is a feature.
Birrell
M
M
Pharmacology Dept, Research & Development, Aventis Pharma, Dagenham Research Centre, Essex, UK.
Hele
D
D
McCluskie
K
K
Webber
S
S
Foster
M
M
Belvisi
M G
MG
D000818:Animals; D003911:Dextrans; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D007202:Indicators and Reagents; D008168:Lung / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D011014:Pneumonia / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D003911:Dextrans; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007202:Indicators and Reagents; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C025614:sephadex; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580