New insights into the molecular mechanisms of corticosteroids actions.
Corticosteroids produce a marked improvement in clinical parameters in most asthmatic patients; in contrast, corticosteroids have little effect on lung function measurements in patients with chronic obstructive pulmonary disease. By uncovering the reason for this paradox, it should be possible to implement treatment regimens that restore corticosteroid sensitivity. Corticosteroids exert their effects by binding to a cytoplasmic receptor, which is subjected to post-translational modifications. Receptor phosphorylation may influence hormone binding and nuclear translocation, alter glucocorticoid receptor interactions and protein half-life. Other modifications such as nitration/nitrosylation may also affect glucocorticoid receptor function. Oxidative stress due to cigarette smoke may be a mechanism for the corticosteroid resistance observed in chronic obstructive pulmonary disease, as it enhances proinflammatory transcription and reduces glucocorticoid receptor-associated repressor functions. Therapies targeting these aspects of the glucocorticoid receptor activation pathway may reverse steroid resistance in patients with chronic obstructive pulmonary disease.
Adcock
Ian M
IM
Cell & Molecular Biology, Airways Disease Section, National Heart & Lung Institute, Imperial College London, UK. ian.adcock@imperial.ac.uk
Caramori
Gaetano
G
Ito
Kazuhiro
K
D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004351:Drug Resistance; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects
D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D011965:Receptors, Glucocorticoid