Reviews and feature articleCorticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease
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.