New effects of theophylline in patients with chronic obstructive pulmonary disease: Anti-inflammatory action and its underlying mechanism

Oxidative and nitrosative stress and the activation of inflammatory cells including neutrophils are considered to have important roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). This study was designed to examine the effects of oral theophylline in patients with COPD. In a randomized crossover trial, we studied 16 patients with stable stage II or III COPD who gave informed consent. Their mean age was 71±2 years (range, 55 to 80). Their mean pack-year history of cigarette smoking was 68.0±8.0. Patients were randomly assigned to receive theophylline (400 mg/day) for 4 weeks or fluticasone propionate (400 μg/day) for 4 weeks. The other drug was then given for 4 weeks after 4 weeks washout period. The mean (±SD) serum theophylline concentration was 6.32±0.94 μg/mL. Lung function was not significantly altered by treatment with theophylline. During theophylline treatment, the mean total number of cells in induced sputum samples decreased significantly from 2.74± 0.28 to 2.12±0.33 (× 10 ⁶/mL). The mean number of neutrophils fell significantly from 1.97±0.18 to 1.38±0.19 (× 10⁶/mL). The mean concentration of interleukin-8 in the supernatant of induced sputum samples decreased significantly from 3.00±0.68 to 1.72±0.39 ng/mL. The mean number of 3-nitrotyrosine positive cells fell significantly from 1.63±0.28 to 1.10±0.29 (× 10⁶/mL). We conclude that theophylline inhibits airway neutrophil infiltration in patients with COPD. The underlying mechanism may involve the suppression of interleukin-8 production. Theophylline may also inhibit nitrosative stress in the airway of patients with COPD.