Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects.
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.
University Of Manchester, Medicines Evaluation Unit, University Hospital of South Manchester Foundation Trust, Manchester, M23 9QZ, UK. dsingh@meu.org.uk.
Dave
D
Singh
Quintiles Drug Research Unit, Respiratory and Inflammation Early Clinical Development, Quintiles Ltd, London, SE1 1YR, UK.
Leonard
L
Siew
Pfizer Inc. Inflammation and Remodeling Unit, Cambridge, MA, USA.
Jared
J
Christensen
University Of Manchester, Medicines Evaluation Unit, University Hospital of South Manchester Foundation Trust, Manchester, M23 9QZ, UK.
Jonathan
J
Plumb
Quintiles Drug Research Unit, Respiratory and Inflammation Early Clinical Development, Quintiles Ltd, London, SE1 1YR, UK.|Department of Cardiothoracic Pharmacology, Imperial College, National Heart and Lung Institute, London, UK.
Graham W
GW
Clarke
Quintiles Drug Research Unit, Respiratory and Inflammation Early Clinical Development, Quintiles Ltd, London, SE1 1YR, UK.
Steve
S
Greenaway
Pfizer Inc. Inflammation and Remodeling Unit, Cambridge, MA, USA.
Christelle
C
Perros-Huguet
Pfizer Inc. Inflammation and Remodeling Unit, Cambridge, MA, USA.
Nick
N
Clarke
Pfizer Inc. Inflammation and Remodeling Unit, Cambridge, MA, USA.
Iain
I
Kilty
Pfizer Inc. Inflammation and Remodeling Unit, Cambridge, MA, USA.
Lisa
L
Tan
D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D001985:Bronchial Provocation Tests; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D000068298:Fluticasone / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008782:Methylurea Compounds / Q000494:pharmacology*; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D013183:Sputum / Q000166:cytology; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D007191:Indazoles; D013440:Sulfides; D014230:Triazoles
D000893:Anti-Inflammatory Agents; D053961:Azabicyclo Compounds; D001549:Benzamides; D000068298:Fluticasone; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008782:Methylurea Compounds; D011728:Pyridones; D048051:p38 Mitogen-Activated Protein Kinases; C542398:PH 797804; C569762:N-(1-(3-chloro-4-hydroxyphenyl)-3-(1,1-dimethylethyl)-1H-pyrazol-5-yl)-N'-((2-((3-(2-((2-hydroxyethyl)thio)phenyl)-1,2,4-triazolo(4,3-a)pyridin-6-yl)thio)phenyl)methyl)-urea; D007191:Indazoles; D013440:Sulfides; D014230:Triazoles
Induced sputum; LPS challenge; p38 MAPK inhibitors