In this issue of the Journal, Ito and colleagues show that the proinflammatory state in severe stages of chronic obstructive pulmonary disease (COPD) is related to chromatin unwinding.1 To review basic gene regulation quickly, the balance between histone deacetylases (HDACs) and histone acetylases determines the state of histone acetylation. Acetylated histone prompts the unwinding of chromatin, allowing transcriptional complexes to bind to DNA and generate messenger RNA. In COPD, oxidants from cigarette smoke or inflammatory cells modify and deactivate HDAC2 in lung macrophages, allowing RNA polymerase II and nuclear factor-B (NF-B) to bind to DNA and promote transcription of matrix metalloproteinases (MMPs) and the neutrophil chemokines interleukin-8 and tumor necrosis factor . This process results in the destruction of alveolar tissue and airway tissue characteristic of COPD.

This study raises several interesting issues, including the role of inflammation in COPD and the ineffectiveness of inhaled corticosteroids as treatment for this disorder. Since corticosteroids are effective as treatment for asthma, this differential response has been used to argue that the Dutch hypothesis, which suggests that asthma and COPD have a common origin, is not correct. The concepts proposed by Ito et al. provide a way to use drugs that are currently available to test this hypothesis directly. To understand this possibility, we need to focus on the cell biology of COPD.

Macrophages are the predominant inflammatory cells patrolling the lower air space under normal conditions and in chronic inflammatory states such as COPD. Oxidants from cigarette smoke and perhaps inflammatory cells affect the macrophage both by inducing activation of NF-B and by inactivating HDAC2, as discussed above, leading to recruitment of neutrophils to the lung. Neutrophils have traditionally been viewed as the main effector cells in COPD, releasing neutrophil elastase, a potent matrix-degrading protein. However, the macrophage also produces MMPs (e.g., MMP-9 and MMP-12) that have elastin-degrading activity. It is likely that the destruction of tissue in COPD is not the product of a single proteinase or a single inflammatory cell but, rather, of a combination of cells and effector molecules working in tandem (Figure 1), resulting in these changes. For example, neutrophil elastase cleaves and inactivates the tissue inhibitor of metalloproteinases, and MMPs degrade and inactivate the serine proteinase inhibitor, alpha1-antitrypsin.2 Hence, the enzymes augment one another's proteolytic activity, enhancing the destruction and enlargement of the alveolar structures that we recognize as emphysema.

   Figure 1. Inflammatory-Cell Interactions in Chronic Obstructive Pulmonary Disease (COPD) and the Role of Histone Acetylation.

Reactive oxygen species resulting from inhaled cigarette smoke (and potentially from the inflammatory cells themselves) promote transcription of nuclear factor-B (NF-B)mediated proinflammatory factors by way of two mechanisms. First, oxidation results in the degradation of IK-B, releasing NF-B, which then translocates to the nucleus of the targeted cell. Oxidation also inactivates histone deacetylase (HDAC), shifting the balance to increased DNA acetylation, weakening the interactions between histone and DNA and "unwinding" DNA, allowing NF-B greater access to the DNA promoter elements, and leading to transcription of neutrophil chemokines and cytokines (tumor necrosis factor  [TNF-] and interleukin-8) and matrix metalloproteinases (MMPs). These factors recruit and activate neutrophils to the lung. In addition, CD8+ T cells augment the production of macrophage MMPs through interactions with surface-bound CD40 molecules and interferon-inducible chemokines (inducible protein of 10 kD [IP-10], interferon-inducible T-cell alpha chemoattractant [I-TAC], and monokine induced by interferon- [MIG]). Macrophage MMPs and neutrophil elastase degrade each other's inhibitors, the tissue inhibitor of metalloproteinases and alpha1-antitrypsin, respectively, augmenting their matrix-degrading capacities. These interactions illustrate the highly interactive nature of the immune inflammatory response and suggest that breaking this cycle, perhaps by way of augmentation of HDAC with the use of theophylline, may prevent inflammatory-mediated destruction of the lung in COPD. Dashed lines indicate inhibition.

In addition, T cells, particularly CD8+ cells, accumulate in the lungs of patients with COPD and generate signals, such as interferon-inducible proteins (inducible protein of 10 kD, monokine induced by interferon-, and interferon-inducible T-cell alpha chemoattractant) that promote the production of macrophage MMP-12.3,4 The challenge now is to understand the interplay between different immune and inflammatory cells and the mediators they produce that lead to tissue destruction. If we can do this, then we may be able to find safe and effective means to inhibit this destructive cascade and prevent disease progression.

