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The Proceedings of the American Thoracic Society 5:857-864 (2008)
© 2008 The American Thoracic Society
doi: 10.1513/pats.200807-069TH
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Future Treatments for Chronic Obstructive Pulmonary Disease and Its Comorbidities

Peter J. Barnes1

1 National Heart and Lung Institute, Imperial College, London, United Kingdom

Correspondence and requests for reprint should be addressed to Peter J. Barnes, D.M., F.R.S., 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

The recognition that patients with chronic obstructive pulmonary disease (COPD) may have systemic manifestations and often suffer from comorbid conditions has important implications for therapy that require further research. The most likely link between COPD and extrapulmonary effects is that inflammation in the lung periphery "spills over" into the systemic circulation and effects on other organs that may also be affected by the systemic effects of cigarette smoking. The peripheral lung inflammation of COPD and systemic inflammatory effects could be treated by systemic antiinflammatory treatments, but this may have a high risk of systemic side effects, or by inhaled administration of antiinflammatory treatments that suppress inflammation in the lung and prevent the spillover of inflammatory mediators into the systemic circulation. Current therapies for COPD, including inhaled corticosteroids, long-acting β2-agonists, and theophylline, have the potential to reduce systemic features of COPD and comorbid diseases. Treatments for comorbid diseases, such as statins, angiotensin-converting enzyme inhibitors, and peroxisome proliferator–activated agonist agonists, may also have beneficial effects on COPD inflammation. Novel antiinflammatory treatments, such as phosphodiesterase-4, nuclear factor-{kappa}B, and p38 mitogen-activated protein kinase inhibitors, may provide benefits in both COPD and comorbidities, but have a high risk of adverse effects when given systemically, and may need to be given by inhalation. Increased oxidative stress may be an important mechanism linking COPD inflammation, systemic effects, and comorbid disease, so the development of antioxidants, including nuclear factor erythroid-2–related factor 2 activators, is a priority. Accelerated aging may be associates in common to COPD and several comorbidities, prompting the development of antiaging molecules, such as sirtuin 1 agonists, which may also be effective in reducing the risk of lung cancer.

Key Words: statins • peroxisome proliferator-activated receptor agonists • phosphodiesterase-4 inhibitors • nuclear factor-{kappa}B inhibitors • antioxidants

There are two broad approaches to the treatment of chronic obstructive pulmonary disease (COPD) and its comorbidities. The first involves suppression of pulmonary inflammation to prevent associated systemic diseases if they are due to or exacerbated by "spillover" of inflammatory mediators from the lung into the systemic circulation (Figure 1). The second is to treat the systemic disease and see whether this reduces features of COPD pulmonary disease. It has proven extremely difficult to discover novel treatments for COPD, other than bronchodilators (1–3). Novel antiinflammatory treatments, such as phosphodiesterase (PDE)-4, p38 mitogen-activated protein kinase (MAPK), and nuclear factor (NF)-{kappa}B inhibitors, are likely to be toxic or have dose-limiting side effects when given systemically, because of widespread target distribution, nonselectivity, and interference with innate immunity. This is well illustrated for PDE4 inhibitors, which have major mechanism-related side effects when given systemically (nausea, vomiting, diarrhea) that limit the doses to those that are largely ineffective on clinical outcome measures (4). The obvious solution is to give these drugs by inhalation, but this may not reach peripheral lung (small airways and alveoli), which is the main site of inflammation in patients with COPD, and may not treat associated systemic inflammation and comorbid diseases if the drugs are retained in the lung. Two inhaled PDE4 inhibitors have so far been found to be without side effects, but are also without clinical effect, indicating that it is not easy to develop inhaled therapies.


Figure 1
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  		Figure 1. Inflammatory mediators from the peripheral lung of patient with chronic obstructive pulmonary disease (COPD), such as IL-6 and tumor necrosis factor (TNF)-{alpha}, may spill over into the systemic circulation where they may promote systemic abnormalities such as skeletal muscle weakness and exacerbate cardiovascular disease directly or through the increased production of C-reactive protein (CRP) from the liver.

 
TREATMENTS OF COMORBIDITIES THAT MAY BE BENEFICIAL IN COPD

Chance observation and epidemiological studies have shown that some treatments used for comorbid diseases, such as statins and angiotensin-converting enzyme (ACE) inhibitors, may apparently be beneficial in COPD, with reduction in exacerbations and mortality (5–7). This may reflect beneficial effects of these drugs on the comorbidities associated with COPD, such as cardiovascular disease, but there may also be a therapeutic effect on the inflammatory disease process of COPD.

Statins
Although 3-hydroxy-3-methyl-3-glutaryl coenzyme A reductase inhibitors (statins) reduce cholesterol, they have several other pharmacological actions that might be beneficial in COPD, including antioxidant, antiinflammatory, and immunomodulatory effects. Many of these pleiotropic effects of statins are mediated by inhibition of isoprenylation of small GTP-binding signaling molecules, such as Rho, Ras, and Rac (8). Through these mechanisms, statins reduce the expression of adhesion molecules, such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin, that are involved in recruitment of inflammatory cells (neutrophils, monocytes, and lymphocytes) from the circulation into the lungs. Statins also reduce the expression of chemokines, such as CCL2 and CXCL8, and matrix metalloproteinases (MMPs), such as MMP-9, all of which are increased in COPD (9). Some of these effects may be mediated via activation of peroxisome proliferator–activated receptors (PPAR)-{alpha} and -{gamma}, and some via inhibition of NF-{kappa}B. Statins prevent the development of emphysema in mice exposed to cigarette smoke, and this is associated with a reduction in expression of tumor necrosis factor (TNF)-{alpha}, IFN-{gamma}, and MMP-2, -9, and -12, and a reduction in neutrophils in bronchoalveolar lavage fluid (10). Statins also prevent elastase-mediated emphysema in mice, and are associated with evidence for proliferation and regeneration of alveolar epithelial cells (11). At a cellular level, statins inhibit the effects of IL-17 and transforming growth factor (TGF)-β in stimulating mediator release from primary airway epithelial cells, indicating their potential to modulate the inflammatory response and small airway fibrosis in COPD (12). Statins also stimulate the uptake of apoptotic neutrophils by alveolar macrophages (efferocytosis), an effect that is mediated via inhibition of the prenylation and activation of RhoA, which is involved in the phagocytosis of apoptotic cells (13). Because phagocytosis of apoptotic cells is impaired in COPD (14), this suggests that statins may accelerate the resolution of neutrophilic inflammation in COPD. Recently, statins have been shown to inhibit Th17 cells through an inhibitory effect on their regulatory transcription factor, retinoic acid orphan receptor-{gamma}t (15). Th17 cells may play an important role in orchestrating neutrophilic inflammation in COPD through the effect of IL-17 on epithelial cells to release CXCL1 and CXCL8 (16). All of these studies on the pleiotropic effects of statins suggest that they may have a beneficial effect in COPD, and this may contribute to the reduction in exacerbations in patients with COPD treated with statins in observational studies (5–7, 17). Through their pleiotropic effects, statins may have beneficial effects not only on cardiovascular disease, but also on other comorbidities associated with COPD, including diabetes, osteoporosis, and lung cancer (18). However, prospective, controlled trials are needed to establish whether statins have a beneficial effect in patients with COPD, especially those with systemic complications and comorbidities. The dose–response for the pleiotropic effects of statins has not yet been established and may differ from their cholesterol-lowering effects. High doses of statins may have adverse effects, particularly on skeletal muscles, so it is possible that statins could be delivered by the inhaled route.

