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* From the National Heart and Lung Institute, Imperial College, London, UK.
Correspondence to: Peter J. Barnes, DM, DSc, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse St, London SW3 6LY, UK; e-mail: p.j.barnes{at}imperial.ac.uk
Abstract
COPD is characterized by progressive inflammation in the small airways and lung parenchyma, and this is mediated by the increased expression of multiple inflammatory genes. The increased expression of inflammatory genes is regulated by acetylation of core histones around which DNA is wound, and conversely these activated genes are switched off by deacetylation of these histones. Histone deacetylases (HDACs) suppress inflammatory gene expression, but their activity and expression (particularly of HDAC-2) is reduced in the peripheral lung and in alveolar macrophages of patients with COPD. This results in amplification of the inflammatory response as COPD progresses but also accounts for corticosteroid resistance in COPD, since HDAC-2 is required by corticosteroids to switch off activated inflammatory genes. The reduction in HDAC-2 appears to be secondary to the increased oxidative and nitrative stress in COPD lungs. Antioxidants and inhibitors of nitric oxide synthesis may therefore restore corticosteroid sensitivity in COPD, but this can also be achieved by low doses of theophylline, which is an HDAC activator. This mechanism is also relevant to asthmatic patients who smoke, patients with severe asthma and cystic fibrosis, in whom oxidative stress is also increased.
Key Words: asthma • COPD • cystic fibrosis • histone deacetylase
COPD is an increasing global health problem that is characterized by a specific pattern of chronic inflammation in small airways and lung parenchyma.1 The airway obstruction is relentlessly progressive, leading to respiratory failure and death. Recently new insights into the molecular basis of chronic inflammation and the failure of corticosteroids to suppress this inflammatory response, in sharp contrast to the steroid sensitivity of asthma, have been gained though studies2 of histone acetylation.
Inflammation in COPD
The pulmonary inflammation in COPD is associated with fibrosis and irreversible narrowing of small airways and destruction of the lung parenchyma or emphysema. These pathologic changes result in closure of small airways and air trapping that leads to dyspnea and impaired exercise capacity, the key clinical features of COPD. There is a specific pattern of inflammation in COPD, characterized by increased numbers of macrophages, neutrophils, and T-lymphocytes, particularly cytotoxic (CD8+) cells.3 This pattern of inflammation is also seen in cigarette smokers with normal lung function, but the intensity of the inflammation is increased in COPD with increased numbers of inflammatory cells and mediators, suggesting that there is an amplifying mechanism. Research4 has demonstrated that as COPD progresses, the degree of inflammation and scarring in small airways increases. This suggests that the amplifying mechanism of inflammation increases as COPD progresses. The chronic inflammation in COPD is associated with increased expression of multiple inflammatory genes encoding cytokines, chemokines, and adhesion molecules. Many of these inflammatory genes are regulated by the transcription factor nuclear factor (NF)-
B. NF-B has been shown to be activated in COPD lungs and inflammatory cells, particularly in alveolar macrophages.5
Histone Acetylation and Deacetylation
Gene expression is regulated by acetylation of core histones that open up the chromatin structure to allow transcription factors and RNA polymerase to bind to DNA, thus initiating transcription. Gene expression is regulated by various coactivator molecules, such as cyclic adenosine monophosphate response element binding protein, all of which have intrinsic histone acetyltransferase activity. Expression of inflammatory genes is regulated by increased acetylation of histone 4.26 In COPD peripheral lung, airway biopsy specimens, and alveolar macrophages, there is an increase in the acetylation of histones associated with the promoter region of inflammatory genes, such as interleukin (IL)-8, that are regulated by NF-B and the degree of acetylation increases with disease severity.7 This increased acetylation of inflammatory genes is not due to any increase in histone acetyltransferase activity in the lungs or macrophages, however.
Histone acetylation is reversed by histone deacetylases (HDACs). There are 11 HDAC isoenzymes that deacetylate histones within the nucleus, and specific HDACs appear to be differentially regulated and to regulate different groups of genes.8 HDACs play a critical role in the suppression of gene expression by reversing the hyperacetylation of core histones. Thus, expression of inflammatory genes is determined by a balance between histone acetylation (which activates transcription) and deacetylation, which switches off transcription (Fig 1 ).
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HDAC activity is reduced in alveolar macrophages of cigarette smokers compared to nonsmokers, and this is correlated with increased expression of inflammatory genes in these cells.9 There is also a reduction in total HDAC activity in peripheral lung, bronchial biopsy specimens, and alveolar macrophages from COPD patients, and this is correlated with disease severity and with increased gene expression of IL-8.7 There is a selective reduction in the expression of HDAC-2, with lesser reductions in HDAC-3 and HDAC-5. In patients with very severe COPD (Global Initiative for Chronic Obstructive Lung Disease stage 4), the expression of HDAC-2 was < 5% of that seen in normal lung.
Response to Corticosteroids
Corticosteroids are very effective in suppressing inflammation in asthmatic airways. An important molecular mechanism of action of corticosteroids is the recruitment by activated glucocorticoid receptors of HDAC-2 to activated inflammatory genes, which reverses the acetylation of activated inflammatory genes, thus switching off their transcription.610 In patients with COPD, the reduction in HDAC-2 expression may thus account for the corticosteroids insensitivity that is seen in this disease. Corticosteroids provide little clinical benefit in COPD patients and fail to significantly reduce progression of the disease. This may reflect the fact that corticosteroids, even in high doses, do not suppress inflammation in the lungs, in marked contrast to their high level of efficacy in asthma.1112 The reduction in HDAC-2 expression in COPD cells may therefore not only account for the amplification of inflammation but also the insensitivity to the anti-inflammatory effects of corticosteroids (Fig 2 ).
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The reasons for the reduction in HDAC, particularly HDAC-2, in COPD are not yet completely understood. However, there is increasing evidence that this may be due to inactivation of the enzyme of oxidative and nitrative stress1314 (Fig 3 ). Oxidative stress is increased in COPD and increases with disease severity.1516 Nitrative stress is also increased in peripheral lung of COPD patients.17 Oxidative and nitrative stress lead to the rapid formation of peroxynitrite, which nitrates selected tyrosine residues on certain proteins. HDAC-2, but not other isoforms of HDAC, shows increased tyrosine nitration in macrophages and peripheral lung of COPD patients, and this is correlated with increased expression of IL-8. Nitration of proteins such as HDAC-2 leads to their ubiquitination, which marks them for degradation by the proteasome, resulting in the very low levels of HDAC-2 protein in the lungs of patients with severe COPD. The high level of oxidative/nitrative stress in COPD lungs, particularly as the disease progresses, may therefore result in increased tyrosine nitration and impaired HDAC-2 function and reduction in expression, which thereby leads to increased expression of inflammatory genes and impaired responses to corticosteroids.
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Corticosteroid resistance in COPD is a major clinical problem, as these drugs have little clinical benefit and there are no alternative anti-inflammatory treatments currently available.18 Understanding the molecular basis for corticosteroid resistance in COPD provides several new therapeutic opportunities to reverse or bypass this resistance (Fig 3). Since oxidative/nitrative stress appears to be a mechanism that can lead to corticosteroid resistance, antioxidants and inhibitors of inducible nitric oxide synthase (iNOS) may be effective through inhibiting the generation of peroxynitrite. Currently available antioxidants, such as vitamins C and E and N-acetylcysteine, are not very potent and may not reduce oxidative stress in the lung sufficiently. Selective iNOS inhibitors are now in clinical development and may be effective.19 Peroxynitrite scavenger drugs are also in development.
Theophylline as an HDAC Activator
We have discovered that theophylline, used to treat airway diseases for > 70 years, is an activator of HDACs. Low concentrations (10-6 mol/L) increase HDAC activity and expression through a mechanism that is independent of phosphodiesterase inhibition or adenosine receptor antagonism, which together account for all of the side effects of theophylline.20 Low concentrations of theophylline are able to restore the activity and expression of HDAC-2 to normal in alveolar macrophages in COPD patients and to restore the response of these cells to corticosteroids.21 This effect of theophylline is reversed by an HDAC inhibitor, confirming that the mechanism of action of theophylline is through HDAC activation. The clinical implications are that low doses of theophylline (that give a plasma concentration of 5 to 10 mg/L) may restore the responsiveness of COPD patients to corticosteroids, resulting in effective suppression of the inflammation and reduced progression of the disease. Clinical trials to test this idea are hampered by the fact that theophylline is inexpensive and research funding is difficult to obtain. The molecular mechanism whereby theophylline activates HDACs is currently unknown, but it appears to occur within the nucleus and through the activation of specific kinase pathways. In the future, new drugs that activate HDAC-2 selectively may be developed, especially as the molecular mechanisms of theophylline are elucidated.
Implications for Other Diseases
Oxidative/nitrative stress is increased in other inflammatory diseases, suggesting that reduction in HDAC activity may contribute to amplification of inflammation and reduced responses to corticosteroids. Asthmatic patients who smoke have more severe asthma and show markedly reduced responses to corticosteroids.22 In a preliminary study,23 we have shown that HDAC-2 is markedly reduced in the airways of smoking asthmatic patients compared to nonsmoking asthmatics of a similar disease severity. We have also shown that HDAC activity is also impaired in patients with severe asthma who have a high level of oxidative stress and who require high doses for corticosteroids for adequate control. Although no measurements have been made, it is likely that in other severe inflammatory diseases, such as rheumatoid arthritis, cystic fibrosis, and inflammatory bowel disease, the increased oxidative stress may reduce HDAC-2 activity leading to increased inflammation and reduced responsiveness to corticosteroids.
Conclusions
In COPD patients, there is a reduction in HDAC activity in peripheral lung, airways, and in alveolar macrophages that worsens as the disease becomes more severe. This may account for the increased pulmonary inflammation and resistance to corticosteroids as COPD progresses. There appears to be a selective reduction in HDAC-2 expression, and this may be due to oxidative and nitrative stress that is increased in COPD lungs. Therapeutic options aimed at increasing HDAC activity, such as antioxidants, iNOS inhibitors, and theophylline, may be beneficial. Reduced HDAC activity may also occur in other inflammatory diseases, including asthmatic patients who smoke and those with severe disease, rheumatoid arthritis, and inflammatory bowel disease. This area of research may lead to the development of novel anti-inflammatory therapies aimed at increasing HDAC-2 activity in the future.
Footnotes
Abbreviations: HDAC = histone deacetylase; IL = interleukin; iNOS = inducible nitric oxide synthase; NF = nuclear factor
Received for publication October 10, 2005. Accepted for publication October 11, 2005.
References
B in bronchial biopsies from smokers and patients with COPD. Eur Respir J 2002;20,556-563B and pro-inflammatory gene expression. Biochem Pharmacol 2004;68,1255-1267[CrossRef][ISI][Medline]This article has been cited by other articles:
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  R. Chaudhuri, E. Livingston, A. D. McMahon, J. Lafferty, I. Fraser, M. Spears, C. P. McSharry, and N. C. Thomson Effects of Smoking Cessation on Lung Function and Airway Inflammation in Smokers with Asthma Am. J. Respir. Crit. Care Med., July 15, 2006; 174(2): 127 - 133. [Abstract] [Full Text] [PDF]
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 R. S. Irwin The New "Face" of CHEST Heralds a New Era Chest, January 1, 2006; 129(1): 1 - 3. [Full Text] [PDF]
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