Most of the patients with asthma are found to be successfully treated with conventional therapy. However, there are a small proportion of asthmatic patients who fail to respond to corticosteroids even at high doses or with supplementary therapy. In addition, even high doses of corticosteroids have a minimal effect on the inexorable decline in lung function in COPD (chronic obstructive pulmonary disease) and only a small effect in reducing exacerbations. Corticosteroid-insensitivity therefore presents a profound management problem. Corticosteroids act through a cytosolic receptor [GR (glucocorticoid receptor)], which is activated and translocates to the nucleus. Once in the nucleus, it either binds to DNA and switches on the expression of anti-inflammatory genes or represses the activity of distinct signalling pathways such as NF-κB (nuclear factor κB), AP-1 (activator protein-1) or MAPKs (mitogen-activated protein kinases). This latter step requires the recruitment of co-repressor molecules. A failure to respond to corticosteroids may therefore result from lack of binding to GR, reduced GR expression, lack of co-repressor activity or enhanced activation of inflammatory pathways. These events can be modulated by oxidative stress or high levels of inflammatory cytokines, which may lead to a reduced clinical outcome. Understanding the molecular mechanisms of GR action, and inaction, may lead to the development of new anti-inflammatory drugs or reverse the relative corticosteroid-insensitivity that is characteristic of these diseases.
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August 2009
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Conference Article|
July 22 2009
Overcoming steroid unresponsiveness in airways disease
Ian M. Adcock;
Ian M. Adcock
1
*Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, U.K.
†MRC-Asthma UK Centre for Allergic Mechanisms in Asthma, 5th Floor, Tower Wing, Guy's Hospital, London SE1 9RT, U.K.
1To whom correspondence should be addressed (email ian.adcock@imperial.ac.uk).
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Pai-Chien Chou;
Pai-Chien Chou
*Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, U.K.
†MRC-Asthma UK Centre for Allergic Mechanisms in Asthma, 5th Floor, Tower Wing, Guy's Hospital, London SE1 9RT, U.K.
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Andrew Durham;
Andrew Durham
*Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, U.K.
†MRC-Asthma UK Centre for Allergic Mechanisms in Asthma, 5th Floor, Tower Wing, Guy's Hospital, London SE1 9RT, U.K.
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Paul Ford
Paul Ford
*Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, U.K.
†MRC-Asthma UK Centre for Allergic Mechanisms in Asthma, 5th Floor, Tower Wing, Guy's Hospital, London SE1 9RT, U.K.
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Publisher: Portland Press Ltd
Received:
February 17 2009
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem Soc Trans (2009) 37 (4): 824–829.
Article history
Received:
February 17 2009
Citation
Ian M. Adcock, Pai-Chien Chou, Andrew Durham, Paul Ford; Overcoming steroid unresponsiveness in airways disease. Biochem Soc Trans 1 August 2009; 37 (4): 824–829. doi: https://doi.org/10.1042/BST0370824
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