ACE Inhibitors
ACE inhibitors are widely used to treat hypertension and heart failure and, in observational studies, these drugs have been associated with reduced exacerbation and mortality in patients with COPD (5). ACE inhibitors reduce pulmonary hypertension, but may have other beneficial effects in COPD, as angiotensin II may have proinflammatory effects (19). Indeed, an angiotensin II receptor (AT1) antagonist, irbesartan, has been shown to reduce hyperinflation in patients with COPD, although its mechanism of action is uncertain (20). Polymorphisms of the ACE gene have been linked to increased susceptibility to COPD (21) and quadriceps strength in patients with COPD (22). Because ACE inhibitors are routinely used in the management of hypertension, cardiac failure, and diabetes, all of which are common comorbidities of COPD, prospective trials of ACE inhibitors in patients with COPD are now warranted.

PPAR Agonists
PPARs play an important role in the regulation of cellular metabolism and energy homeostasis, and have been implicated in several systemic manifestations of COPD, including cachexia, skeletal muscle weakness, and systemic inflammation (23). Several antiinflammatory mechanisms of PPAR agonists have now been documented, including suppression of adhesion molecule expression, chemokines secretion, and certain Toll-like receptors (24) (Figure 2). Of particular interest to COPD inflammation is the immunomodulatory effects of PPAR agonists on IL-17 and IFN-{gamma} secretion, which may account for the effects of statins described above. There is reduced expression of PPAR-{alpha} and PPAR-{delta} in skeletal muscle of patients with COPD who have cachexia, as well as reduced expression of the transcription factor, PPAR-{gamma} coactivator 1{alpha} (25). Reduced PPAR-{alpha} expression is correlated with cachexia and systemic inflammation, suggesting that PPAR-{alpha} agonists, such as clofibrate and fenofibrate, may have therapeutic potential in treating the systemic features of COPD. PPAR-{alpha} and -{gamma} agonists inhibit the expression of several inflammatory genes in inflammatory cells, such as macrophages, suggesting that they have potential for treating pulmonary inflammation in COPD as well as systemic effects. PPAR-{gamma} agonists, such as rosiglitazone, which are used to treat diabetes, reduce neutrophilic inflammation in lungs of mice exposed to intratracheal endotoxin, and this is associated with a reduction in CXC chemokines and granulocyte-macrophage colony–stimulating factor (26). Recently, it has been shown that PPAR-{gamma} agonists inhibit the profibrotic effect of TGF-β on fibroblasts, and have been shown to reduce pulmonary fibrosis in animal models (27). Thus, rosiglitazone inhibits the effects of TGF-β on differentiation and collagen secretion by human lung fibroblasts and myofibroblasts (28, 29) and in animal models of bleomycin-induced pulmonary fibrosis (29). This suggests that PPAR-{gamma} agonists might reduce small airway fibrosis in COPD, which is currently untreatable. So far, no trials of PPAR-{alpha} agonists (fibrates) or PPAR-{gamma} agonists (thiazolidinediones) in COPD have been reported. Concern about the cardiovascular side effects of thiazolidinediones has recently limited their use in the treatment of diabetes, but it is possible that these drugs may work by inhalation to avoid any cardiovascular risk in a high-risk population, such as patients with COPD.


Figure 2
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  		Figure 2. Peroxisome proliferator–activated agonist (PPAR)-{gamma} may have many effects on inflammatory and structural cells. iNOS = inducible nitric oxide synthase; COX2 = cyclooxygenase 2.

 
TREATMENT OF SYSTEMIC EFFECTS OF COPD WITH CURRENT THERAPY

Inhaled therapy may reduce inflammation in the lung and thereby reduce systemic inflammation that results from spill-over from the lungs into the systemic circulation. Alternatively, inhaled drugs may reach the systemic circulation after absorption from the lungs or from the gastrointestinal tract after swallowing.

Inhaled Corticosteroids
Although high-dose inhaled corticosteroids (ICS) are widely used in the management of COPD, either alone or combined with a long-acting β2-agonist (LABA). ICS, even in high doses, fails to suppress inflammation in COPD lungs and airways, and this may be due to an active resistance mechanism linked to a reduction in histone deacetylase-2 (HDAC2) expression (30). Observational studies suggested that ICS reduce all-cause mortality in patients with COPD, including cardiovascular mortality (31), and were shown prospectively to reduce markers of systemic inflammation, such as C-reactive protein (CRP) (32). However, a prospective study of high-dose ICS in patients with COPD (the TORCH [Towards a Revolution in COPD Health] study) showed no reduction in all-cause mortality, indicating that there is unlikely to be a significant clinical benefit of ICS on COPD comorbidities, such as cardiovascular disease or lung cancer, which are the commonest causes of death in patients with COPD (33). A controlled trial of high-dose ICS with or without a LABA showed no reduction in systemic inflammation in patients with COPD, as measured by circulating IL-6 and CRP concentrations, indicating likely corticosteroid resistance of systemic, as well as local inflammation in patients with COPD (34).

LABAs
LABAs are useful bronchodilators in patients with COPD, but it is uncertain whether they have antiinflammatory effects. Formoterol reduces neutrophilic inflammation in patients with asthma, but this has not been studied in COPD (35). The combination inhaler, salmeterol/fluticasone, reduces inflammation in COPD airways (36, 37), whereas a corticosteroid is ineffective (37). This suggests that there is a synergistic interaction between the LABA and the corticosteroid, or that the LABA is responsible for the antiinflammatory effects. Indeed, the benefits of combination inhaler in the TORCH study appear to be due to salmeterol rather than to fluticasone (38). Whether inhaled LABA or oral β2-agonists have any beneficial effects on systemic features of COPD has not yet been systematically investigated. There is a large body of literature documenting the effects of various β2-agonists increasing skeletal muscle mass and strength, and preventing fatigue (39), suggesting that there is potential for improving skeletal (and respiratory) muscle weakness in patients with COPD. However, cardiovascular complications of systemic β2-agonists may be a problem, although the sustained effects over 24 hours of the prodrug, bambuterol, are relatively well tolerated in patients with COPD, in whom it is an effective bronchodilator (40).

