Oral and inhaled p38 MAPK inhibitors: Effects on inhaled LPS challenge in healthy subjects

Abstract

Background: Inhaled LPS causes neutrophilic airway inflammation in healthy subjects. We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response. Methods: Three randomised, double-blind, placebo-controlled, single dose crossover studies were performed. Active treatments were the oral p38 MAPK inhibitor PH-797804 30 mg (study 1), PH-797804 30 mg and the inhaled p38 MAPK inhibitor PF-03715455 20 mg (study 2) and inhaled fluticasone propionate 500 μg (study 3). The primary endpoint was sputum neutrophil percentage. Results: Sputum neutrophil percentage post-LPS challenge was significantly inhibited (15.1 and 15.3 % reduction) by PH-797804 compared to placebo in studies 1 and 2 (p∈=∈0.0096 and 0.0001, respectively), and by PF-03715455 (8.0 % reduction, p∈=∈0.031); fluticasone propionate had no effect. PH-797804 significantly inhibited the increase in inflammatory mediators (IL-6, MCP-1, MIP1β and CC16) in sputum supernatant, while PF-03715455 had no effect. PH-797804 and PF-03715455 both inhibited IL-6, MCP-1, MIP1β, CC16 and CRP levels in plasma, with PH-797804 having greater effects. Fluticasone propionate had no effect on sputum supernatant or plasma biomarkers. Conclusions: PH-797804 had the greatest impact on neutrophilic airway inflammation. Oral administration of p38 MAPK inhibitors may optimise pulmonary anti-inflammatory effects.