Title: Mechanisms of Corticosteroid Resistance in Severe Asthma and Chronic Obstructive Pulmonary Disease (COPD)
Volume: 16
Issue: 32
Author(s): Ian M. Adcock, John Marwick, Paolo Casolari, Marco Contoli, Kian Fan Chung, Paul Kirkham, Alberto Papi and Gaetano Caramori
Affiliation:
Keywords:
Asthma, COPD, glucocorticoids, GR, HDAC, PI3K, Corticosteroid, ICS therapy, long-acting-agonist, pro-inflammatory mediators, Translocation, nuclear localization sequence, hinge region, leptomycin B, phosphoprotein, phosphorylation, inflammatory genes, GR-GRE binding, vitamin D3 receptor, cyclic AMP, (CREB)-binding protein, RNA polymerase, histone deacetylases, annexin 1, glucocorticoid- inducible leucine zipper, MAPK phosphatase, NF-B, NCoR, HDACs, adenylate-uridylate, –, rich elements, tristetrapolin, airway hyperresponsiveness, European Respiratory Society, beclomethasone, fluticasone, British Thoracic Society, beclomethasone- CFC, leukotriene receptor, theophylline, fluticasone propionate, anti-IgE treatment, Churg-Strauss syndrome, Strongyloides stercoralis, typical Cushingoid, T-helper cells, histone deacetylase, PI3Ks, pleckstrin homology, Immunomodulatory therapies, glucocorticoid receptor, Phosphodiesterases hydrolyse, IL-5 Blockers
Abstract: Inhaled glucocorticoids, also know as corticosteroids (ICS), revolutionized the treatment of asthma by suppressing airways inflammation and ICS therapy now forms the basis of treatment of asthma of all severities. More recently and usually in combination with a long-acting β-agonist (LABA), ICS use has been established in the treatment of chronic obstructive pulmonary disease (COPD). In asthma, ICS improves asthma control, lung function and prevents exacerbations, including hospital admissions and probably decreases mortality. Similar effects are seen in COPD but to a much lesser degree, however, an improvement in symptoms such as breathlessness and reduction in exacerbations occur particularly in more advanced disease with ICS. Chronic inflammation is a feature of both asthma and COPD, although there are differences in the site and characteristics of the inflammatory response. ICS have proven to be less effective in patients with severe asthma, smoking asthmatics and in patients with COPD. ICS act by binding to and activating specific cytosolic receptors (GR), which then translocate to the nucleus where they regulate gene expression by either binding to DNA and inducing anti-inflammatory genes or by repressing the induction of pro-inflammatory mediators. GR is able to selective repress specific inflammatory genes by differing actions on specific intracellular signalling pathways and transcription factors such as nuclear factor κB and on kinases pathways. Abnormal activation of these pathways may result in glucocorticoid resistance. Although, ICS/LABA combinations will remain the main focus of treatment of airways diseases in the near future; other combinations that improve the efficacy of ICS by reducing the abnormal activation of pathways that cause glucocorticoid resistance will be developed.
