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Targeting phosphoinositide-3-kinase-delta with theophylline reverses corticosteroid insensitivity in chronic
Yasuo To1, Kazuhiro Ito, Yasuo Kizawa
1Airway Disease Section, NHLI Imperial College, London, United Kingdom.
Rationale:
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.
Objectives:
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.
Methods:
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.
Measurements And Main Results:
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.
Conclusions:
Inhibition of oxidative stress dependent PI3K-δ activation by a selective inhibitor or theophylline provides a novel approach to reversing corticosteroid insensitivity in COPD.
Insights
Theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease (COPD) by inhibiting phosphoinositide-3-kinase-delta (PI3K-δ) activation. This targeted approach offers a new strategy for treating COPD patients who do not respond well to standard therapies.
Area of Science:
- Pulmonary Medicine
- Molecular Biology
- Pharmacology
Background:
- Patients with chronic obstructive pulmonary disease (COPD) exhibit a diminished response to corticosteroid treatments.
- This corticosteroid insensitivity is associated with reduced histone deacetylase-2 activity, a consequence of oxidative stress.
- Theophylline has been shown to reverse this effect.
Purpose of the Study:
- To investigate the role of phosphoinositide-3-kinase-delta (PI3K-δ) in the development of corticosteroid insensitivity in COPD.
- To explore PI3K-δ as a potential therapeutic target for theophylline in managing corticosteroid insensitivity.
- To understand the impact of oxidative stress on PI3K-δ and corticosteroid sensitivity.
Main Methods:
- Determined corticosteroid sensitivity by measuring dexamethasone's inhibitory concentration on cytokine release in peripheral blood mononuclear cells from COPD and control subjects.
- Assessed the effects of theophylline and a selective PI3K-δ inhibitor (IC87114) on restoring corticosteroid sensitivity.
- Validated findings in cigarette smoke-exposed mouse models.
Main Results:
- COPD patients displayed significantly reduced corticosteroid sensitivity compared to controls.
- Oxidative stress led to corticosteroid insensitivity and decreased histone deacetylase-2 activity, which were reversed by theophylline and a PI3K inhibitor.
- Theophylline selectively inhibited oxidant-activated PI3K-δ, which was elevated in COPD lung tissue. Knock-down of PI3K-δ prevented corticosteroid insensitivity.
- Theophylline and IC87114, with dexamethasone, reduced lung inflammation in a mouse model.
Conclusions:
- Inhibition of oxidative stress-dependent PI3K-δ activation is a promising therapeutic strategy.
- Theophylline or selective PI3K-δ inhibitors can reverse corticosteroid insensitivity in COPD.
- This presents a novel approach for treating corticosteroid-unresponsive COPD patients.
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