Glucocorticoid receptor acetylation and corticosteroid resistance in chronic obstructive pulmonary disease

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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. It 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 binding to a specific recognition protein called a glucocorticoid receptor (GR) which goes into the nucleus of the cell and switches off genes that code for inflammatory products whereas switching on other genes that lead to side effects. We have found that GR becomes changed by acetylation when it interacts with a steroid, but has to be changed back by enzymes called deacetylases if it is to switch off inflammatory genes and control inflammation. We have also found that these deacetylases are markedly defective in cells from COPD patients so GR is less able to be converted to a form which is needed to switch off inflammatory genes, thus accounting for the lack of response to steroids in these patients. The aim of this project is to study acetylation and deacetylation of GR and how this is altered in COPD cells. We hope that this will provide a means to reverse this abnormality and eventually to the development of treatments that will make steroids more effective in the treatment of COPD. 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 understand the mechanisms of steroid resistance and to find treatments that may reverse this situation. The same mechanisms may also be important in other severe inflammatory diseases, such as inflammatory diseases of joints and the gut, so that the health implications of this research are potentially enormous. We have an excellent Media Relations Department at Imperial College and commonly publicise any research that has public interest when it is published. Any advance in understanding the underlying mechanisms could be presented in a very favourable light if the enormous unmet needs in this disease are emphasised.