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Glucocorticoid pathways in chronic obstructive pulmonary disease therapy.
1Cell and Molecular Biology, Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK. ian.adcock@imperial.ac.uk
Proceedings of the American Thoracic Society
|November 4, 2005
Summary
Corticosteroid resistance in chronic obstructive pulmonary disease (COPD) may stem from altered glucocorticoid receptor phosphorylation and oxidative stress. Therapies targeting these pathways could restore steroid sensitivity in COPD patients.
Area of Science:
- Pulmonology
- Cellular Biology
- Pharmacology
Background:
- Lung function in chronic obstructive pulmonary disease (COPD) patients shows limited response to corticosteroids, unlike asthma patients.
- Corticosteroids mediate effects via cytoplasmic glucocorticoid receptors, influenced by post-translational modifications like phosphorylation.
- Understanding this differential response is crucial for developing effective COPD treatments.
Purpose of the Study:
- To investigate the mechanisms behind corticosteroid resistance in COPD.
- To identify potential therapeutic targets for restoring corticosteroid sensitivity in COPD.
Main Methods:
- Analysis of glucocorticoid receptor phosphorylation and its impact on receptor function.
- Investigation of oxidative stress and its role in corticosteroid resistance in COPD models.
- Assessment of nuclear translocation and histone deacetylase activity.
Main Results:
- Glucocorticoid receptor phosphorylation may dictate receptor function through a "phosphorylation code."
- Oxidative stress from cigarette smoke contributes to corticosteroid resistance by enhancing proinflammatory transcription.
- Reduced glucocorticoid nuclear translocation and attenuated histone deacetylase activity are implicated in COPD steroid resistance.
Conclusions:
- Altered glucocorticoid receptor phosphorylation and oxidative stress are key factors in COPD corticosteroid resistance.
- Targeting the glucocorticoid receptor activation pathway, including phosphorylation and oxidative stress, may reverse steroid resistance in COPD.