Anticholinergics
There is considerable evidence that acetylcholine can be released from nonneuronal cells, such as epithelial cells and macrophages, and that it may activate muscarinic receptors on inflammatory and structural cells, including neutrophils, macrophages, T lymphocytes, and epithelial cells (41). This suggests that anticholinergics have the potential for antiinflammatory effects in COPD, particularly because tiotropium bromide reduces exacerbations. However, tiotropium has no effect on inflammatory markers in sputum (IL-6, CXCL8, myeloperoxidase) or in the circulation (IL-6, CRP) of patients with COPD, despite a reduction in exacerbations (42). Anticholinergics (and other bronchodilators) may reduce the mechanical forces in the lung due to airway closure, and this might reduce the expression of TGF-β and other mediators released in response to mechanical strain of epithelial cells (43, 44).

Theophylline
Theophylline has more potential as a treatment for lung inflammation in COPD, as low-dose oral theophylline reduces neutrophilic inflammation and sputum CXCL8 in patients with COPD (45). However, it is not known whether theophylline has any beneficial effects on systemic features or comorbidities of COPD. High doses of theophylline were shown to increase diaphragm strength in patients with COPD, but this was not confirmed in other studies (46). As discussed subsequently here, theophylline has the potential to reverse corticosteroid resistance in COPD.

NEW ANTIINFLAMMATORY TREATMENTS

As corticosteroids fail to suppress inflammation in COPD, in marked contrast to asthma, several alternative antiinflammatory approaches are currently being investigated (2, 3). These drugs have largely been developed as systemic treatments, and would therefore be expected to reduce systemic inflammation and perhaps treat systemic manifestations of COPD, such as skeletal muscle weakness. However, a major limitation of the broad-spectrum antiinflammatory treatments currently in development has been side effects, which have limited the doses that can be given. This has lead to a search for inhaled antiinflammatory drugs that are retained in the lung or inactivated in the systemic circulation.

Anti-TNF Therapy
TNF-{alpha} is increased in sputum of patients with COPD, particularly during exacerbations, and is also released from circulating cells in patients with COPD with cachexia. Increased systemic TNF-{alpha} has been implicated as a mechanism of cachexia, skeletal muscle atrophy, and weakness in patients with COPD. Blocking TNF-{alpha} with monoclonal antibodies (such as infliximab or adalimumab) and soluble receptors (etanercept) has been very effective in treating other chronic inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. However, using the same doses of infliximab that are effective in these inflammatory diseases, there is no clinical benefit in patients with COPD (47), although a post hoc analysis suggested that there might be some improvement in exercise tolerance in patients with cachexia (48). However, a subsequent, small study with infliximab in patients with severe COPD showed no benefit on markers of systemic inflammation (49). A major problem with anti-TNF therapy is the high incidence of cancers and pulmonary infections, indicating that it is unlikely to be safe in patients with COPD (50).

Anti–IL-6
IL-6 is increased in sputum and in the systemic circulation of patients with COPD, particularly during exacerbations, and may account for the increase in circulating CRP found in patients with COPD (51). The functional role for IL-6, apart from increasing acute-phase proteins, has not yet been determined, but there is evidence that it may be related to skeletal muscle weakness. In rats, infusion of IL-6 induces both cardiac failure and skeletal muscle weakness (52). A potent inhibitor of IL-6, the receptor antibody, tocilizumab, is effective in rheumatoid arthritis (53), but has not yet been tested in patients with COPD.

Anti-CRP
CRP is an acute-phase protein, which is increased in plasma of patients with COPD, particularly during acute infective exacerbations. In stable COPD, plasma concentrations are related to all-cause mortality in patients with mild to moderate COPD (54), but not in patients with severe and very severe disease (55). The link between increased CRP and prediction of cardiovascular risk has suggested that it might be a link between COPD and the increased incidence of cardiovascular disease, but this relationship may be confounded by established risk factors, such as smoking (56). The functional role of CRP is uncertain and disputed. CRP binds to damaged tissue and leads to activation of complement, resulting in endothelial injury and tissue inflammation. A small molecule inhibitor of CRP, 1,6-bis(phosphocholine)-hexane, counteracts the effects of CRP in animal models, and therefore may be cardioprotective (57). However, the role of CRP has been questioned by the recent demonstration that transgenic overexpression of human CRP in mice is neither proinflammatory nor proatherogenic (58). Furthermore, there is evidence to suggest that CRP may play an important role in innate defense against Streptococcus pneumoniae, so that inhibiting CRP could have detrimental effects in COPD, as this organism commonly colonizes the lower airways of these patients (59).

PDE4 Inhibitors
PDE4 inhibitors are the most advanced of the new antiinflammatory treatments for COPD, and have usually been administered orally. A selective PDE4 inhibitor, roflumilast, inhibits lung inflammation and emphysema in a smoking model of COPD in mice (60). In patients with COPD, oral roflumilast given over 4 weeks significantly reduces the numbers of neutrophils (by 36%) and CXCL8 concentrations in sputum (61). In clinical trials, roflumilast given over 6 or 12 months improves lung function in patients with COPD to a small extent, but has no significant effect on reducing exacerbations or improving health status (4, 62). These disappointing results likely reflect the fact that side effects, particularly nausea, diarrhea, and headaches, limit the dose that can be tolerated. This indicates that it may not be possible to reach an oral dose that is effective and acceptable to patients. This could be overcome by inhaled delivery, but, to date, two inhaled PDE4 inhibitors have been found to be ineffective, although well tolerated. Systemic inflammation or effects on skeletal muscles or comorbidities in patients with COPD have not yet been assessed. However, in rats, a PDE4 inhibitor prevented bone loss and increased skeletal muscle mass in ovariectomized animals, suggesting that PDE4 has the potential to prevent osteoporosis and skeletal muscle wasting in patients with COPD (63).

NF-{kappa}B Inhibitors
NF-{kappa}B regulates the expression of chemokines, TNF-{alpha}, and other inflammatory cytokines, as well as MMP-9. NF-{kappa}B is activated in macrophages and epithelial cells of patients with COPD, particularly during exacerbations (64). Although there are several possible approaches to inhibition of NF-{kappa}B, small molecule inhibitors of inhibitor of NF-{kappa}B kinase (IKK) 2 are the most promising. An IKK2 inhibitor is effective in some animal models of COPD (LPS exposure), but not in others (neutrophil elastase instillation), indicating that the effects may be complex (65). Although several IKK2 inhibitors are now in development, so far none have been tested in patients with COPD. NF-{kappa}B activation is also implicated in mediating systemic inflammation, and may be involved in skeletal muscle weakness in patients with COPD (66). NF-{kappa}B activation is important in skeletal muscle atrophy and inhibition of NF-{kappa}B may prevent this in animals (67). This suggests that IKK2 inhibitors may also treat some of the systemic complications of COPD. However, there is concern that long-term inhibition of NF-{kappa}B may result in immune suppression and impair host defenses, because mice that lack NF-{kappa}B–associated genes succumb to septicemia.

p38 MAPK Inhibitors
p38 MAPK is activated by cellular stress and regulates the expression of inflammatory cytokines, including CXCL8, TNF-{alpha}, and MMPs. p38 MAPK (measured by phosphorylated p38 MAPK) is activated in alveolar macrophages of COPD lungs, indicating the activation of this pathway in COPD (68). Several small molecule inhibitors of p38 MAPK have now been developed. A potent inhibitor of p38-{alpha} isoform, SD-282, is effective in inhibiting TNF-{alpha} release from human lung macrophages in vitro (69), and the same inhibitor is also effective in suppressing inflammation in a smoking model of COPD in mice in which corticosteroids are ineffective (70). The role of p38 MAPK in mediating systemic effects of COPD has not yet been determined. Several p38 MAPK inhibitors have now entered clinical trials, but there have been major problems of side effects and toxicity, indicating that it is probably necessary to deliver these drugs by inhalation to reduce systemic exposure.

