Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of COPD
- B G Cosio1,2,3,
- A Iglesias2,
- A Rios3,
- A Noguera1,2,3,
- E Sala1,2,3,
- K Ito4,
- P J Barnes4,
- A Agusti1,2,3
- 1Department of Respiratory Medicine, Hospital Universitario Son Dureta, Palma de Mallorca, Spain
- 2CIBER de Enfermedades Respiratorias, Unidad de Investigacion, Hospital Son Dureta, Palma de Mallorca, Spain
- 3Epidemiology and Clinical Research Unit, Fundacion Caubet-Cimera, Bunyola, Spain
- 4Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK
- Dr B G Cosío, Department of Respiratory Medicine, Hospital Universitario Son Dureta, Andrea Doria 55, 07014 Palma de Mallorca, Spain; borja.cosio{at}ssib.es
- Received 16 June 2008
- Accepted 8 January 2009
- Published Online First 21 January 2009
Abstract
Background: 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 anti-inflammatory effect of steroids in these patients. A study was 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-κB (NF-κB) activity in sputum macrophages, the concentration of nitric oxide in exhaled air (eNO) and total antioxidant status (TAS), tumour necrosis factor α (TNFα), interleukin (IL)-6 and IL8 levels in sputum supernatants were measured.
Results: Patients receiving standard therapy showed decreased NF-κB activity, eNO concentration and sputum levels of TNFα, 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 TNFα concentrations.
Conclusions: During ECOPD, low-dose theophylline increases HDAC activity and improves the anti-inflammatory effects of steroids.
Trial registration number: NCT00671151
Footnotes
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Funding: Supported in part by FIS 04/2146, ABEMAR, SEPAR and Medical Research Council (UK).
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Competing interests: BGC has received lecture fees and has served on Scientific Advisory Boards for GlaxoSmithKline (GSK), AstraZeneca and Novartis. KI is an employee of RespiVert Ltd. PB has received research funding, lecture fees and has served on Scientific Advisory Boards for GSK, AstraZeneca, Boehringer-Ingelheim, Novartis, Altana and Pfizer, all of whom have an interest in new therapies for COPD. AA has received research funding from AstraZeneca, Pfizer and Boehringer Ingelheim and lecture fees for speaking at conferences sponsored by GSK, AstraZeneca and Almirall during the past five years. He has also served on advisory boards for GSK, Almirall and Altana. The other authors have no competing interests with this paper.
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Ethics approval: All patients were informed of the nature and purpose of the study and gave their written consent. The study was approved by the local ethics committee.
