RT Journal Article
SR Electronic
T1 Synergistic effects of p38 MAPK inhibition with a corticosteroid in alveolar macrophages from corticosteroid insensitive asthma patients
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1763
VO 42
IS Suppl 57
A1 Simon Lea
A1 Chris Harbron
A1 Jane Armstrong
A1 Naimat Khan
A1 Keith Wreggett
A1 Dave Singh
YR 2013
UL http://erj.ersjournals.com/content/42/Suppl_57/1763.abstract
AB Background: Some asthma patients remain symptomatic despite using inhaled corticosteroids (CS) and long-acting-β2-agonists. P38 MAPK inhibitors are novel anti-inflammatory drugs that may be useful in CS insensitive asthma patients. We used alveolar macrophages (AM) to investigate the effects of p38 MAPK inhibition in CS insensitive asthma patients.Methods: AM from 27 asthma patients (6 GINA1, 10 GINA2 and 11 GINA3/4) were stimulated with LPS (1μg/ml). The effects of dexamethasone (dex: 1-1000nM), the p38 MAPK inhibitor BIRB-796 (1-1000nM) and both drugs combined at all concentrations on supernatant TNFα, IL-6 and IL-8 levels were analysed by ELISA. Dose-sparing and efficacy enhancing effects of combination treatment were determined as per Armstrong et al. J Pharmacol Exp Ther 2011; 338:732-40.Results: Dex reduced LPS-induced TNFα, IL-6 and IL-8 in all groups, but the maximum inhibition was significantly reduced for GINA3/4 compared to GINA2 and GINA1 (p<0.01). A subgroup of CS 'insensitive' patients (n=7; 6 GINA3/4 and 1 GINA2) were identified by the in vitro AM response to dex. BIRB-796 in combination with dex significantly increased cytokine inhibition compared to dex alone (p<0.001) in all groups. This effect was greater in ‘insensitive’ compared to ‘sensitive’ patients with efficay enhancing benefits of 36.4 and 10.8 respectively for inhibition of LPS-induced TNFα.Conclusion: A high proportion of GINA3/4 patients have CS ‘insensitive’ AM. P38 MAPK inhibitors enhance the efficacy of CS; This effect is greater in the 'insensitive' population, suggesting that identifying subsets of patients may be key to developing novel therapeutics.