OXIDATIVE STRESS

Oxidative stress, an imbalance between oxidants and antioxidants, is increased in patients with COPD, particularly during exacerbations (71), and reactive oxygen species contribute to its pathophysiology (72). Oxidative stress also reduces steroid responsiveness via a reduction in HDAC2 activity and expression (30). Oxidative stress may also be critical to accelerated, nonprogrammed aging of the lung through inhibitory effects on antiaging molecules, such as sirtuin (SIRT) 1, thus resulting in accelerated decline in lung function (73). Systemic oxidative stress is also increased in patients with COPD, particularly during exacerbations, and this is linked to reduced antioxidant capacity (74). Systemic oxidative stress has been linked to skeletal muscle weakness, as evidenced by increased protein carbonylation in the quadriceps of patients with COPD, which is correlated with muscle weakness (75).

Increased oxidative stress in COPD may be due to reduced concentrations of endogenous antioxidants, and many of the genes encoding these endogenous antioxidants are regulated by the transcription factor, NF erythroid-2–related factor 2 (Nrf2), the master controller of antioxidant genes (76). Nrf2 in the cytoplasm is associated with the cysteine-rich protein, Keap1, an adapter protein for the enzyme, Cul3 ubiquitin ligase, which ubiquitinates Nrf2 and thus targets it for destruction by the proteasome, so that, under normal conditions, Nrf2 is undetectable. Oxidants oxidize cysteine residues on Keap1, so that it dissociates from Nrf2, thereby preventing its degradation so that it is able to translocate to the nucleus. Within the nucleus, Nrf2 combines with other transcription factors (small Maf proteins) and binds to antioxidant response elements, which are found on more than 200 antioxidant enzyme and detoxifying enzyme genes, including heme oxygenase-1, glutathione peroxidase, glutathione-S-transferase, glutathione reductase, {gamma}-glutamylcysteine synthetase, thioredoxin, and catalase (77). The protein, DJ-1 (or PARK7), which has previously been implicated in early-onset Parkinson's disease, acts as a stabilizer of Nrf2 to facilitate its effects (78). In this way, oxidant exposure up-regulates endogenous antioxidants to counteract the increased oxidative stress and restore normal oxidant–antioxidant balance. Nrf2 plays an important role in defense of the lung against oxidative stress, and defective Nrf2 function has been implicated in COPD (76). Disruption of the Nrf2 gene in mice results in increased susceptibility to emphysema after cigarette exposure (79, 80), indicating that Nrf2 plays an important role in defending against oxidative stress in the lungs. Nrf2 activity and expression are reduced in peripheral lungs of patients with COPD and are associated with decreased expression of Nrf2-regulated antioxidant genes (81). This defect in patients with COPD appears to be related to a reduction in the stabilizing protein DJ-1, resulting in degradation of Nrf2, reduced antioxidant responses, and, therefore, persistent oxidative stress.

Reduction in oxidative stress in patients with COPD should provide clinical benefit through reducing inflammation and reversing corticosteroid resistance, but currently available antioxidants, such as N-acetyl cysteine, have proven disappointing in reducing progression and exacerbations of COPD (82). However, these glutathione-based antioxidants are consumed by oxidative stress, and so may not be efficient in the face of continued high oxidant exposure. It has been difficult to find new, more effective antioxidants that are not toxic. A more attractive approach may be to restore Nrf2 levels to normal through inhibiting the action of Keap1. This has been achieved in vitro and in vivo by isothiocyanate compounds, such as sulforaphane, which occurs naturally in broccoli (83). Sulforaphane restores antioxidant gene expression in a human bronchial epithelial cell line in which DJ-1 had been reduced by small interfering RNA (13). This interaction of isothiocyanates and Keap1 prevents the degradation of Nrf2, and might form the basis for the development of novel Nrf2 activators in the future. By implication, these drugs may also treat some aspects of systemic inflammation, such as skeletal muscle wasting.

REVERSING CORTICOSTEROID RESISTANCE

Resistance to the antiinflammatory actions of corticosteroids is a critical feature of COPD inflammation, and may also be relevant to systemic inflammation. The molecular pathways involved in corticosteroid resistance are now better understood and provide novel targets for COPD therapy, which may be less toxic than the drugs currently in development. A major mechanism for corticosteroid resistance in COPD is a reduction in the critical nuclear enzyme, HDAC2, which switches off multiple inflammatory genes in response to corticosteroid therapy. HDAC2 is markedly defective in COPD lungs and alveolar macrophages, but is also reduced in circulating leukocytes. This abnormity may be secondary to oxidative stress activity, through phosphoinositide-3-kinase (PI3K) pathways to phosphorylate and inactivate HDAC2 and with nitrative stress through tyrosine nitration leading to ubiquitination and degradation of HDAC2 (84, 85). Oral theophylline reverses corticosteroid resistance in COPD cells, smoking mice, and patients with COPD at doses that have no side effects (86). This molecular mechanism of theophylline is mediated via a direct inhibitory effect on PI3K-{delta}, which is activated by oxidative stress (85), and the effects of theophylline are mimicked by selective PI3K-{delta} inhibitors (which are currently being developed for the treatment of diabetes). Reversing corticosteroid resistance may also be useful in reducing systemic inflammation in patients with COPD, which also appears to be corticosteroid resistant. As theophylline markedly enhances the antiinflammatory effects of corticosteroids that are due to suppression of activated inflammatory genes rather than activation of the genes believed to cause side effects (87), it is possible that a combined tablet of low-dose theophylline and prednisolone might be a valuable treatment for COPD, systemic manifestations, and comorbidities (including lung cancer) worsened by chronic inflammation.

ACCELERATED AGING

Emphysema can be regarded as an acceleration of the normal aging process in the lung (73), and many of the comorbid diseases associated with COPD are also degenerative diseases of accelerated senescence, including heart failure, atherosclerosis, osteoporosis, and diabetes. There is relationship between COPD, systemic inflammation, arterial stiffness, and osteoporosis (88). Patients with COPD show increased wrinkling of the skin (89), and there may be a mechanistic link between skin wrinkling, emphysema, and other degenerative diseases through the increased expression of MMP-9. Many novel molecular targets are now being revealed by better understanding of aging pathways, and there is an association of aging with inflammation arising from activation of NF-{kappa}B and PI3K pathways (90). The concept of inflamm-aging is now gaining strength, with a reduction in adaptive immunity and an increase in innate immunity driven by NF-{kappa}B activation (91). Aging may be programmed as a result of telomere shortening from repeated cell division or nonprogrammed, mediated largely via oxidative stress. There is evidence of telomere shortening in alveolar macrophages from patients with COPD (92) and in circulating lymphocytes in smokers, irrespective of whether they have airflow limitation (93). Oxidative stress may be a more important mechanism of aging in COPD, and may result in NF-{kappa}B activation, as well as DNA damage and inability to repair this damage, thus linking oxidative stress, aging, and cancer (94). Animal models of accelerated aging, including the Klotho mouse and the SMP30 mouse, both develop early emphysema, which is associated with increased oxidative stress (95, 96).

