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Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of chronic obstructive pulmonary disease
  1. Borja G Cosio (bcosio{at}hsd.es)
  1. Hospital Universitario Son Dureta, Spain
    1. Amanda Iglesias (aiglesias{at}hsd.es)
    1. CIBER enfermedades respiratorias, Spain
      1. Angel Rios (arios{at}hsd.es)
      1. Fundación Caubet-Cimera, Spain
        1. Aina Noguera (anoguera{at}hsd.es)
        1. Hospital Universitario Son Dureta, Spain
          1. Ernest Sala (esala{at}hsd.es)
          1. Hospital Universitario Son Dureta, Spain
            1. Kazuhiro Ito (k.ito{at}imperial.ac.uk)
            1. National Heart and Lung Institute, United Kingdom
              1. Peter J Barnes (p.j.barnes{at}ic.ac.uk)
              1. National Heart and Lung Institute, United Kingdom
                1. Alvar Agusti (aagusti{at}hsd.es)
                1. Hospital Universitario Son Dureta, Spain

                  Abstract

                  Rationale: Chronic obstructive pulmonary disease (COPD) is characterised by an abnormal inflammatory response to mainly cigarette smoke that flares up during exacerbations of the disease (ECOPD). A reduced activity of histone deacetylases (HDAC) contributes to enhanced inflammation in stable COPD. We hypothesized that HDAC activity is further reduced during ECOPD, and that theophylline, an HDAC activator, potentiates the anti-inflammatory effect of steroids in these patients.

                  Objectives: To investigate HDAC activity during ECOPD and the effects of theophylline on the anti-inflammatory effects of steroids.

                  Methods: Thirty-five patients hospitalised because of ECOPD and treated according to international guidelines (including systemic steroids) were randomised to receive (or not) low-dose oral theophylline (100 mg bid). Before treatment and 3 months after discharge we measured HDAC and nuclear factor (NF)-κB activity in sputum macrophages, the concentration of nitric oxide in exhaled gas (eNO), and total anti-oxidant status (TAS), TNF-α, IL-6 and IL-8 levels in sputum supernatants.

                  Measurements and Main results: Patients receiving standard therapy showed decreased NF-κB activity, eNO concentration and sputum levels of TNF-α, IL-6 and IL-8, as well as increased TAS during recovery of ECOPD, but HDAC activity did not change. The addition of low-dose theophylline increased HDAC activity (p=0.02)and further reduced IL-8 and TNF-α concentrations (p=0.031).

                  Conclusions: During ECOPD, low dose theophylline increases HDAC activity and improves the anti-inflammatory effects of steroids.

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