Reversal of corticosteroid insensitivity in COPD by theophylline

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.

Chronic obstructive pulmonary disease (COPD) is a major and increasing global health problem. It is characterised by a specific pattern of chronic inflammation in small airways and lung parenchyma which increases with disease progression. While corticosteroids are highly effective in suppressing airway inflammation in asthmatic patients, they are essentially ineffective in COPD. We have shown that this corticosteroid insensitivity in COPD is due to a reduction in histone deacetylase(HDAC)2 activity and expression in the lungs and macrophages. The reduction in HDAC2 can account for the amplification of inflammation in COPD and also for corticosteroid resistance, since activated glucocorticoid receptors recruit HDAC2 to switch off activated inflammatory genes in the lung. We have also demonstrated that low concentrations of theophylline restore HDAC2 activity and expression and restore corticosteroid responsiveness in macrophages in vitro and in the lungs of animals exposed to cigarette smoke in vivo. We now propose to test the hypothesis that theophylline reverses steroid resistance in COPD in a clinical trial of COPD patients. We will initially study the effect of low doses of theophylline on HDAC and inflammatory gene expression in macrophages from induced sputum of COPD patients, matched normal smokers and non-smokers. We will then undertake a double-blind controlled trial of theophylline or placebo alone and in combination with an inhaled corticosteroid in COPD patients and measure the effect on inflammatory cells and mediators in induced sputum. We will also investigate the molecular mechanisms of HDAC activation by theophylline based on preliminary studies in which we have shown that the activating effect of theophylline is blocked by a p38 MAP kinase inhibitor and that oxidative stress-induced activation of phosphoinositide-3-kinase, which reduces HDAC activity, is reversed by theophylline, indicating that theophylline may activate HDAC2 by phosphorylation. These studies may have important implications since low doses of theophylline may allow corticosteroids to suppress inflammation in COPD and thus slow the progression of the disease. This would have profound implications for the future management of COPD and markedly reduce health care costs. Identification of the molecular mechanism of action of theophylline may also lead to the development of new drugs in the future that avoid the side effects which limit the dose of theophylline.