This suggests that antiaging molecules may be beneficial in COPD and its associated degenerative diseases. There has been particular interest in the protein deacetylase, SIRT1, which plays an important role in determining lifespan of all organisms, including mammals (97). SIRT1 has multiple cellular effects that counteract cellular stress and DNA damage by deacetylating multiple protein targets, including inhibiting NF-{kappa}B, forkhead box O transcription factors, PGC-1{alpha}, tumor suppressor p53, and DNA repair proteins, such as Ku70 (Figure 3). SIRT1 is markedly reduced in COPD lungs as a result of oxidative stress (98, 99). SIRT1 may be activated by resveratrol and more active drugs, known as SIRT1-activating compounds (STACs) (97, 100). STACs may provide a novel therapeutic approach to COPD and its associated aging diseases, and several novel drugs are now in clinical development for other aging diseases, such as diabetes. As the molecular pathways involved in aging are elucidated, it is likely that several new therapeutic targets will emerge.


Figure 3
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  		Figure 3. Aging pathways in COPD. Oxidative stress may reduce the activity and expression of sirtuin (SIRT) 1 in lungs via activation of phosphoinositide-3-kinase (PI3K) pathways, resulting in acetylation of several key target proteins linked to aging and cancer, including the transcription factors forkhead box (FOX) O and nuclear factor (NF)-{kappa}B, the tumor suppressor p53, and matrix metalloproteinase (MMP)-9.

 
LUNG CANCER

Patients with COPD are three to four times more likely to develop lung cancer than smokers without lung cancer (101), and this is probably linked to the increased inflammation and oxidative stress in COPD (102, 103). There are common factors involved in the aging lung and lung cancer, suggesting that antiaging therapies may also be beneficial in preventing the high risk of lung cancer in patients with COPD. As discussed above, these treatments may include STACs and Nrf2 activators. Defective function of Nrf2 may also contribute to the increased susceptibility of patients with COPD to lung cancer with smoking, as Nrf2 plays an important role in defense against certain carcinogens in tobacco smoke by regulating the expression of several detoxifying enzymes (76). However increased Nrf2 activation due to genetic mutations of Keap1 has been reported in lung cancer cells, so the role of Nrf2 in carcinogenesis is currently uncertain (104). NF-{kappa}B activation may be a link between inflammation and cancer, so IKK2 inhibitors may inhibit inflammation in COPD and prevent the development of cancers (105).

Patients with COPD show increased expression of epidermal growth factor receptors in airway epithelium (106), and this may be a mechanism of mucus hypersecretion and also of cell proliferation, leading to cancer. The epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib, which is used to treat non–small cell lung carcinoma (107), might also be effective in reducing mucus hypersecretion (108).

FOOTNOTES

Conflict of Interest Statement: P.J.B. has previously served as a consultant to GlaxoSmithKline (GSK). He is a member of scientific advisory boards for GSK, Boehringer Ingelheim, Altana, and Pfizer. He has received lecture fees from GSK, AstraZeneca, Boehringer Ingelheim, and unrestricted grants from GSK, AstraZeneca, Boehringer Ingelheim, and Novartis.

(Received in original form July 14, 2008; accepted in final form August 11, 2008)

