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

ABSTRACT: Inhaled LPS causes neutrophilic airway inflammation in healthy subjects. We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response.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 ?g (study 3). The primary endpoint was sputum neutrophil percentage.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, MIP1? and CC16) in sputum supernatant, while PF-03715455 had no effect. PH-797804 and PF-03715455 both inhibited IL-6, MCP-1, MIP1?, CC16 and CRP levels in plasma, with PH-797804 having greater effects. Fluticasone propionate had no effect on sputum supernatant or plasma biomarkers.PH-797804 had the greatest impact on neutrophilic airway inflammation. Oral administration of p38 MAPK inhibitors may optimise pulmonary anti-inflammatory effects.

SUBMITTER: Singh D 

PROVIDER: S-EPMC4564450 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature