Role of p38 MAP kinase in LPS-induced airway inflammation in the rat.
We investigated the effect of the p38 kinase inhibitor SB 203580 on airway inflammation induced by aerosolized lipopolysaccharide (LPS) in male Wistar rats. SB 203580 significantly inhibited (ED(50)=15.8 mg kg(-1)) plasma levels of TNF-alpha in rats challenged with LPS (1.5 mg kg(-1), i.p.). Aerosolized LPS induced a peak in TNF-alpha levels and the initiation of a neutrophilic response in bronchoalveolar lavage (BAL) fluid at the 2 h time point. Furthermore, the 4 h time point was associated with the peak in IL-1beta levels and the initial plateau of neutrophilia observed in the BAL fluid. SB 203580 (100 mg kg(-1)), had no effect on peak TNF-alpha levels or the associated neutrophilia in the BAL. Interestingly, the PDE 4 inhibitor RP 73401 (100 mg kg(-1)) significantly reduced both TNF-alpha levels and neutrophilic inflammation. However, the BAL fluid from rats pre-treated with either compound significantly inhibited TNF-alpha release from cultured human monocytes 18 h after LPS treatment (83.6 and 44.5% inhibition, respectively). Alternatively, SB 203580 (100 mg kg(-1)) produced dose-related inhibition of BAL IL-1beta levels (67.5% inhibition, P<0.01) and BAL neutrophilia (45.9% inhibition, P<0.01) 4 h after LPS challenge. P38 protein was present in lung tissue and the level of expression was not affected by LPS treatment. P38 kinase appears to be involved in the release of IL-1beta and the sustained neutrophilic response in the BAL fluid. This data may suggest a role for p38 inhibitors in the treatment of airway inflammatory diseases in which neutrophilia is a feature of the lung pathology.
Haddad
E B
EB
Pharmacology Department, Aventis Pharma, Rainham Road South, Dagenham, Essex RM10 7XS.
Birrell
M
M
McCluskie
K
K
Ling
A
A
Webber
S E
SE
Foster
M L
ML
Belvisi
M G
MG
D000336:Aerosols; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D003600:Cytosol / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004731:Endotoxins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011014:Pneumonia / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D000336:Aerosols; D000893:Anti-Inflammatory Agents; D001549:Benzamides; D004731:Endotoxins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C044101:endotoxin, Escherichia coli; D003907:Dexamethasone; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C087566:piclamilast