REFERENCES

  1. Barnes PJ, Hansel TT. Prospects for new drugs for chronic obstructive pulmonary disease. Lancet 2004;364:985–996.[CrossRef][Medline]
  2. Barnes PJ. Frontrunners in novel pharmacotherapy of COPD. Curr Opin.Pharmacol 2008;8:300-307.
  3. Barnes PJ. Emerging pharmacotherapies for COPD. Chest (In press)
  4. Calverley PM, Sanchez-Toril F, McIvor A, Teichmann P, Bredenbroeker D, Fabbri LM. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176:154–161.[Abstract/Free Full Text]
  5. Mancini GB, Etminan M, Zhang B, Levesque LE, FitzGerald JM, Brophy JM. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol 2006;47:2554–2560.[Abstract/Free Full Text]
  6. Soyseth V, Brekke PH, Smith P, Omland T. Statin use is associated with reduced mortality in chronic obstructive pulmonary disease. Eur Respir J 2006;29:279–283.[CrossRef][Medline]
  7. Keddissi JI, Younis WG, Chbeir EA, Daher NN, Dernaika TA, Kinasewitz GT. The use of statins and lung function in current and former smokers. Chest 2007;132:1764–1771.
  8. Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005;45:89–118.[CrossRef][Medline]
  9. Hothersall E, McSharry C, Thomson NC. Potential therapeutic role for statins in respiratory disease. Thorax 2006;61:729–734.[Abstract/Free Full Text]
  10. Lee JH, Lee DS, Kim EK, Choe KH, Oh YM, Shim TS, Kim SE, Lee YS, Lee SD. Simvastatin inhibits cigarette smoking-induced emphysema and pulmonary hypertension in rat lungs. Am J Respir Crit Care Med 2005;172:987–993.[Abstract/Free Full Text]
  11. Takahashi S, Nakamura H, Seki M, Shiraishi Y, Yamamoto M, Furuuchi M, Nakajima T, Tsujimura S, Shirahata T, Nakamura M, et al. Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice. Am J Physiol Lung Cell Mol Physiol 2008;294:L882–L890.[Abstract/Free Full Text]
  12. Murphy DM, Forrest IA, Corris PA, Johnson GE, Small T, Jones D, Fisher AJ, Egan JJ, Cawston TE, Ward C, et al. Simvastatin attenuates release of neutrophilic and remodeling factors from primary bronchial epithelial cells derived from stable lung transplant recipients. Am J Physiol Lung Cell Mol Physiol 2008;294:L592–L599.[Abstract/Free Full Text]
  13. Morimoto K, Janssen WJ, Fessler MB, McPhillips KA, Borges VM, Bowler RP, Xiao YQ, Kench JA, Henson PM, Vandivier RW. Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease. J Immunol 2006;176:7657–7665.[Abstract/Free Full Text]
  14. Hodge S, Hodge G, Scicchitano R, Reynolds PN, Holmes M. Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells. Immunol Cell Biol 2003;81:289–296.[CrossRef][Medline]
  15. Zhang X, Jin J, Peng X, Ramgolam VS, Markovic-Plese S. Simvastatin inhibits IL-17 secretion by targeting multiple IL-17–regulatory cytokines and by inhibiting the expression of IL-17 transcription factor RORC in CD4+ lymphocytes. J Immunol 2008;180:6988–6996.[Abstract/Free Full Text]
  16. Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol 2008;8:183–192.[CrossRef][Medline]
  17. Blamoun AI, Batty GN, Debari VA, Rashid AO, Sheikh M, Khan MA. Statins may reduce episodes of exacerbation and the requirement for intubation in patients with COPD: evidence from a retrospective cohort study. Int J Clin Pract 2008;62:1373–1378.
  18. Paraskevas KI, Tzovaras AA, Briana DD, Mikhailidis DP. Emerging indications for statins: a pluripotent family of agents with several potential applications. Curr Pharm Des 2007;13:3622–3636.[CrossRef][Medline]
  19. Dandona P, Dhindsa S, Ghanim H, Chaudhuri A. Angiotensin II and inflammation: the effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade. J Hum Hypertens 2007;21:20–27.[CrossRef][Medline]
  20. Andreas S, Herrmann-Lingen C, Raupach T, Luthje L, Fabricius JA, Hruska N, Korber W, Buchner B, Criee CP, Hasenfuss G, et al. Angiotensin II blockers in obstructive pulmonary disease: a randomised controlled trial. Eur Respir J 2006;27:972–979.[Abstract/Free Full Text]
  21. Busquets X, MacFarlane NG, Heine-Suner D, Morla M, Torres-Juan L, Iglesias A, Llado J, Sauleda J, Agusti AG. Angiotensin-converting-enzyme gene polymorphisms, smoking and chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2007;2:329–334.
  22. Hopkinson NS, Nickol AH, Payne J, Hawe E, Man WD, Moxham J, Montgomery H, Polkey MI. Angiotensin converting enzyme genotype and strength in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:395–399.[Abstract/Free Full Text]
  23. Remels AH, Gosker HR, Schrauwen P, Langen RC, Schols AM. Peroxisome proliferator–activated receptors: a therapeutic target in COPD? Eur Respir J 2008;31:502–508.[Abstract/Free Full Text]
  24. Straus DS, Glass CK. Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol 2007;28:551–558.[Medline]
  25. Remels AH, Schrauwen P, Broekhuizen R, Willems J, Kersten S, Gosker HR, Schols AM. Peroxisome proliferator–activated receptor expression is reduced in skeletal muscle in COPD. Eur Respir J 2007;30:245–252.[Abstract/Free Full Text]
  26. Birrell MA, Patel HJ, McCluskie K, Wong S, Leonard T, Yacoub MH, Belvisi MG. PPAR-{gamma} agonists as therapy for diseases involving airway neutrophilia. Eur Respir J 2004;24:18–23.[Abstract/Free Full Text]
  27. Sime PJ. The antifibrogenic potential of PPARgamma ligands in pulmonary fibrosis. J Investig Med 2008;56:534–538.[Medline]
  28. Burgess HA, Daugherty LE, Thatcher TH, Lakatos HF, Ray DM, Redonnet M, Phipps RP, Sime PJ. PPARgamma agonists inhibit TGF-beta induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis. Am J Physiol Lung Cell Mol Physiol 2005;288:L1146–L1153.[Abstract/Free Full Text]
  29. Milam JE, Keshamouni VG, Phan SH, Hu B, Gangireddy SR, Hogaboam CM, Standiford TJ, Thannickal VJ, Reddy RC. PPAR-gamma agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2008;294:L891–L901.[Abstract/Free Full Text]
  30. Barnes PJ. Reduced histone deacetylase in COPD: clinical implications. Chest 2006;129:151–155.[CrossRef][Medline]
  31. Sin DD, Wu L, Anderson JA, Anthonisen NR, Buist AS, Burge PS, Calverley PM, Connett JE, Lindmark B, Pauwels RA, et al. Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease. Thorax 2005;60:992–997.[Abstract/Free Full Text]
  32. Sin DD, Lacy P, York E, Man SF. Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:760–765.[Abstract/Free Full Text]
  33. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–789.[Abstract/Free Full Text]
  34. Sin DD, Man SF, Marciniuk DD, Ford G, Fitzgerald M, Wong E, York E, Mainra RR, Ramesh W, Melenka LS, et al. The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;177:1207–1214.[Abstract/Free Full Text]
  35. Maneechotesuwan K, Essilfie-Quaye S, Meah S, Kelly C, Kharitonov SA, Adcock IM, Barnes PJ. Formoterol attenuates neutrophilic airway inflammation in asthma. Chest 2005;128:1936–1942.[CrossRef][Medline]
  36. Barnes NC, Qiu YS, Pavord ID, Parker D, Davis PA, Zhu J, Johnson M, Thomson NC, Jeffery PK. Antiinflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease. Am J Respir Crit Care Med 2006;173:736–743.[Abstract/Free Full Text]
