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Mainz University Hospital, Mainz, Germany; and AstraZeneca Pharmaceuticals, Wilmington, Delaware
Correspondence and requests for reprints should be addressed to Roland Buhl, M.D., Mainz University Hospital, Langenbeckstrasse 1, Mainz, D-55131, Germany. E-mail: r.buhl{at}3-med.klinik.uni-mainz.de
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ABSTRACT |
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Key Words: COPD • drug development • pulmonary inflammation • systemic inflammation • therapy
Chronic obstructive pulmonary disease (COPD) is an important cause of morbidity, mortality, increased health care use, and hospital admissions. This disorder is characterized by airflow limitation that is not fully reversible with bronchodilator therapy, that usually worsens progressively, and that is associated with an exaggerated inflammatory response of the lung to the inhalation of noxious particles or gases (1–3). The term COPD encompasses other, more specific conditions—in particular, chronic obstructive bronchitis and emphysema. Patients have chronic progressive symptoms, such as breathlessness, cough and phlegm, airflow obstruction, and impaired health status. Moreover, they are predisposed to exacerbation—that is, an acute worsening of respiratory symptoms (4).
COPD is the only major cause of mortality with a rising incidence and prevalence worldwide (5), rendering it as an increasingly worrisome phenomenon for clinicians, health care organizations, society, and patients. Moreover, even if currently available smoking cessation programs and/or nicotine addiction therapy were effective, patients and society would continue to share the burden of COPD for the next 20 years (6). Thus, there is an urgent need to improve current treatment strategies and to develop new classes of drugs to more efficiently relieve symptoms, reduce the frequency and severity of exacerbations, and provide better health-related quality of life for individual patients.
Increasingly, COPD is recognized as a disorder that impairs not only the functioning of the lungs but also the heart and the peripheral and pulmonary circulation. Furthermore, COPD is more accurately described as a systemic syndrome associated with multiple comorbidities not only of the cardiovascular system but also with weight loss and muscle wasting, cancer, and other pathologies associated with chronic smoking and aging (7–13). Future therapeutic strategies in COPD, therefore, should aim not only at improving airflow and the symptoms associated with hypoxia but also at systemic inflammation, hypercoagulability, atherosclerosis, exercise tolerance, and abnormal changes in body weight and metabolism. The present article outlines recent developments in the pharmacologic therapy of COPD as well as describes some of the emerging approaches currently being explored in early clinical trials.
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RECENT IMPROVEMENTS IN CURRENT TREATMENT FOR COPD |
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Bronchodilators
Long-acting ß2-agonists (LABA), such as formoterol and salmeterol, are now recommended in patients with moderate and severe COPD (2). Single inhaled doses both of formoterol (12 µg) and salmeterol (50 µg) provide comparable bronchodilatation over 12 hours and have tolerable side effects (19).
A recent addition to the treatment options for COPD is tiotropium bromide, a long-acting, competitive antagonist of muscarinic M1 and M3 receptors, the subtypes that mediate bronchoconstriction (20). The maximum bronchodilator effects of tiotropium are reached 90 to 120 minutes after inhalation. Bronchodilatation is evident over a further 12 to 15 hours before the effects gradually subside, thus allowing once-daily dosing (21). Because of the longer duration of action, the effects of tiotropium on lung function, dyspnea, quality of life, and exercise tolerance are superior to ipratropium. In addition, tiotropium is also effective in preventing COPD exacerbations and related hospitalizations when compared both with placebo (22) and with ipratropium (23). The potential ability of long-acting bronchodilators to reduce COPD exacerbations raises interesting questions about the underlying mechanisms (22–26).
If a prompt, beneficial response to a single bronchodilator does not occur in a patient with COPD, recent guidelines recommend the addition of a second bronchodilator (2, 27–31). Although the evidence supporting the effectiveness of combinations of bronchodilators is controversial, such an approach may improve efficacy and, importantly, decrease the risk of side effects compared with increasing the dose of either single agent (32, 33). New developments in this field may therefore include combinations of LABA with anticholinergic drugs. The possible combination of tiotropium with an LABA holds the prospect of a further improvement in the treatment of COPD (17). Previous studies in patients with moderate-to-severe, stable COPD demonstrated that treatment with a combination of ipratropium and either formoterol or salmeterol is more effective than a combination of the anticholinergic with short-acting ß2-agonists, and shows additive effects in improving lung function (34, 35). Pilot trials indicate that, at least in patients with stable, moderate-to-severe COPD, addition of formoterol in the morning to maintenance therapy with tiotropium significantly improves spirometric lung function parameters for more than 12 hours. Add-on therapy of a second dose of formoterol, administered in the evening, produces a further increase in FEV1, FVC, and inspiratory capacity (36, 37). It is tempting to speculate that a combination of both drugs may also be beneficial in a COPD exacerbation.
New bronchodilators in development.
