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The Proceedings of the American Thoracic Society 2:313-319 (2005)
© 2005 The American Thoracic Society

Glucocorticoid Pathways in Chronic Obstructive Pulmonary Disease Therapy

Ian M. Adcock and Kazuhiro Ito

Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom

Correspondence and requests for reprints should be addressed to Ian M. Adcock, Ph.D., Cell and Molecular Biology, Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK. E-mail: ian.adcock{at}imperial.ac.uk

Lung function measures in patients with chronic obstructive pulmonary disease remain insensitive to corticosteroid actions, in contrast to the clinical improvements observed in most patients with asthma. By uncovering the reason for this paradox, physicians should be able to implement treatment regimens that restore corticosteroid sensitivity. Corticosteroids exert their effects by binding to a cytoplasmic glucocorticoid receptor, which is subjected to post-translational modification by phosphorylation. Receptor phosphorylation may influence hormone binding and nuclear translocation, as well as alter other glucocorticoid receptor interactions, its protein half-life, and downregulation processes. This suggests that a "phosphorylation code" may exist for glucocorticoid receptor function. Oxidative stress due to cigarette smoke may also be a mechanism for the corticosteroid resistance observed in chronic obstructive pulmonary disease, as it enhances proinflammatory transcription. Reduced glucocorticoid nuclear translocation along with attenuated histone deacetylase activity may be partially responsible for this effect. Therapies targeting these aspects of the glucocorticoid receptor activation pathway may reverse steroid resistance in patients with chronic obstructive pulmonary disease.

Key Words: glucocorticoid receptor phosphorylation • inhaled corticosteroids • oxidative stress • steroid resistance




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