We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Targeting phosphoinositide-3-kinase-delta with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease.
- Authors
To Y; Ito K; Kizawa Y; Failla M; Ito M; Kusama T; Elliott WM; Hogg JC; Adcock IM; Barnes PJ; To, Yasuo; Ito, Kazuhiro; Kizawa, Yasuo; Failla, Marco; Ito, Misako; Kusama, Tadashi; Elliott, W Mark; Hogg, James C; Adcock, Ian M; Barnes, Peter J
- Abstract
<bold>Rationale: </bold>Patients 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.<bold>Objectives: </bold>To 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.<bold>Methods: </bold>Corticosteroid 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.<bold>Measurements and Main Results: </bold>Peripheral 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.<bold>Conclusions: </bold>Inhibition of oxidative stress dependent PI3K-δ activation by a selective inhibitor or theophylline provides a novel approach to reversing corticosteroid insensitivity in COPD.
- Publication
American Journal of Respiratory & Critical Care Medicine, 2010, Vol 182, Issue 7, p897
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.200906-0937OC