Several LABA with durations of action up to 24 hours and suitable for once-daily dosing are currently in advanced stages of clinical testing. These include R,R-formoterol, the active enantiomer of formoterol (38), other LABA (e.g., 597901 and 159797; GlaxoSmithKline [Brentford, UK] in collaboration with Theravance [San Francisco, CA]), and muscarinic antagonists, such as AD-237 (Arakis [Saffron Walden, UK]) and LAS-34273 (Almirall [Barcelona, Spain]). These drugs are reported by their respective companies to be in phase II or earlier clinical trials. In addition, Novartis (Basel, Switzerland) is developing an oral formulation of their once-daily LABA, QAB-149, for therapy for both COPD and asthma. Some of these new drugs may eventually replace formoterol and salmeterol alone and in fixed combinations with inhaled corticosteroids (ICS). To our knowledge, however, apart from these improvements to tried and tested pharmacologic mechanisms (i.e., ß2-adrenoceptor agonism and M1/M3 muscarinic receptor antagonism), there are currently no new classes of bronchodilator drugs in clinical testing.
ICS
A major stimulus to research was the redefinition of COPD as an inflammatory disorder of the lungs (1), a step now supported by substantial data demonstrating persistent inflammation at all stages of the disease that is related to structural changes in the small airways (39). There is preliminary evidence suggesting that regular use of ICS is associated with increased survival of patients with COPD managed in primary care (40, 41). Also, low-dose therapy with ICS was inferior compared with medium- or high-dose therapy in protecting against mortality from COPD (42). The concept that ICS in COPD have an effect beyond the lungs is further supported by effects on systemic markers of inflammation (e.g., C-reactive protein) (10). The apparent ability of therapy with ICS to reduce mortality in patients with COPD, however, is not generally accepted, and there is good evidence that the large-scale cohort studies that reported a reduction in mortality and COPD morbidity with ICS may be biased. A reanalysis of these studies did not find any reduction in mortality and morbidity caused by ICS use after hospitalization for COPD (43, 44). A definite answer to the question of a clinically relevant ICS effect in COPD will probably be given by the Towards a Revolution in COPD Health, or TORCH, study, a placebo-controlled trial with mortality as an endpoint (45).
New corticosteroids in development.
In addition to the currently used budesonide and fluticasone, newer "soft" inhaled corticosteroids in clinical development include ciclesonide, which recently was given an approvable letter from the U.S. Food and Drug Administration for the treatment of persistent asthma. Several pharmaceutical companies are investigating once-daily ICS as well as "nonsteroidal" or "dissociated glucocorticoid" receptor agonists (46). These agents may have fewer undesirable side effects than currently available glucocorticoids, and may eventually be administered alone or in combination with the newer, once-daily LABA and anticholinergic drugs noted previously as novel therapy for COPD.
Combinations of Inhaled Corticosteroids and Long-acting ß2-Agonists
The combination of ICS and LABA has proven superior to both classes of drug administered alone (24–26). It is tempting to speculate that positive interactions between the ICS and the LABA similar to those seen in asthma may explain why combinations of both drugs are superior to the additive effects of the individual components, supporting a role for the fixed combination of ICS and LABA in COPD therapy.
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In marked contrast to asthma, COPD is characterized by chronic inflammation dominated by neutrophils, macrophages, and CD8+ (cytotoxic) lymphocytes, mainly in the small airways and lung parenchyma (39). This inflammatory process involves destructive and aberrant repair processes in the lungs, perhaps mediated by proteases and highly reactive oxygen-free radicals, released from inflammatory cells (see article in this issue by MacNee, pp. 50–60) (47). These processes eventually shape the characteristic COPD pathology: small airway narrowing and destruction of lung parenchyma, underlying chronic obstructive bronchitis, and emphysema.
From a conceptual point of view, substantial progress in the treatment of COPD may require the development of entirely new therapeutic approaches (48–50). In turn, this will require the development of much improved understanding of the genetic, molecular, and cellular changes that underlie the susceptibility to and pathogenesis of this complex syndrome. Some novel, often still exploratory, approaches are outlined in the next section.
Reducing Pulmonary Inflammation
Smoking cessation.
Smoking cessation is the only intervention able to slow down the otherwise relentless progression of COPD (51). In addition to nicotine replacement and behavioral therapies, an antidepressant drug, bupropion, has been shown to increase quit rates in patients with COPD by up to nearly 20% (52, 53). However, as promising as this may be, this drug is associated with severe neurologic side effects—in particular, epileptic fits in about 0.1% of patients. A better understanding of the central neural pathways underlying drug addiction may eventually lead to more effective drugs to reduce the potent addictive qualities of nicotine, as well as the currently high rates of relapse after cessation of smoking. Furthermore, as noted earlier, even if a smoking cessation therapy with a 100% success rate was introduced today, COPD would continue to be a major clinical problem for the next 15 to 20 years. There is an unavoidable increase in the burden of COPD because of past smoking behavior and the aging of the population. As such, changes in smoking behavior will have only a small effect in the near future (6).
New approaches to counter addiction to nicotine.
Novel approaches to the treatment of drug addiction that are currently in development include vaccines directed against circulating nicotine (54). In addition, several companies are researching the central receptor pathways implicated in drug dependence and use relapse. Targets include nicotinic, dopamine D2, opioid, and cannabinoid receptors, as well as neuronal serotonin-uptake mechanisms (55, 55).
Phosphodiesterase-4 inhibitors.
Despite their widespread clinical use, the role of methylxanthines, such as theophylline, in the treatment of COPD is contentious. Their toxicity profile makes them potentially harmful and because of the age of patients with COPD, as well as their often comorbid conditions, this is a particular concern in this population. Adverse effects associated with this class of drugs include nausea, vomiting, headache, cardiac arrhythmia, and seizure. These effects are more significant among those patients with higher blood levels of theophylline (see Reference 2 and citations therein for review).
