Corticosteroid resistance in airway disease.
Resistance to the antiinflammatory effects of corticosteroids is very uncommon in asthma but common in chronic obstructive pulmonary disease. Recent understanding of the molecular mechanisms involved in the antiinflammatory actions of corticosteroids has revealed that there are several possible mechanisms for corticosteroid resistance. Certain cytokines activate p38 mitogen-activated protein kinase, which may interfere with the nuclear localization of glucocorticoid receptors (GRs). In other patients, nuclear localization of GR is normal but there is a reduction in acetylation of a lysine residue in histone-4, thus leading to impaired activation of certain antiinflammatory genes. In chronic obstructive pulmonary disease and severe asthma, oxidative stress may reduce the activity and expression of certain histone deacetylases and therefore interfere with the antiinflammatory action of corticosteroids. These mechanisms suggest that there may be several therapeutic approaches to treating corticosteroid resistance in the future, including antioxidants, p38 mitogen-activated protein kinase inhibitors, and theophylline, which activates histone deacetylases.
Barnes
Peter J
PJ
National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK. p.j.barnes@imperial.ac.uk
D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004351:Drug Resistance / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000188:drug therapy*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D012129:Respiratory Function Tests; D012307:Risk Factors; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index
D000305:Adrenal Cortex Hormones; D007378:Interleukins; D011987:Receptors, Steroid; D048049:Extracellular Signal-Regulated MAP Kinases; D006655:Histone Deacetylases