  37. Bourbeau J, Christodoulopoulos P, Maltais F, Yamauchi Y, Olivenstein R, Hamid Q. Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: a randomised controlled trial. Thorax 2007;62:938–943.[Abstract/Free Full Text]
  38. Suissa S, Ernst P, Vandemheen KL, Aaron SD. Methodological issues in therapeutic trials of COPD. Eur Respir J 2008;31:927–933.[Abstract/Free Full Text]
  39. Lynch GS, Ryall JG. Role of beta-adrenoceptor signaling in skeletal muscle: implications for muscle wasting and disease. Physiol Rev 2008;88:729–767.[Abstract/Free Full Text]
  40. Cazzola M, Calderaro F, Califano C, Di Pema F, Vinciguerra A, Donner CF, Matera MG. Oral bambuterol compared to inhaled salmeterol in patients with partially reversible chronic obstructive pulmonary disease. Eur J Clin Pharmacol 1999;54:829–833.[CrossRef][Medline]
  41. Grando SA, Kawashima K, Kirkpatrick CJ, Wessler I. Recent progress in understanding the non-neuronal cholinergic system in humans. Life Sci 2007;80:2181–2185.[CrossRef][Medline]
  42. Powrie DJ, Wilkinson TM, Donaldson GC, Jones P, Scrine K, Viel K, Kesten S, Wedzicha JA. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD. Eur Respir J 2007;30:472–478.[Abstract/Free Full Text]
  43. Tschumperlin DJ, Drazen JM. Chronic effects of mechanical force on airways. Annu Rev Physiol 2006;68:563–583..[CrossRef][Medline]
  44. Milic-Emili J. Does mechanical injury of the peripheral airways play a role in the genesis of COPD in smokers? COPD 2004;1:85–92.
  45. Culpitt SV, de Matos C, Russell RE, Donnelly LE, Rogers DF, Barnes PJ. Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in COPD. Am J Respir Crit Care Med 2002;165:1371–1376.[Abstract/Free Full Text]
  46. Moxham J. Aminophylline and the respiratory muscles: an alternative view. Clin Chest Med 1988;2:325–336.
  47. Rennard SI, Fogarty C, Kelsen S, Long W, Ramsdell J, Allison J, Mahler D, Saadeh C, Siler T, Snell P, et al. The safety and efficacy of infliximab in moderate-to-severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:926–934.[Abstract/Free Full Text]
  48. van derVart H, Koeter GH, Postma DS, Kauffman HF, ten Hacken NH. First study of infliximab treatment in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;172:465–469.[Abstract/Free Full Text]
  49. Dentener MA, Creutzberg EC, Pennings HJ, Rijkers GT, Mercken E, Wouters EF. Effect of infliximab on local and systemic inflammation in chronic obstructive pulmonary disease: a pilot study. Respiration 2008;76:275–282.[Medline]
  50. Barnes PJ. Unexpected failure of anti–tumor necrosis factor therapy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:866–867.[Free Full Text]
  51. Bhowmik A, Seemungal TA, Sapsford RJ, Wedzicha JA. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax 2000;55:114–120.[Abstract/Free Full Text]
  52. Janssen SP, Gayan-Ramirez G, Van den Bergh A, Herijgers P, Maes K, Verbeken E, Decramer M. Interleukin-6 causes myocardial failure and skeletal muscle atrophy in rats. Circulation 2005;111:996–1005.[Abstract/Free Full Text]
  53. Paul-Pletzer K. Tocilizumab: blockade of interleukin-6 signaling pathway as a therapeutic strategy for inflammatory disorders. Drugs Today (Barc.) 2006;42:559–576.[CrossRef][Medline]
  54. Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:250–255.[Abstract/Free Full Text]
  55. de Torres JP, Pinto-Plata V, Casanova C, Mullerova H, Cordoba-Lanus E, Muros dF, Aguirre-Jaime A, Celli BR. C-reactive protein levels and survival in patients with moderate to very severe COPD. Chest 2008;133:1336–1343.
  56. Lowe GD, Pepys MB. C-reactive protein and cardiovascular disease: weighing the evidence. Curr Atheroscler Rep 2006;8:421–428.[Medline]
  57. Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, Hawkins PN, Myers RM, Smith MD, Polara A, et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 2006;440:1217–1221.[CrossRef][Medline]
  58. Tennent GA, Hutchinson WL, Kahan MC, Hirschfield GM, Gallimore JR, Lewin J, Sabin CA, Dhillon AP, Pepys MB. Transgenic human CRP is not pro-atherogenic, pro-atherothrombotic or pro-inflammatory in apoE–/– mice. Atherosclerosis 2008;196:248–255.[CrossRef][Medline]
  59. Mold C, Rodic-Polic B, Du Clos TW. Protection from Streptococcus pneumoniae infection by C-reactive protein and natural antibody requires complement but not Fc gamma receptors. J Immunol 2002;168:6375–6381.[Abstract/Free Full Text]
  60. Martorana PA, Beume R, Lucattelli M, Wollin L, Lungarella G. Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. Am J Respir Crit Care Med 2005;172:848–853.[Abstract/Free Full Text]
  61. Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbroker D, Bethke TD, Hiemstra PS, Rabe KF. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007;62:1081–1087.[Abstract/Free Full Text]
  62. Rabe KF, Bateman ED, O'Donnell D, Witte S, Bredenbroker D, Bethke TD. Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2005;366:563–571.[CrossRef][Medline]
  63. Yao W, Tian XY, Chen J, Setterberg RB, Lundy MW, Chmielzwski P, Froman CA, Jee WS. Rolipram, a phosphodiesterase 4 inhibitor, prevented cancellous and cortical bone loss by inhibiting endosteal bone resorption and maintaining the elevated periosteal bone formation in adult ovariectomized rats. J Musculoskelet Neuronal Interact 2007;7:119–130.[Medline]
  64. Caramori G, Romagnoli M, Casolari P, Bellettato C, Casoni G, Boschetto P, Fan CK, Barnes PJ, Adcock IM, Ciaccia A, et al. Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations. Thorax 2003;58:348–351.[Abstract/Free Full Text]
  65. Birrell MA, Wong S, Hardaker EL, Catley MC, McCluskie K, Collins M, Haj-Yahia S, Belvisi MG. IkappaB kinase-2–independent and –dependent inflammation in airway disease models: relevance of IKK-2 inhibition to the clinic. Mol Pharmacol 2006;69:1791–1800.[Abstract/Free Full Text]
  66. Agusti A, Morla M, Sauleda J, Saus C, Busquets X. NF-{kappa}B activation and iNOS upregulation in skeletal muscle of patients with COPD and low body weight. Thorax 2004;59:483–487.[Abstract/Free Full Text]
  67. Li H, Malhotra S, Kumar A. Nuclear factor-{kappa}B signaling in skeletal muscle atrophy. J Mol Med 2008;86:1113–1126.[CrossRef][Medline]
  68. Renda T, Baraldo S, Pelaia G, Bazzan E, Turato G, Papi A, Maestrelli P, Maselli R, Vatrella A, Fabbri LM, et al. Increased activation of p38 MAPK in COPD. Eur Respir J 2008;31:62–69.[Abstract/Free Full Text]
  69. Smith SJ, Fenwick PS, Nicholson AG, Kirschenbaum F, Finney-Hayward TK, Higgins LS, Giembycz MA, Barnes PJ, Donnelly LE. Inhibitory effect of p38 mitogen–activated protein kinase inhibitors on cytokine release from human macrophages. Br J Pharmacol 2006;149:393–404.[CrossRef][Medline]
  70. Medicherla S, Fitzgerald M, Spicer D, Woodman P, Ma JY, Kapoun AM, Chakravarty S, Dugar S, Protter AA, Higgins LS. p38{alpha} selective MAP kinase inhibitor, SD-282, reduces inflammation in a sub-chronic model of tobacco smoke-induced airway inflammation. J Pharmacol Exp Ther 2007;324:921–929.[CrossRef][Medline]