The methylxanthines have multiple pharmacologic actions (e.g., adenosine antagonism), including being weak inhibitors of intracellular phosphodiesterases (PDE). The observation that PDE type 4 is expressed predominantly in inflammatory cells, such as neutrophils, CD8+ lymphocytes, and macrophages, makes this enzyme an attractive target for the development of new drugs to treat pulmonary inflammation that is characteristic of COPD. There are now in late stages of clinical development oral PDE4 inhibitors that, as a consequence of elevated intracellular levels of cyclic AMP, are bronchodilators as well as antiinflammatory agents, which may find a place in the therapy for COPD (56). Examples of two such agents are cilomilast, which is in preregistration as a therapy for COPD, and roflumilast, which is in phase III clinical development for both COPD and asthma (57–59). In addition, several new PDE4 inhibitors are in earlier stages of clinical development as therapies for chronic inflammatory conditions of the lungs, including COPD (60).
In a randomized, double-blind, and placebo-controlled clinical trial with roflumilast in patients with moderate-to-severe COPD over a 26-week period, treatment was associated not only with a positive effect on lung function but also on the frequency of exacerbations. Roflumilast decreased the number of exacerbations by 48% relative to placebo, although this effect did not reach statistical significance (61). A similar trend was observed in a dose-ranging study with cilomilast, although exacerbations were not an outcome parameter (62). A potential explanation for these observations may be an ability of the PDE4 inhibitor to reduce inflammatory cell functions and the release of cytokines, such as tumor necrosis factor 
(TNF-) and interleukin 8 (IL-8) (63, 64). There is a direct correlation between the sputum volume and its concentration of neutrophil elastase, and PDE4 inhibitors reduce pulmonary neutrophil numbers. This is also true for lymphocytes, which could be relevant in the context that CD8+ T cells may modulate the inflammatory damage underlying COPD (56). These findings raise the question whether PDE4 inhibitors may also slow disease progression.
However, although there are some encouraging data on the effects of inhibitors of PDE4 on lung inflammation and clinical symptoms in COPD, this class of drug has long been plagued with adverse, sometimes serious side effects (14). Such events, which include headaches, sleep disturbance, and nausea, may be dose-limiting, particularly in patients with COPD, many of whom are quite ill and may have other comorbidities. Of note, in laboratory animals, the pharmacologic inhibition of PDE4 is associated with histopathologic lesions that are consistent with vascular inflammation (arteritis) in the mesentery and other organs. This association has been reported in rats (65) and nonhuman primates (66), and may be a "class effect" of the PDE4 inhibitors. Furthermore, irreversible mesenteric arteritis was the most serious toxicity reported after the administration of cilomilast, a PDE4 inhibitor, to rodents and was noted as a major concern by the United States Food and Drug Administration's Pulmonary-Allergy Drug Advisory Committee in their review of a new drug application for the use of this agent as a novel therapy for COPD (United States Food and Drug Administration, data on file [www.fda.gov/ohrms/dockets/ac/03/slides/3976s1.htm]). Whether PDE4 inhibitors cause mesenteric arteritis in humans, however, and whether this has any causal role in the gastrointestinal adverse effects of PDE4 inhibitors reported in humans (abdominal pain, diarrhea, nausea, vomiting) is unclear at this time.
Potentially, these problems could be overcome by developing isoenzyme subtype selective inhibitors. Furthermore, it is as yet unclear to what degree these drugs can provide true clinical improvement compared with theophylline, and whether they will compete against current COPD treatments or be used only as adjunct therapy together with standard therapies.
Antileukotriene drugs.
Novel drugs aimed at ameliorating inflammatory processes, which are likely pivotal in COPD pathogenesis, may represent exciting new treatment approaches. Neutrophilic inflammation is an important feature of COPD and may contribute to mucus hypersecretion and destruction of alveoli. Agents suppressing neutrophil influx into the lungs may potentially reduce the rate of decline of lung function in patients with COPD by ameliorating neutrophil-mediated tissue destruction, and may also have a role in the prevention and treatment of exacerbation. Several endogenous chemoattractants for peripheral blood neutrophils may mediate increased trafficking of these cells to bronchial tissues, among them leukotriene (LT) B4. High concentrations of LTB4 are found in the sputum of patients with COPD (67, 68). Therapy with LTB4 receptor antagonists, therefore, has been postulated to be a potentially disease-modifying approach in diseases, such as COPD, characterized by neutrophil infiltration.
Orally active competitive antagonists of human neutrophil B LT (BLT) receptors are in advanced stages of clinical testing. To date, however, and in marked contrast to experiments ex vivo, clinical trial results have been disappointing. For example, LTB-109, an oral LTB4 receptor antagonist, had no effect on neutrophil numbers, and concentrations of myeloperoxidase, IL-8, and TNF- in induced sputum of patients with COPD treated with the drug for 4 weeks (69). These data question the role of LTB4 as a neutrophil chemoattractant in vivo and raise significant doubts about the putative utility of LTB4 antagonists as a treatment option in COPD. A BLT subtype has been described recently to be expressed on T lymphocytes, although any functional significance in COPD is unknown (70). Amelubant (BIIL-284), another LTB4 antagonist, has been reported to be in phase I development for the potential treatment of COPD. To our knowledge, no clinical results have been reported for this agent. An earlier study reported improved lung function in patients with stable COPD treated with zafirlukast, an oral antagonist of CysLT1-receptors (40 mg). This finding was likely caused by bronchodilatation (71).
