Elsevier

The Lancet

Volume 363, Issue 9410, 28 February 2004, Pages 731-733
The Lancet

Hypothesis
Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase

https://doi.org/10.1016/S0140-6736(04)15650-XGet rights and content

Summary

By contrast with patients with asthma, those with chronic obstructive pulmonary disease (COPD) are poorly responsive to the anti-inflammatory actions of corticosteroids, and these drugs provide little clinical benefit. In both diseases, multiple inflammatory genes are activated, which results from acetylation of core histones around which DNA is wound. This acetylation opens up the chromatin structure allowing gene transcription and synthesis of inflammatory proteins to proceed. Corticosteroids recruit histone deacetylase 2 (HDAC2) to the actively transcribing gene, which reverses this process and switches off inflammatory gene transcription. We propose that in patients with COPD, HDAC2 function is impaired by cigarette smoking and oxidative stress, leading to a pronounced reduction in responsiveness to corticosteroids. Oxidative stress could generate peroxynitrite, which impairs HDAC2 activity through nitration of critical tyrosine residues. This hypothesis raises the possibility that novel therapeutic approaches might unlock this corticosteroid resistance, leading to more effective anti-inflammatory treatments for COPD and other severe inflammatory diseases.

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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