Reversal of corticosteroid insensitivity in COPD by theophylline

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Chronic obstructive pulmonary disease (COPD) or smokers? lung is a growing problem and already one of the commonest causes of death and disability in the UK. COPD accounts for over #800 million in direct healthcare costs. COPD is associated with inflammation in the lung, which gets worse as the disease progresses. Asthma also involves inflammation in the lung but this is usually easy to control with steroid inhalers, which are very effective treatment. By contrast, the inflammation in COPD does not respond to steroid therapy and we have shown that cells from COPD patients also fail to respond, indicating that this problem is likely to be due to a molecular defect. Steroids work by switching off genes that code for inflammatory products by an enzyme in the nucleus called histone deacetylase-2 (HDAC2). We have shown that HDAC2 is impaired in the lungs and cells of COPD patients, so that steroids can no longer switch off inflammation. We have found that theophylline, an old drug used to treat asthma, is able to active HDAC2 and restore its levels to normal, thus reversing steroid resistance in cells from COPD patients. We now plan to test this in patients with COPD by giving low doses of theophylline to see whether this allows inhaled steroids to control inflammation. We also plan to look into how theophylline is able to active HDAC in these cells, as this might lead to new treatments in the future. As no anti-inflammatory treatments currently exist for the treatment of COPD and stopping smoking does appear to little or no effect on the inflammation, there is an urgent need to find treatments that may reverse steroid resistance in COPD or to find alternative anti-inflammatory drugs.