Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease - 27/02/13
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Abstract |
Reduced responsiveness to the anti-inflammatory effects of corticosteroids is a major barrier to effective management of asthma in smokers and patients with severe asthma and in the majority of patients with chronic obstructive pulmonary disease (COPD). The molecular mechanisms leading to steroid resistance are now better understood, and this has identified new targets for therapy. In patients with severe asthma, several molecular mechanisms have been identified that might account for reduced steroid responsiveness, including reduced nuclear translocation of glucocorticoid receptor (GR) ⍺ after binding corticosteroids. This might be due to modification of the GR by means of phosphorylation as a result of activation of several kinases (p38 mitogen-activated protein kinase ⍺, p38 mitogen-activated protein kinase γ, and c-Jun N-terminal kinase 1), which in turn might be due to reduced activity and expression of phosphatases, such as mitogen-activated protein kinase phosphatase 1 and protein phosphatase A2. Other mechanisms proposed include increased expression of GRβ, which competes with and thus inhibits activated GR⍺; increased secretion of macrophage migration inhibitory factor; competition with the transcription factor activator protein 1; and reduced expression of histone deacetylase (HDAC) 2. HDAC2 appears to mediate the action of steroids to switch off activated inflammatory genes, but in patients with COPD, patients with severe asthma, and smokers with asthma, HDAC2 activity and expression are reduced by oxidative stress through activation of phosphoinositide 3-kinase δ. Strategies for managing steroid resistance include alternative anti-inflammatory drugs, but a novel approach is to reverse steroid resistance by increasing HDAC2 expression, which can be achieved with theophylline and phosphoinositide 3-kinase δ inhibitors. Long-acting β2-agonists can also increase steroid responsiveness by reversing GR⍺ phosphorylation. Identifying the molecular mechanisms of steroid resistance in asthmatic patients and patients with COPD can thus lead to more effective anti-inflammatory treatments.
Le texte complet de cet article est disponible en PDF.Key words : Glucocorticoid receptor, histone deacetylase, p38 mitogen-activated protein kinase, protein phosphatase, theophylline, phosphoinositide 3-kinase
Abbreviations used : AP-1, COPD, GR, GRE, HDAC, ICS, JNK, LABA, MAPK, MKP, NF-κB, NO, Nrf2, PDE, PI3K, PP2A
Plan
Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, and William T. Shearer, MD, PhD |
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Disclosure of potential conflict of interest: P. J. Barnes has provided expert testimony for Boehringer Ingelheim and Teva; has received grants from AstraZeneca, Nycomed, Novartis, Boehringer Ingelheim, Chiesi, Aquinox, and Pfizer; and has received payment for lectures from AstraZeneca, Nycomed, Chiesi, Novartis, and Pfizer. |
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Terms in boldface and italics are defined in the glossary on page 637. |
Vol 131 - N° 3
P. 636-645 - mars 2013 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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