An alternative approach to receptor antagonism is to interfere pharmacologically with the generation of LTB4, LTC4, and LTD4. In a small phase II trial to assess the effects of an LT synthesis inhibitor on bronchial inflammation in patients with stable COPD (mean FEV1, 35.5% predicted), 14 days of treatment with an oral LT synthesis inhibitor, BAYx1005 (500 mg twice daily), produced a significantly greater median reduction in sputum LTB4 compared with placebo (72). This suggests that an LT synthesis inhibitor may produce modest reductions in some measures of pulmonary neutrophilic inflammation in COPD, but larger clinical trails are required to determine a potential clinical benefit. Finally, although there is limited "off label" use of antiasthma cysteinyl LT antagonists, such as montelukast, as well as zileuton, a 5-lipoxygenase inhibitor, in COPD, their clinical effectiveness in this disorder is modest (73).
Inflammatory chemokines and cytokines.
Chemokine inhibitors.
Other endogenous leukocyte chemoattractants, the chemokines, have been implicated in the mechanisms leading to airway neutrophilia in COPD, and may represent targets for future drugs. A notable example is IL-8, a potent neutrophil chemoattractant that may play significant roles in pulmonary inflammation in both cystic fibrosis (74) and COPD (75). Studies with anti–IL-8 antibodies have confirmed that IL-8 is an important factor contributing to the neutrophil chemotactic activity of sputum obtained from patients with stable COPD, accounting for 29% of the total chemotactic activity (68, 76). This finding suggests, however, that other as yet unidentified chemoattractants are also involved in neutrophil migration in vivo (68).
Humanized monoclonal antibodies directed against IL-8 effectively block the chemotactic response of neutrophils to IL-8 in vitro and neutrophilic inflammation in animal models (77). One such antibody, ABX-IL8, has been shown in a recent pilot clinical trial in patients with stable COPD to be well tolerated and safe over the study period (78). ABX-IL8 was administered as three intravenous infusions over 3 months, the primary outcome measure being dyspnea, as determined by the transitional dyspnea index total score versus placebo. Secondary outcomes included lung function (FEV1), health status, and exercise tolerance. Patients who received ABX-IL8 showed an increase in the transitional dyspnea index score at 2 weeks. This improvement in dyspnea persisted throughout the 3 months of treatment, whereas transitional dyspnea index scores in the placebo group declined. None of the secondary outcomes were altered significantly by the anti–IL-8 therapy (78).
This is the first report of a clinical trial with an antibody targeted against a chemokine in COPD. There may also be lessons from this preliminary study. For example, the reduction in dyspnea likely did not result from improved lung function, at least as determined by FEV1, the only such measure reported. Furthermore, it also provides potentially important "proof of concept" that, although neutrophil numbers were not reported, this cell type may play a key role in the symptom of dyspnea, perhaps via elastase-induced mucus hypersecretion. These data also raise the increasingly important question of how to design clinical trials as well as register new drugs whose primary clinical efficacy in COPD may not be on lung function.
Another approach to targeting chemokines is the use of antagonists of their receptors. Several companies have small molecule antagonists to a variety of chemokine receptors in early phases of development for COPD. One example is a recently described series of N,N'-diarylurea antagonists of CXCR2, one of the two subtypes of IL-8 receptor that is expressed on neutrophils and endothelial cells (79). These agents display potent (nanomolar) and selective antagonism of CXCR2 in vitro and in animal models, and may find a place in the therapy for neutrophil-mediated inflammation in several disorders, including COPD.
However, whether antichemokine approaches will ultimately prove to be effective clinically and safe in humans remains unknown, especially in chronic therapy with such agents. It can be (and is) argued that inhibition of the actions or biosynthesis of a single mediator, such as IL-8, in the complexity of the inflammatory response, taking into account the documented redundancy of endogenous chemoattractants, may not be as effective in treating COPD as hoped. Furthermore, the potential importance of IL-8 in eliciting host-defense responses to microbiological infections raises important questions regarding the safety and tolerability of a therapeutic approach aimed at blocking neutrophil effector functions in patients with COPD who are subject to frequent lung infections and ensuing exacerbations of their symptoms. Regardless, the preliminary results with anti–IL-8 described previously are encouraging, and larger, more protracted trials with such therapies in COPD are awaited with interest.
TNF- inhibition.
TNF- is a ubiquitous and pleiotropic cytokine that exerts multiple proinflammatory activities, including chemotaxis and activation of macrophages and neutrophils. As such, TNF- is likely an important mediator of pulmonary inflammation in COPD (68, 80). TNF- levels are elevated in the sputum of patients with COPD, and this cytokine also induces increased expression of IL-8 in airway epithelial cells via activation of the nuclear transcription factor 
B (NF-B) (75). Furthermore, the severe wasting in some patients with advanced COPD might be caused by skeletal muscle apoptosis resulting from increased circulating levels of TNF- (81, 82), providing evidence for a potentially important role of this cytokine in systemic inflammation (see articles in this issue by van Eeden and coworkers, pp. 61–67, and Wouters, pp. 26–33).
