HypothesisCorticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase
Section snippets
Corticosteroid resistance
Response to treatments for chronic obstructive pulmonary disease (COPD) is poor, and no existing treatment slows disease progression. Although inhaled corticosteroids are highly effective in asthma, they provide much less clinical benefit in COPD.1 In particular, long-term treatment with high doses of inhaled steroids fails to reduce the accelerated progression of airway obstruction in COPD, which is though to be a consequence of a chronic inflammatory process.2 Airway inflammation in asthma is
Effect of corticosteroids in inflammation
The molecular mechanism by which corticosteroids switch off the expression of inflammatory genes in diseases such as asthma is well understood.8, 9 In chronic inflammation there is a co-ordinated expression of multiple inflammatory genes, including cytokines, chemokines, adhesion molecules, and inflammatory enzymes, that have been activated by pro-inflammatory transcription factors, such as nuclear factor κB and activator protein 1. This increase in gene expression is brought about by
Histone deacetylase activity
Alveolar macrophages of cigarette smokers show reduced HDAC activity and expression of HDAC2 compared with cells from healthy individuals.12 This action is correlated with increased release of the inflammatory proteins TNFα and interleukin 8 and a reduction in the inhibitory effect of a corticosteroid, dexamethasone, on the expression of these cytokines. Furthermore, in peripheral lung tissue and alveolar macrophages there is a reduction in HDAC activity and expression of HDAC2 in healthy
Oxidative stress
Oxidative stress, an imbalance between production of reactive oxygen species and antioxidant defences, is increased in inflammatory diseases, especially when they become severe. Exhaled markers of oxidative stress, such as 8-isoprostane and ethane, are increased in healthy smokers but are raised to a much greater extent in patients with COPD, even when they have stopped smoking.14, 15 Oxidative stress and cigarette smoke increase histone acetylation and activate inflammatory gene transcription.
What needs to be explained
Although patients with COPD are fairly resistant to the anti-inflammatory effects of corticosteroids, individuals with asthma usually respond well. Both diseases involve inflammation of the respiratory tract, but the nature of the inflammation differs, indicating that different regulatory mechanisms are likely to be involved. In asthma oxidative stress is low,20 but in COPD oxidative stress is increased to a greater extent due, in part, to a striking increase in the numbers of neutrophils and
Therapeutic implications
Our proposed mechanism of steroid resistance in COPD is testable and has important therapeutic implications. We predict that several strategies could overcome steroid resistance in COPD, so that corticosteroids become able to switch off the multiple inflammatory cytokines, chemokines, and proteases that mediate the disease. Effective antioxidants that can neutralise oxidative stress would increase the response to corticosteroids. However, existing antioxidants are unlikely to reduce the high
Implication for other inflammatory diseases
The reduction in corticosteroid responsiveness after oxidative stress as a result of reduced HDAC activity might have implications beyond COPD. Patients with severe asthma also have increased oxidative stress, which could account for the need for high doses of inhaled or oral corticosteroids in these patients. Those with other severe inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, are also likely to have oxidative stress at the sites of inflammation, which
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