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Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease

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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) α 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 α, 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 GRα; 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 GRα phosphorylation. Identifying the molecular mechanisms of steroid resistance in asthmatic patients and patients with COPD can thus lead to more effective anti-inflammatory treatments.

Section snippets

Mechanism of action of corticosteroids

It is necessary to understand the molecular mechanisms whereby corticosteroids suppress inflammation to understand the various mechanisms of steroid resistance in asthmatic patients and patients with COPD.3, 4 Corticosteroids activate several anti-inflammatory genes and suppress many inflammatory genes but can also modulate inflammation through additional posttranscriptional mechanisms.

Steroid resistance in asthmatic patients

The symptoms of most asthmatic patients can be controlled with low doses of ICSs, which have revolutionized management and become first-line treatment for the majority of patients. However, approximately 10% of patients require the maximal ICS dose, and approximately 1% require regular oral corticosteroids (corticosteroid-dependent asthma), whereas a small number of patients appear to be completely corticosteroid resistant, as defined by no clinical improvement after high doses of an oral

Steroid resistance in patients with COPD

In sharp contrast to asthmatic patients, most patients with COPD respond very poorly to even high doses of ICSs or oral corticosteroids. ICSs have no effect on disease progression or mortality, but there is a small reduction in exacerbations,26 although even this has been questioned.27 ICSs do not reduce inflammatory cell counts and mediator levels in the sputum or airways of patients with COPD,28, 29, 30 nor do they inhibit cytokine release from alveolar macrophages in vitro.31 Approximately

Molecular mechanisms of steroid resistance

Several molecular mechanisms contributing to decreased anti-inflammatory effects of corticosteroids have been identified in asthmatic patients, many of which have also been described in patients with other inflammatory diseases, including COPD (Table I).1

Therapeutic implications

Resistance to the anti-inflammatory effects of steroids is a major barrier to the effective treatment of COPD and severe asthma. Better understanding of the molecular mechanisms involved in steroid resistance has identified several potential therapeutic strategies for better treating COPD and severe asthma.

A novel strategy for the treatment of steroid-resistant/severe asthma and COPD is reversal of steroid resistance by interfering with the pathways that cause it.84, 85 Understanding these

Conclusions and future directions

Steroid resistance in patients with severe asthma or smokers with asthma and in patients with COPD is a major barrier to effective therapy of these diseases. Considerable progress has recently been made in understanding the molecular basis for steroid resistance in both patients with severe asthma and those with COPD. In asthmatic patients there appear to be several different molecular mechanisms that can contribute to reduced responsiveness to corticosteroids, suggesting that it might be

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    Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, and William T. Shearer, MD, PhD

    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.

    Terms in boldface and italics are defined in the glossary on page 637.

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