A humanized monoclonal antibody directed against TNF- (infliximab) and a soluble TNF- receptor (etanercept) are marketed currently for the therapy of chronic inflammatory disorders, such as rheumatoid arthritis and Crohn's disease (83, 84). Patient recruitment into clinical trials with at least one anti–TNF- biopharmaceutical product in COPD is reportedly ongoing. As with anti–IL-8 approaches, the results of clinical trials with anticytokines are awaited eagerly, bearing in mind that some of the same concerns about host defense may be relevant to the chronic inhibition of TNF- in susceptible patients.
An alternative to protein biopharmaceutical approaches may be the development of small molecule inhibitors of TNF-–converting enzyme (TACE). TACE is required for the release of soluble TNF- (85). Moreover, several companies are exploring the potential of small molecule inhibitors of key signaling components in the intracellular production of TNF-. Among these is, as discussed in the following section, p38 mitogen-activated protein kinase (MAPK), a potentially attractive target for inhibition in COPD and other inflammatory disorders (86)
Inhibition of cellular signal transduction.
The analysis of bronchial biopsies and lung parenchyma obtained from patients with COPD compared with those from smokers with normal lung function and nonsmokers has provided new insights into the signaling pathways and mediators of different inflammatory and structural cells involved in COPD pathogenesis. These include the various intracellular signaling cascades that result in upregulated production of proinflammatory cytokines and including, for example, at the level of NF-B, phosphoinositide-3 kinases [PI3K], and p38 MAPK (87–89).
In patients with COPD, both the numbers of CD4+ and CD8+ cells as well as alveolar macrophages expressing transcription factors, such as NF-B and STAT-4, are increased (90, 91). Although there are various possible ways to interfere with such transcription factors, one promising route is with inhibitors of the kinases involved in the regulation of their activity (e.g., B kinases, NF-B–inducing kinase, and B ubiquitin ligase) (87, 88). These kinases are believed to play a crucial role in the expression and activation of inflammatory mediators in the airway, in T-cell function, and in airway remodeling.
Other signal transduction pathways that control airway inflammation and possible structural modification (remodeling) are the extracellular signal-regulated kinase, or ERK, and PI3K pathways. PI3K and the downstream serine/threonine kinase Akt/protein kinase B have a central role in modulating neutrophil function, including respiratory burst, chemotaxis, and apoptosis. Stimulation of neutrophils results in phosphorylation of Akt, activation of NF-B, and expression of IL-1ß and TNF- through PI3K-dependent pathways. PI3K and particularly the PI3K
isoform occupy a central position in the regulation of neutrophil activation. Specifically designed kinase inhibitors may ultimately find a place in the therapy for pulmonary inflammation in COPD (92, 93).
As noted previously, it is also possible that airway inflammatory stimuli concurrently elicit signaling through regulatory intermediates, such as p38 MAPK (89) and protein kinase C-
(94). In an animal model, a small molecule inhibitor of p38 reduced neutrophil infiltration after inhalation of bacterial endotoxin, and decreased the concentration of proinflammatory cytokines and metalloproteinases in lung lavage fluid, suggesting a potential in the therapy for COPD (95, 96).
Cell adhesion inhibitors.
The induction and maintenance of inflammation in COPD is mediated by recruiting inflammatory cells from the circulation via lung tissue to the airways. In this orchestrated cascade of molecular events, involving leukocyte adhesion, transmigration, maturation, and activation, the initial tethering and rolling of blood cells is mediated by selectins expressed on the surfaces both of leukocytes and vascular endothelial cells (97, 98). As such, the selectins may constitute a promising target for therapeutic intervention (99, 100).
The selectin family of vascular cell adhesion molecules is composed of three structurally related calcium-dependent carbohydrate-binding proteins: E-, P-, and L-selectin. P-selectin is a rapidly inducible form found primarily on activated platelets and endothelium. E-selectin is found primarily on activated endothelial cells and maximal expression occurs 3 to 6 hours after the inflammatory process begins. L-selectin is expressed constitutively on the surface of several leukocyte subtypes, including neutrophils, monocytes, the majority of circulating B and T cells, and on a subset of natural killer cells (101).
Pharmacologic inhibitors of adhesion molecules include bimosiamose (TBC1269, 1,6-Bis [3-(3-carboxymethylphenyl)-4-(2--D-mannopyrano-syloxy)-phenyl] hexane), a synthetic, computer-designed antagonist targeted against all three identified selectins (102). Studies in vitro, under static and dynamic flow conditions, demonstrate that this compound blocks adhesion of neutrophils, eosinophils, and lymphoid cells, with a preferential effect on neutrophils (103, 104). Consistent with this finding, bimosiamose also exhibits efficacy in acute and chronic disease models in vivo by prevention of influx of neutrophils into inflamed tissue (103, 105–107). To our knowledge, this compound has not been tested in patients with COPD. However, 3.5 days of treatment with bimosiamose is effective at least in a human allergen challenge model of asthma. Inhaled bimosiamose significantly attenuated the maximum late allergic response compared with placebo (108). The result of this proof-of-concept exploratory trial is the first study to demonstrate clinical efficacy of a selectin-antagonist in an inflammatory airway disease.
