Targeting Phosphoinositide-3-Kinase-δ with Theophylline Reverses Corticosteroid Insensitivity in Chronic Obstructive Pulmonary Disease

• Published in: American journal of respiratory and critical care medicine Vol. 182; no. 7; pp. 897 - 904
• Main Authors: To, Yasuo, Ito, Kazuhiro, Kizawa, Yasuo, Failla, Marco, Ito, Misako, Kusama, Tadashi, Elliott, W. Mark, Hogg, James C., Adcock, Ian M., Barnes, Peter J.
• Format: Journal Article
• Language: English
• Published: New York, NY American Thoracic Society 01.10.2010
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Anti-Inflammatory Agents - pharmacology; B. Chronic Obstructive Pulmonary Disease; Biological and medical sciences; Case-Control Studies; Chronic obstructive pulmonary disease, asthma; Dexamethasone - pharmacology; Drug Resistance - drug effects; Drug Resistance - genetics; Histone Deacetylase 2 - metabolism; Humans; Intensive care medicine; Leukocytes, Mononuclear; Medical sciences; Mice; Oxidative Stress; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphodiesterase Inhibitors - pharmacology; Phosphodiesterase Inhibitors - therapeutic use; Pneumology; Pulmonary Disease, Chronic Obstructive - drug therapy; Quinazolines - pharmacology; RNA Interference; Smoking - adverse effects; Theophylline - pharmacology; Theophylline - therapeutic use; Tobacco Smoke Pollution; Lung disease; Corticosteroid; Oxidative stress; Intensive care; Dexamethasone; RNA interference; Targeting; Steroid hormone; Respiratory disease; Bronchodilator; Antiinflammatory agent; Histone deacetylase 2; Antiasthma agent; cigarette smoke; Phosphodiesterase inhibitor; Respiratory analeptic; Phosphodiesterase 4 inhibitor; Bronchus disease; Xanthine derivatives; Chronic obstructive pulmonary disease; Histone; Resuscitation; Theophylline
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.200906-0937OC

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. 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. 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. 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. Inhibition of oxidative stress dependent PI3K-δ activation by a selective inhibitor or theophylline provides a novel approach to reversing corticosteroid insensitivity in COPD.