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Corticosteroid insensitive alveolar macrophages from asthma patients; synergistic interaction with a p38 mitogen‐activated protein kinase ( MAPK ) inhibitor
Author(s) -
Lea Simon,
Harbron Chris,
Khan Naimat,
Booth George,
Armstrong Jane,
Singh Dave
Publication year - 2015
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12536
Subject(s) - dexamethasone , corticosteroid , medicine , pharmacology , p38 mitogen activated protein kinases , asthma , cytokine , mapk/erk pathway , protein kinase a , tumor necrosis factor alpha , immunology , endocrinology , kinase , chemistry , biochemistry
Aims Some asthma patients remain symptomatic despite using high doses of inhaled corticosteroids (ICS). We used alveolar macrophages to identify individual patients with insensitivity to corticosteroids and to evaluate the anti‐inflammatory effects of a p38 mitogen‐activated protein kinase ( MAPK ) inhibitor combined with a corticosteroid on these cells. Methods Alveolar macrophages from 27 asthma patients (classified according to the Global Initiative for Asthma ( GINA ) treatment stage. Six GINA1 , 10 GINA2 and 11 GINA3 /4) were stimulated with lipoploysaccharide ( LPS ) (1 μg ml −1 ). The effects of dexamethasone (dex 1–1000 n m ), the p38 MAPK inhibitor 1‐(5‐ tert ‐butyl‐2‐ p ‐tolyl‐2 H pyrazol‐3‐yl)‐3(4‐(2‐morpholin‐4‐yl‐ethoxy)naphthalen‐1‐yl)urea ( BIRB ‐796 1–1000 n m ) and both drugs combined at all concentrations on supernatant TNFα, IL ‐6 and CXCL ‐8 concentrations were analyzed by ELISA . Dose‐sparing and efficacy enhancing effects of combination treatment were determined. Results Dexamethasone reduced LPS ‐induced TNFα , IL ‐6 and CXCL ‐8 in all groups, but maximum inhibition was significantly reduced for GINA 3/4 compared with GINA2 and GINA1 ( P < 0.01). A subgroup of corticosteroid insensitive patients with a reduced effect of dexamethasone on cytokine secretion were identified. BIRB ‐796 in combination with dexamethasone significantly increased cytokine inhibition compared with either drug alone ( P < 0.001) in all groups. This effect was greater in corticosteroid insensitive compared with sensitive patients. There were significant synergistic dose‐sparing effects ( P < 0.05) for the combination treatment on inhibition of TNFα , IL ‐6 and CXCL ‐8 in all groups. There was also significant efficacy enhancing benefits ( P < 0.05) on TNFα and IL ‐6. Conclusions p38 MAPK inhibitors synergistically enhance efficacy of corticosteroids in macrophages from asthma patients. This effect is greater in corticosteroid insensitive asthma patients, suggesting that this class of drug should be targeted to this patient phenotype.