Protease inhibition.
An imbalance in favor of neutrophil elastase activity over endogenous antiproteases may cause lung parenchyma destruction, and has been postulated as a major pathogenic factor in COPD for many years. Neutrophil elastase has therefore long been a target for drug discovery for novel therapies for several inflammatory disorders, including COPD (49, 50, 109). This serine protease has been implicated not only in the proteolytic destruction of lung matrix proteins and development of pulmonary emphysema but also as a potent mediator of airways goblet cell hyperplasia and mucus hypersecretion (110). Lung levels of neutrophils and neutrophil elastase are elevated in COPD (111), and the pharmacologic inhibition of this destructive enzyme may in the future represent a potentially exciting and efficacious therapeutic strategy in the prevention and/or treatment of COPD.
The proof of concept of this strategy has been established in human subjects with hereditary 1-antitrypsin (AAT) deficiency, a rare disorder characterized by low serum levels of AAT and a high risk of pulmonary emphysema at a young age from the resulting unchecked activity of proteases, mainly neutrophil elastase (112). Weekly intravenous infusions of plasma-purified AAT in AAT-deficient patients with emphysema led to a marked reduction in the loss of lung function, particularly the decline in FEV1. In addition, subjects receiving augmentation therapy had decreased mortality as compared with those not receiving therapy (113, 114). Partially purified AAT is available in the United States and several other countries, but its high cost severely limits its use. Regardless of the benefits seen in AAT-deficient patients, however, there is little if any evidence that AAT augmentation therapy alters the clinical course or symptoms in patients with emphysema who do not have AAT deficiency.
The search for methods to block the excessive activity of proteases in inflammatory disorders, such as COPD, has led to the discovery of potent small-molecular-weight human neutrophil elastase inhibitors (115). In animal models of smoking, the oral administration of a small molecule inhibitor of neutrophil elastase, AZD8092, abrogated lung neutrophil infiltration and reduced significantly the development of airspace enlargement (emphysema) by 45% at 4 months (116). Smoke-induced, increased levels of lung lavage desmosine, an elastin breakdown marker, and TNF- were also markedly reduced by the elastase inhibitor. Furthermore, AZD8092 was reported to reduce pulmonary vessel remodeling and growth factor expression in response to cigarette smoke in guinea pigs (117). These studies suggest that smoke-induced airway neutrophilia and emphysema are mediated in part via the activity of neutrophil elastase.
Such agents may in the future occupy an important place in our armamentarium of therapies for COPD. In addition to neutrophil elastase, other proteolytic enzymes such as the matrix metalloproteases (MMP), a family of zinc-dependent proteinases, are being explored as potential therapeutic targets for intervention in COPD (118–120). Oral, nonselective inhibitors of MMP are currently in advanced stages of clinical testing in patients with lung cancer. However, the MMP exert multiple effects required for normal cell function and also in host-defense mechanisms in addition to degrading extracellular matrix. As such, it is desirable to design inhibitors that selectively block the activity of targets such as MMP-9 and MMP-12, which are implicated in inflammatory tissue remodeling and pathophysiology, to mitigate the likely adverse effects of nonselective blockade of multiple MMP (121).
The proteinase-antiproteinase concept assumes, however, that excess proteolytic activity is the major cause of pulmonary emphysema. If unchecked proteinases represent only one of several mechanisms eventually leading to elastic fiber breakdown, it is rational to design strategies to protect lung elastic fibers from damage. Hyaluronan, a long-chain polysaccharide, preferentially binds to elastic fibers, thereby preventing elastolysis. Targeted directly to the lower respiratory tract via the aerosol route, hyaluronan limited airspace enlargement in animal models of emphysema (122). To our knowledge, this new approach to treating emphysema has not yet entered clinical trials.
Antioxidants.
Oxidative stress resulting from an imbalance between highly reactive and cytotoxic oxidants and protective antioxidants likely plays a major role in the initiation and pathogenesis of COPD (123). There is now substantial evidence that increased oxidative stress occurs both in the airspaces and systemically in COPD, and that it plays an important role in the injurious and inflammatory responses in the respiratory tract. The Bronchitis Randomized on NAC Cost-Utility or BRONCUS study was designed to assess the effectiveness of 600 mg of N-acetylcysteine, a glutathione precursor and weak antioxidant, in patients with moderate-to-severe COPD on the rate of lung function decline (FEV1) and yearly exacerbation rate. Over the study period of 3 years, neither the rate of decline in FEV1 or vital capacity nor the yearly exacerbation rate was influenced by this agent (124). At present, effective antioxidant therapy that has good bioavailability and sufficient potency to be effective in vivo is not available. The same is true for dietary antioxidants. There is epidemiologic evidence suggesting that a beneficial impact of nutrition on COPD is most evident for fruit and vegetables, sources of antioxidant vitamins. However, so far there are no convincing clinical trials demonstrating the effectiveness of dietary supplementation in open-population samples (125–127).
This topic is reviewed extensively in articles in this issue by MacNee, pp. 50–60, and Semenza, pp. 68–70, and will not be discussed in detail here. Drugs that target the generation of oxidant radicals or that increase the generation or activity of antioxidant defenses may find utility as future novel therapy in abrogating not only pulmonary damage but also systemic inflammation in COPD.