If only it were so simple; the data suggest the presence of a moving inflammatory target. Cigarette smoke initiates inflammation, in part by way of the oxidation effects discussed above, yet in severe COPD, other factors appear to sustain inflammation long after smoking cessation. This difference was best shown in a study that examined the lung tissue of patients with end-stage COPD who had not smoked a cigarette in more than nine years (on average).5 Rather than being "burned out," as expected, the lungs were filled with a variety of inflammatory cells. Whether the inflammation is related to bacterial colonization, latent viral infection, residual matrix fragments, or other mechanisms is not clear. What is clear is that after a certain threshold of disease severity is passed, simply quitting smoking may not be sufficient to prevent disease progression.

Asthma is another common inflammatory lung disease. The similarities and differences between asthma and COPD engendered a feud between the Dutch and the British that has raged for nearly half a century. The difference in the response to corticosteroids in patients with asthma and in those with COPD in relation to HDAC signaling has worked its way into this debate. The controversy centers on an explanation of the observation that even though cigarette smoking is the overwhelming risk factor for COPD, the disease develops in only a minority of smokers. In 1961, Orie and colleagues advanced the hypothesis that the obstructive airway diseases, including asthma, chronic bronchitis, and emphysema, represent different phenotypes of a common pathogenetic process.6 This theory was later labeled the Dutch hypothesis and has evolved into the concept that asthma and COPD have common origins. The British proposed a competing theory that stated that smokers with chronic production of sputum were the ones at increased risk for the development of COPD.

Epidemiologic studies have not supported the British hypothesis. However, this does not mean that there is universal acceptance of the Dutch hypothesis. In fact, at the 2003 meeting of the American Thoracic Society, one of the authors, Dr. Barnes, claimed in discussion that "the Dutch were confused. Some patients with COPD also have asthma." Arguing against the Dutch hypothesis, Dr. Barnes could point to the fact that corticosteroids are much more effective in asthma than in COPD. The reason for this difference is that in asthma corticosteroids stimulate the glucocorticoid receptor that binds HDAC and translocates it to the nucleus for action, whereas in COPD oxidant-modified HDAC will not interact with the glucocorticoid receptor. This theory would also predict that corticosteroids are less effective in patients with asthma who smoke. Indeed, two small prospective studies confirmed that patients with stable asthma who smoked had an impaired response to either inhaled or oral corticosteroids.7 The National Heart, Lung, and Blood Institute's Asthma Clinical Research Network has almost completed a larger prospective randomized trial based on this issue (Smoking Modulates Outcomes of Glucocorticoid Therapy in Asthma).

Although, admittedly, asthma and COPD are unlikely to represent a single disease, they probably share pathogenetic mechanisms that interact, each making the other disease process worse. These interactions may become important as we search for effective therapy for steroid-resistant asthma and COPD.

COPD is now epidemic worldwide, and we have few effective therapies to offer patients as they slowly suffocate. But the HDAC theory may be more than molecular medicine for its own sake. A potential practical implication of the theory derives from the observation that low-dose theophylline markedly induces HDAC transcription. If true, then the combination of corticosteroids and theophylline should restore delivery of HDAC to the nucleus and disarm inflammation in COPD.8 I look forward to a future study showing that the combination of these two well-known drugs inhibits disease progression in patients with COPD.

Source Information

From the Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston.

References

Ito K, Ito M, Elliott WM, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med 2005;352:1967-1976.

Shapiro SD, Goldstein NM, Houghton AM, Kobayashi DK, Kelley D, Belaaouaj A. Neutrophil elastase contributes to cigarette smoke-induced emphysema in mice. Am J Pathol 2003;163:2329-2335.
 
Grumelli S, Corry DB, Song LZ, et al. An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema. PLoS Med 2004;1(1):e8.

Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 1997;277:2002-2004.

Retamales I, Elliott WM, Meshi B, et al. Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Med 2001;164:469-473.
 
Orie NGM, Sluiter HJ, Vries K, Tammeling G, Witkop J. The host factor in bronchitis. In: Orie NGM, Sluiter HJ, eds. Bronchitis: an international symposium. Assen, the Netherlands: Royal van Gorcum, 1961:43-59.

Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med 2003;168:1308-1311.
 
Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med 2004;200:689-695.