Haddad E B, Birrell M, McCluskie K, Ling A, Webber S E, Foster M L, Belvisi M G
Pharmacology Department, Aventis Pharma, Rainham Road South, Dagenham, Essex RM10 7XS.
Br J Pharmacol. 2001 Apr;132(8):1715-24. doi: 10.1038/sj.bjp.0704022.
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.
我们研究了p38激酶抑制剂SB 203580对雄性Wistar大鼠雾化脂多糖（LPS）诱导的气道炎症的影响。SB 203580显著抑制（ED(50)=15.8 mg kg(-1)）腹腔注射LPS（1.5 mg kg(-1)）的大鼠血浆中TNF-α水平。雾化LPS在2小时时间点诱导TNF-α水平达到峰值，并引发支气管肺泡灌洗（BAL）液中的中性粒细胞反应。此外，4小时时间点与BAL液中IL-1β水平的峰值以及观察到的中性粒细胞增多的初始平台期相关。SB 203580（100 mg kg(-1)）对BAL中TNF-α峰值水平或相关的中性粒细胞增多没有影响。有趣的是，PDE 4抑制剂RP 73401（100 mg kg(-1)）显著降低了TNF-α水平和中性粒细胞炎症。然而，用这两种化合物预处理的大鼠的BAL液在LPS处理18小时后显著抑制了培养的人单核细胞中TNF-α的释放（分别抑制83.6%和44.5%）。另外，SB 203580（100 mg kg(-1)）在LPS攻击后4小时产生了与剂量相关的对BAL中IL-1β水平的抑制（67.5%抑制，P<0.01）和BAL中性粒细胞增多（45.9%抑制，P<0.01）。P38蛋白存在于肺组织中，其表达水平不受LPS处理的影响。P38激酶似乎参与了IL-1β的释放以及BAL液中持续的中性粒细胞反应。这些数据可能表明p38抑制剂在治疗以中性粒细胞增多为肺部病理特征的气道炎症性疾病中具有作用。