Inhibitors of inducible nitric oxide synthase.
COPD is characterized by an increased oxidative burden in the lower respiratory tract of affected patients in stable disease or exacerbations. Nitric oxide (NO), a simple free-radical gas, elicits a diverse range of physiologic and pathophysiologic effects, and may play an important role in pulmonary diseases. Several investigations have also linked COPD to increased nitrosative stress in sputum, breath condensate, or airway biopsies, despite normal or mildly increased levels of exhaled NO (128). Despite normal levels of exhaled NO, increased nitrogen metabolites and protein nitrosylation are found in patients with COPD (129). This observation may reflect the rapid reaction of NO with neutrophil-derived superoxide anion, leading to the formation of reactive nitrogen species, such as peroxynitrite (130). Peroxynitrite itself is detoxified by thiol antioxidants, such as glutathione, to form nitrosothiols (131). NO modulators (e.g., NO synthase inhibitors and NO donors) may have clinical benefit in asthma and COPD (132).
Maintenance and Repair of Lung Structure and Inhibition of Apoptosis
Airspace enlargement and alveolar destruction are characteristic features of emphysema. An attractive therapeutic approach, albeit an ambitious one given our present knowledge, would be to reinduce alveolus morphogenesis and "rebuild" the oxygen exchange units in the lungs of patients with COPD with emphysema. The retinoids are key molecules in wound repair where they regulate cell proliferation, differentiation, morphogenesis, and apoptosis. In isolated cell systems and in animals, exogenous retinoids, such as retinoic acid (RA), stimulate growth of alveolar tissue. The administration of RA has been reported to induce alveolar regeneration in a rat model of elastase-induced emphysema (133, 134). Alveolar regeneration with RA may therefore be an important novel therapeutic approach to the treatment of respiratory diseases characterized by a reduced gas-exchanging surface area, such as emphysema, for which there are currently no effective treatments (134, 135).
The feasibility of treatment with all-trans-RA in patients with severe emphysema was explored in a small pilot trial (136). On the basis of this study, the Feasibility of Retinoic Acid Treatment in Emphysema (FORTE) trial was conducted, involving ex-smoking (
6 months) patients with emphysema (FEV1, 25–80%; DLCO 
80%; spiral computed tomographic scan with evidence of emphysema) randomized to high- and low-dose RA as well as 13-cis RA, each with matched placebo for several months. The measured variables included pulmonary function and clinical parameters as well as computed tomographic lung scan density. However, the overall results of this trial were reported to be disappointing at a recent symposium given at the American Thoracic Society International Conference (Wise RA, Weinmann GG, chairmen. Results of FORTE. Orlando, FL; May 24, 2004). Arguably, this may not be not surprising because RA is required throughout life in the rat for the maintenance of lung alveoli and this species can regenerate lung tissue into adulthood. Humans stop regenerating alveolar tissue in early life (133–135).
The induction of pulmonary endothelial cell apoptosis in animals causes emphysema, and increased numbers of apoptotic cells are observed in the alveolar septae of emphysematous human lungs (137, 138). If apoptotic cell death of alveolar tissue cells, either as a sequela of inflammatory damage or because of a direct cellular effect of toxins in tobacco smoke, plays a role in the pathogenesis of emphysema, pharmacologic inhibition of apoptosis might prevent further loss of alveoli and emphysema (139), and possibly allow at least limited repair of lung structure. Furthermore, the mechanisms that underlie the loss of alveoli in emphysema associated with smoking and COPD are unknown, and the classic assumptions about protease/antiprotease imbalance discussed earlier may only partly explain such apparently destructive processes. Questions arise regarding the "regulated" loss of pulmonary alveoli and their regeneration in rodents, and its possible relevance to human lung (patho)physiology, as opposed to the "unregulated" loss of alveoli, which is associated with inflammation and tissue destruction (140, 141). This promises to be an exciting, growing area for research in our quest to understand the pathogenesis of emphysema in COPD, and for its eventual cure.
Mucus Clearance Strategies
Mucus hypersecretion is a characteristic feature of COPD, and increased sputum volume and/or purulence are used frequently as diagnostic markers of exacerbation (142). The cellular and molecular components involved in mucus formation, content, release, and transport are, consequently, potentially attractive targets for therapeutic intervention. Such strategies include drugs that inhibit mucus production by regulation of goblet and glandular mucous cells, ion channel–activating agents that increase the hydration of mucus thereby enhancing mucociliary clearance, chemical mediators of mucous secretion, growth factors for cellular hyperplasia, as well as signal transduction pathways involved in mucin gene expression (143, 144). Novel drugs aimed at reducing mucus hypersecretion or improving mucociliary clearance include inhibition of epidermal growth factor receptor signaling and agents that block Ca-activated chloride channels (50).
Expectorants, mucolytics, and mucokinetic drugs have not been demonstrated to shorten the course of treatment for patients with exacerbation of COPD, although there is a possibility that these agents may improve symptoms (145). The majority of COPD exacerbations are associated with an increase in sputum volume and/or purulence, and it is tempting to speculate that mucus-clearing strategies may influence the frequency and severity of exacerbations as well as the risk of rehospitalization (146). Interestingly, there are marked international differences in the prescribing of mucolytics, such as N-acetylcysteine, depending on their perceived local or national effectiveness. A meta-analysis in 2000 revealed a small reduction in acute exacerbations and a somewhat greater reduction in total number of days of disability in patients with COPD on treatment with expectorant, mucolytic, and mucokinetic drugs (145). These results must be interpreted with caution, however, and even more so given the results of the BRONCUS trial discussed previously, because the reduction in the exacerbation rate was greater for the studies which lasted 3 months or less than for those that were more than 3 months in duration (145).