  71. Biernacki WA, Kharitonov SA, Barnes PJ. Increased leukotriene B4 and 8-isoprostane in exhaled breath condensate of patients with exacerbations of COPD. Thorax 2003;58:294–298.[Abstract/Free Full Text]
  72. Bowler RP, Barnes PJ, Crapo JD. The role of oxidative stress in chronic obstructive pulmonary disease. COPD 2004;2:255–277.
  73. Ito K, Barnes PJ. COPD as a disease of accelerated lung aging. Chest (In press).
  74. Rahman I, Morrison D, Donaldson K, Macnee W. Systemic oxidative stress in asthma, COPD, and smokers. Am J Respir Crit Care Med 1996;154:1055–1060.[Abstract]
  75. Barreiro E, Schols AM, Polkey MI, Galdiz JB, Gosker HR, Swallow EB, Coronell C, Gea J. Cytokine profile in quadriceps muscles of patients with severe COPD. Thorax 2008;63:100–107.[Abstract/Free Full Text]
  76. Cho HY, Reddy SP, Kleeberger SR. Nrf2 defends the lung from oxidative stress. Antioxid Redox Signal 2006;8:76–87.[CrossRef][Medline]
  77. Kobayashi M, Yamamoto M. Nrf2–Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzyme Regul 2006;46:113–140.[CrossRef][Medline]
  78. Clements CM, McNally RS, Conti BJ, Mak TW, Ting JP. DJ-1, a cancer- and Parkinson's disease–associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci USA 2006;103:15091–15096.[Abstract/Free Full Text]
  79. Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, Yamamoto M, Petrache I, Tuder RM, Biswal S. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke–induced emphysema in mice. J Clin Invest 2004;114:1248–1259.[CrossRef][Medline]
  80. Iizuka T, Ishii Y, Itoh K, Kiwamoto T, Kimura T, Matsuno Y, Morishima Y, Hegab AE, Homma S, Nomura A, et al. Nrf2-deficient mice are highly susceptible to cigarette smoke-induced emphysema. Genes Cells 2005;10:1113–1125.[Abstract/Free Full Text]
  81. Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, Singh A, Chen L, Zhuang X, Hogg J, Pare P, et al.. Decline in Nrf2 regulated antioxidants in COPD lungs due to loss of its positive regulator DJ-1. Am J Respir Crit Care Med 2008;178:592–604.[Abstract/Free Full Text]
  82. Decramer M, Rutten-van Molken M, Dekhuijzen PN, Troosters T, van Herwaarden C, Pellegrino R, Van Schayck CP, Olivieri D, Del Donno M, De Backer W, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet 2005;365:1552–1560.[CrossRef][Medline]
  83. Morimitsu Y, Nakagawa Y, Hayashi K, Fujii H, Kumagai T, Nakamura Y, Osawa T, Horio F, Itoh K, Iida K, et al. A sulforaphane analogue that potently activates the Nrf2-dependent detoxification pathway. J Biol Chem 2002;277:3456–3463.[Abstract/Free Full Text]
  84. Ito K, Tomita T, Barnes PJ, Adcock IM. Oxidative stress reduces histone deacetylase (HDAC)2 activity and enhances IL-8 gene expression: role of tyrosine nitration. Biochem Biophys Res Commun 2004;315:240–245.[CrossRef][Medline]
  85. Failla M, To Y, Ito M, Adcock IM, Barnes PJ, Ito K. Oxidative stress–induced PI3-kinase activation reduces HDAC activity and is inhibited by theophylline. Proc Am Thorac Soc 2007;2:A45.
  86. Barnes PJ. Theophylline for COPD. Thorax 2006;61:742–743.[Free Full Text]
  87. Barnes PJ. How corticosteroids control inflammation. Br J Pharmacol 2006;148:245–254.[CrossRef][Medline]
  88. Sabit R, Bolton CE, Edwards PH, Pettit RJ, Evans WD, McEniery CM, Wilkinson IB, Cockcroft JR, Shale DJ. Arterial stiffness and osteoporosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:1259–1265.[Abstract/Free Full Text]
  89. Patel BD, Loo WJ, Tasker AD, Screaton NJ, Burrows NP, Silverman EK, Lomas DA. Smoking related COPD and facial wrinkling: is there a common susceptibility? Thorax 2006;61:568–671.[Abstract/Free Full Text]
  90. Chung HY, Sung B, Jung KJ, Zou Y, Yu BP. The molecular inflammatory process in aging. Antioxid Redox Signal 2006;8:572–581.[CrossRef][Medline]
  91. Salminen A, Huuskonen J, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T. Activation of innate immunity system during aging: NF-{kappa}B signaling is the molecular culprit of inflamm-aging. Ageing Res Rev 2008;7:83–105.[CrossRef][Medline]
  92. Tsuji T, Aoshiba K, Nagai A. Alveolar cell senescence in patients with pulmonary emphysema. Am J Respir Crit Care Med 2006;174:886–893.[Abstract/Free Full Text]
  93. Morla M, Busquets X, Pons J, Sauleda J, Macnee W, Agusti AG. Telomere shortening in smokers with and without COPD. Eur Respir J 2006;27:525–528.[Abstract/Free Full Text]
  94. Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H. Trends in oxidative aging theories. Free Radic Biol Med 2007;43:477–503.[CrossRef][Medline]
  95. Sato A, Hirai T, Imura A, Kita N, Iwano A, Muro S, Nabeshima Y, Suki B, Mishima M. Morphological mechanism of the development of pulmonary emphysema in Klotho mice. Proc Natl Acad Sci USA 2007;104:2361–2365.[Abstract/Free Full Text]
  96. Sato T, Seyama K, Sato Y, Mori H, Souma S, Akiyoshi T, Kodama Y, Mori T, Goto S, Takahashi K, Fukuchi Y, Maruyama N, Ishigami A. Senescence marker protein-30 protects mice lungs from oxidative stress, aging and smoking. Am J Respir Crit Care Med 2006;174:530–537.[Abstract/Free Full Text]
  97. Westphal CH, Dipp MA, Guarente L. A therapeutic role for sirtuins in diseases of aging? Trends Biochem Sci 2007;32:555–560.[Medline]
  98. Vuppusetty C, Ito M, Elliott M, Hogg JC, Barnes PJ, Ito K. Expression of SIRT1, an anti-aging molecule, decreases with an increasing severity of COPD. Am J Respir Crit Care Med 2007;175:A553.
  99. Rajendrasozhan S, Yang SR, Kinnula VL, Rahman I. SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;177:861–870.[Abstract/Free Full Text]
  100. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006;127:1109–1122.[CrossRef][Medline]
  101. Tockman MS, Anthonisen NR, Wright EC, Donithan MG. Airways obstruction and the risk for lung cancer. Ann Intern Med 1987;106:512–518.[Abstract/Free Full Text]
  102. Zhang H. Molecular signaling and genetic pathways of senescence: its role in tumorigenesis and aging. J Cell Physiol 2007;210:567–574.[CrossRef][Medline]
  103. Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 2007;117:1175–1183.[CrossRef][Medline]
  104. Ohta T, Iijima K, Miyamoto M, Nakahara I, Tanaka H, Ohtsuji M, Suzuki T, Kobayashi A, Yokota J, Sakiyama T, et al. Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res 2008;68:1303–1309.[Abstract/Free Full Text]
  105. Karin M. The IkappaB kinase—a bridge between inflammation and cancer. Cell Res 2008;18:334–342.[CrossRef][Medline]
  106. de Boer WI, Hau CM, van Schadewijk A, Stolk J, van Krieken JH, Hiemstra PS. Expression of epidermal growth factors and their receptors in the bronchial epithelium of subjects with chronic obstructive pulmonary disease. Am J Clin Pathol 2006;125:184–192.[CrossRef][Medline]
  107. Felip E, Rosell R. Clinical experience with erlotinib in non–small-cell lung cancer. Drugs Today (Barc.) 2006;42:147–156.[CrossRef][Medline]
  108. Burgel PR, Nadel JA. Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium. Thorax 2004;59:992–996.[Abstract/Free Full Text]



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Systemic manifestations and comorbidities of COPD
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