CHI-91040, a novel inhaled p38α inhibitor, counteracts lung inflammation induced by IL-1β in the rat

INTRODUCTION: Intratracheal (i.t.) instillation of IL-1β in rodents has been reported to induce airway neutrophilia. Moreover, it has been shown that p38α MAPK is involved in IL-1β signalling in lung cells. In the present study CHI-91040, a new inhaled p38α inhibitor, has been tested in a newly developed rat model of neutrophilic inflammation induced by IL-1β i.t. instillation. METHODS AND RESULTS: Recombinant rat IL-1β at 0.3µg/kg significantly increased neutrophil numbers and IL-6 levels in bronchoalveolar lavage (BAL) at 4h after challenge. Levels of pHSP27, a marker of p38 MAPK pathway activation, were elevated by 7-fold in lung homogenates. The oral p38 α inhibitor PH-797804, clinically studied for COPD therapy administered 2h before IL-1β challenge inhibited neutrophil recruitment in BAL (ED 50 = 0.3mg/kg) and IL-6 increase (ED 50 =0.27mg/kg). CHI-91040, administered i.t. as a micronised dry powder, dose-dependently counteracted IL-1β-induced neutrophil influx (ED 50 =0.22mg/kg) and the increase in IL-6 levels (ED 50 =0.82mg/kg) with a potency similar to PH-797804. When given 12h before IL1β, PH-797804 lost its anti-inflammatory effect whereas CHI-91040 significantly inhibited both neutrophil influx (53%) and IL-6 increase (50%) at the dose of 0.3mg/kg.CHI-91040 showed a sustained lung retention (t1/2>12h) and low plasma levels; characteristics consistent with the prolonged duration of action. CONCLUSION: The IL-1β model of lung inflammation can be used for the pharmacological characterization of p38 inhibitors. CHI-91040 is a potent inhaled p38α inhibitor that deserves clinical evaluation as a potential novel treatment for COPD and severe asthma.