Reversal of COPD-associated Weight Loss
Poor nutritional status is associated with an increased incidence of morbidity and mortality in patients with COPD. Although a number of factors have been shown to produce tissue catabolism, no single mechanism has been clearly identified as a primary cause for weight loss in severe COPD. Without a clear understanding of the etiology of weight loss, therapeutic strategies to reverse this process have historically been unsuccessful. Potential mechanisms that may be activated singly or simultaneously to cause loss of weight include energy imbalances, elevated levels of cytokines, tissue hypoxia, and the effects of corticosteroid therapy. To date, interventional studies with newer pharmacotherapies, such as growth hormone and anabolic steroids in patients with COPD who are losing weight, have not demonstrated reversal of weight loss or improvement in nutritional status. Currently, early identification of patients at risk for weight loss and aggressive nutritional supplementation coupled with an exercise program has demonstrated the greatest benefit (147). A combination of nutritional support and exercise as an anabolic stimulus appears to be the best approach to obtaining marked functional improvement. Patients responding to this treatment even demonstrated a decreased mortality (148). With increasing understanding of the mechanisms that may be implicated, new targets for therapies are being identified. Of particular interest are molecules such as LT, hormones, TNF-, and acute-phase proteins, which are noted to be elevated in some patients with COPD-associated weight loss. Inhibitors of some of these inflammatory mediators are used to treat other chronic illnesses, such as rheumatoid arthritis and cancer cachexia. Future research may investigate their usefulness in COPD and direct new therapies that target the mechanisms contributing to weight loss in these patients.
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Patients with COPD tend to be in their 50s and older and frequently have other diseases associated with aging, especially if they smoke. Smoking induces significant systemic and cardiovascular effects in addition to lung irritation and inflammation (10, 11, 150, 151). Furthermore, ongoing lung inflammation in COPD may contribute to systemic inflammation caused by chronic hypoxia and the "overspill" of cytokines, such as TNF-, from the lungs into the circulation. As such, therapeutic strategies for these patients arguably should focus on aspects of pathophysiology in addition to improving airflow and reducing pulmonary inflammation. Furthermore, current ICS therapy may influence systemic inflammation in patients with COPD. For example it was reported recently that 8 weeks' treatment of patients with mild-to-moderate COPD with fluticasone (500 µg twice daily) followed by another 8 weeks at 1,000 µg twice a day was associated with a significant reduction in serum levels of C-reactive protein (10). Elevated circulating C-reactive protein is a marker of systemic inflammation and an accepted indicator of risk of cardiovascular disease (as discussed in articles in this issue by Hunninghake, pp. 44–49, MacCallum, pp. 34–43, and van Eeden and colleagues, pp. 61–67). Interestingly, in the report by Sin and colleagues (10), withdrawal of ICS at the initiation of the study was associated with an increase of 71% from baseline C-reactive protein levels, indicating that these subjects with COPD had ongoing systemic inflammation and perhaps elevated risk of cardiovascular complications. The authors suggested that the use of ICS (and oral corticosteroids) may improve cardiovascular outcomes in COPD. The association of cardiovascular outcomes and COPD, and vice versa, is discussed in detail in several of the articles in this issue.
Future strategies in treating COPD may be guided by the individual patient's overall health status and clinical assessment. Several classes of drugs that are used currently or are under development to treat disorders of the cardiovascular system (e.g., atherosclerosis and dyslipidemia [statins], pulmonary hypertension [endothelin antagonists], hypercoagulability [thrombin inhibitors]) may find an important place in the therapy for COPD. Furthermore, many patients with COPD are subject to "polypharmacy" and may already be taking such medicines in addition to their "lung-specific" ICS and bronchodilators. Of course, the adoption of such therapeutic regimens is not without some risks, including increased possibility of drug–drug interactions, and some drug classes (e.g., ß-blockers) may be contraindicated in patients with COPD, as discussed by Rennard in this issue (pp. 94–100).
Regardless, COPD can be viewed as a systemic disorder, or, chronic bronchitis, airways obstruction, and emphysema may be considered among the list of distinct pathologies that afflict patients with what may be termed chronic smoke-induced systemic inflammatory syndrome, including cardiovascular disease, metabolic disorders, and cancer. Perhaps in the future, new courses of therapy with current drugs and some that are emerging will be developed to treat patients rather than the pulmonary symptoms of COPD.
Pharmaceutical companies have research and development programs aimed at discovering drugs that interfere with some of the targets outlined in this article; however, none of these potential new therapeutic agents will offer major advances over existing treatments in the short-to-medium term (< 5–10 years). In the meantime, it is possible to improve our patients' lives with currently available treatments as part of multimodal individualized management programs that include nonpharmacologic interventions.
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(Received in original form November 7, 2004; accepted in final form January 18, 2005)
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in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 1996;153:530–534.[Abstract]
