Steroid resistance in asthma.
Resistance to the anti-inflammatory effects of glucocorticoids in asthma and other inflammatory and immune diseases is uncommon, but presents a management problem. Understanding the mechanisms of steroid resistance provides new insights into the mechanism of steroid action as well as the underlying chronic disease process. In patients with primary steroid-resistant (SR) asthma there is no abnormality in the pharmacokinetics of the exogenous steroid and no significant defect in steroid binding to the glucocorticoid receptor (GR). Recent studies have demonstrated a marked reduction in the binding of GR to DNA; this appears to be due to increased binding of GR to the transcription factor activator protein-1 (AP-1). Secondary steroid resistance in asthma may arise in response to the release of cytokines that activate AP-1 and other transcription factors that bind directly to GR. A similar effect may also be seen with high concentrations of beta 2-agonists that activate another GR binding transcription factor, CREB. Several existing and novel treatment strategies are possible in the management of SR asthma.
Barnes
P J
PJ
Department of Thoracic Medicine, National Heart and Lung Institute, London, UK.
Adcock
I M
IM
D000328:Adult; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002648:Child; D004351:Drug Resistance; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors