Dataset Information

Corticosteroid insensitivity is reversed by formoterol via phosphoinositide-3-kinase inhibition.

ABSTRACT:

Background and purpose

Patients with chronic obstructive pulmonary disease (COPD) show a poor response to corticosteroids, which has been linked to oxidative stress. Here we show that the long-acting ?(2) -agonist formoterol (FM) reversed corticosteroid insensitivity under oxidative stress via inhibition of phosphoinositide-3-kinase (PI3K) signalling.

Experimental approach

Responsiveness to corticosteroids dexamethasone (Dex), budesonide (Bud) and fluticasone propionate (FP) was determined, as IC(50) values on TNF-?-induced interleukin 8 release, in U937 monocytic cell line treated with hydrogen peroxide (H(2) O(2) ) or peripheral blood mononuclear cells (PBMCs) from patients with COPD or severe asthma.

Key results

PBMCs from severe asthma and COPD were less sensitive to Dex compared with those from healthy subjects. Both FM (10(-9) ?M) and salmeterol (SM, 10(-8) ?M) reversed Dex insensitivity in severe asthma, but only FM restored Dex sensitivity in COPD. Although H(2) O(2) exposure decreased steroid sensitivity in U937 cells, FM restored responsiveness to Bud and FP while the effects of SM were weaker. Additionally, FM, but not SM, partially inhibited H(2) O(2) -induced PI3K?-dependent (PKB) phosphorylation. H(2) O(2) decreased SM-induced cAMP production in U937 cells, but did not significantly affect the response to FM. The reduction of SM effects by H(2) O(2) was reversed by pretreatment with LY294002, a PI3K inhibitor, or IC87114, a PI3K? inhibitor.

Conclusion and implications

FM reversed oxidative stress-induced corticosteroid insensitivity and decreased ?(2) adrenoceptor-dependent cAMP production via inhibition of PI3K? signalling. FM will be more effective than SM, when combined with corticosteroids, for the treatment of respiratory diseases under conditions of high oxidative stress, such as in COPD.

SUBMITTER: Rossios C

PROVIDER: S-EPMC3575778 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Corticosteroid insensitivity is reversed by formoterol via phosphoinositide-3-kinase inhibition.

Rossios C C To Y Y Osoata G G Ito M M Barnes P J PJ Ito K K

British journal of pharmacology 20121001 4

<h4>Background and purpose</h4>Patients with chronic obstructive pulmonary disease (COPD) show a poor response to corticosteroids, which has been linked to oxidative stress. Here we show that the long-acting β(2) -agonist formoterol (FM) reversed corticosteroid insensitivity under oxidative stress via inhibition of phosphoinositide-3-kinase (PI3K) signalling.<h4>Experimental approach</h4>Responsiveness to corticosteroids dexamethasone (Dex), budesonide (Bud) and fluticasone propionate (FP) was d ...[more]

PMID: 22251095

Similar Datasets

Project description:RationalePatients with chronic obstructive pulmonary disease (COPD) show a poor response to corticosteroids. This has been linked to a reduction of histone deacetylase-2 as a result of oxidative stress and is reversed by theophylline.ObjectivesTo determine the role of phosphoinositide-3-kinase-delta (PI3K-δ) on the development of corticosteroid insensitivity in COPD and under oxidative stress, and as a target for theophylline.MethodsCorticosteroid sensitivity was determined as the 50% inhibitory concentration of dexamethasone on tumor necrosis factor-α-induced interleukin-8 release in peripheral blood mononuclear cells from patients with COPD (n = 17) and compared with that of nonsmoking (n = 8) and smoking (n = 7) control subjects. The effect of theophylline and a selective PI3K-δ inhibitor (IC87114) on restoration of corticosteroid sensitivity was confirmed in cigarette smoke-exposed mice.Measurements and main resultsPeripheral blood mononuclear cells of COPD (50% inhibitory concentration of dexamethasone: 156.8 ± 32.6 nM) were less corticosteroid sensitive than those of nonsmoking (41.2 ± 10.5 nM; P = 0.018) and smoking control subjects (47.5 ± 19.6 nM; P = 0.031). Corticosteroid insensitivity and reduced histone deacetylase-2 activity after oxidative stress were reversed by a non-selective PI3K inhibitor (LY294002) and low concentrations of theophylline. Theophylline was a potent selective inhibitor of oxidant-activated PI3K-δ, which was up-regulated in peripheral lung tissue of patients with COPD. Furthermore, cells with knock-down of PI3K-δ failed to develop corticosteroid insensitivity with oxidative stress. Both theophylline and IC87114, combined with dexamethasone, inhibited corticosteroid-insensitive lung inflammation in cigarette-smoke-exposed mice in vivo.ConclusionsInhibition of oxidative stress dependent PI3K-δ activation by a selective inhibitor or theophylline provides a novel approach to reversing corticosteroid insensitivity in COPD.

Dataset Information

Corticosteroid insensitivity is reversed by formoterol via phosphoinositide-3-kinase inhibition.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Corticosteroid insensitivity is reversed by formoterol via phosphoinositide-3-kinase inhibition.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets