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.