Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of COPD
Chronic obstructive pulmonary disease (COPD) is characterised by an abnormal inflammatory response mainly to cigarette smoke that flares up during exacerbations of the disease (ECOPD). Reduced activity of histone deacetylases (HDAC) contributes to enhanced inflammation in stable COPD. It was hypothesised that HDAC activity is further reduced during ECOPD and that theophylline, an HDAC activator, potentiates the antiinflammatory effect of steroids in these patients. A study was performed to
... s performed to investigate HDAC activity during ECOPD and the effects of theophylline on the anti-inflammatory effects of steroids in a randomised single-blind controlled study. Methods: 35 patients hospitalised with ECOPD and treated according to international guidelines (including systemic steroids) were randomised to receive or not to receive low-dose oral theophylline (100 mg twice daily). Before treatment and 3 months after discharge, HDAC and nuclear factor-kB (NF-kB) activity in sputum macrophages, the concentration of nitric oxide in exhaled air (eNO) and total antioxidant status (TAS), tumour necrosis factor a (TNFa), interleukin (IL)-6 and IL8 levels in sputum supernatants were measured. Results: Patients receiving standard therapy showed decreased NF-kB activity, eNO concentration and sputum levels of TNFa, IL6 and IL8, as well as increased TAS during recovery of ECOPD, but HDAC activity did not change. The addition of low-dose theophylline increased HDAC activity and further reduced IL8 and TNFa concentrations. Conclusions: During ECOPD, low-dose theophylline increases HDAC activity and improves the anti-inflammatory effects of steroids. Trial registration number: NCT00671151 Chronic obstructive pulmonary disease (COPD) is characterised by an enhanced inflammatory response to inhaled particles and gases, mostly cigarette smoking. 1 We have previously shown that the activity of histone deacetylases (HDAC) is decreased in patients with stable COPD, and that this can contribute to the abnormal inflammatory response that characterises the disease. 2 3 Patients with COPD often experience acute episodes of exacerbation (ECOPD) during the course of their disease. These episodes are characterised by nuclear factor-kB (NF-kB) activation 4 5 and a burst of airway inflammation, with increased oxidative and nitrative stress, 6 7 increased neutrophil counts and raised levels of several proinflammatory cytokines such as tumour necrosis factor a (TNFa) and interleukin-8 (IL8) and IL6. 8-10 Because both oxidative 11 and nitrative stress 12 can impair HDAC function, we hypothesised that HDAC activity will be further reduced during ECOPD, thus contributing to amplify baseline inflammation. Current international guidelines recommend the use of high-dose oral or intravenous steroids (in combination with inhaled bronchodilators) for the treatment of ECOPD. 1 Low concentrations of theophylline enhance HDAC activity and have anti-inflammatory effects, both in asthma and COPD, 13-15 that have been shown to add clinical benefits and safety in the long-term treatment of COPD. 16 We have previously shown that an impaired HDAC activity reduces the anti-inflammatory effects of steroids in patients with stable COPD, 2 3 and that this can be reversed by lowdose theophylline. 17 We hypothesised here that theophylline can also enhance HDAC activity and improve steroid responsiveness during ECOPD. Accordingly, in this prospective randomised single-blind controlled study, we determined as the primary outcome the activity of HDAC in sputum macrophages of patients hospitalised with ECOPD and investigated whether the addition of low-dose oral theophylline to standard therapy enhances its activity and the anti-inflammatory effects of steroids.