INTRODUCTION

TOP ABSTRACT INTRODUCTION NEW BRONCHODILATORS SMOKING CESSATION MEDIATOR ANTAGONISTS NEW ANTIINFLAMMATORY TREATMENTS PROTEASE INHIBITORS MUCOREGULATORS ALVEOLAR REPAIR ROUTE OF DELIVERY FUTURE DIRECTIONS REFERENCES

In sharp contrast to the developments in understanding and treating asthma, chronic obstructive pulmonary disease (COPD) has received little attention and there are few new drugs in development for this important disease. There are several possible reasons for the lack of drug development for this disease. First, COPD has been perceived as "untreatable" fixed airflow obstruction. Second, patients with COPD have been treated with antiasthma therapies, but these drugs may be inappropriate in a disease with a different pathophysiology. Third, since in most patients COPD is the result of long-term heavy cigarette smoking it has been felt to be the "fault" of the patient. Fourth, there has been little interest in investigating the molecular and cell biology of COPD to identify new therapeutic targets, and there are no satisfactory animal models for early drug testing. Last, there are uncertainties about how to test new drugs for COPD, which may require long-term studies in large numbers of patients and surrogate markers (currently lacking) to monitor the short-term efficacy of new treatments. However, some progress is underway and there are several classes of drug that are now in preclinical and clinical development (1, 2).

	NEW BRONCHODILATORS

TOP ABSTRACT INTRODUCTION NEW BRONCHODILATORS SMOKING CESSATION MEDIATOR ANTAGONISTS NEW ANTIINFLAMMATORY TREATMENTS PROTEASE INHIBITORS MUCOREGULATORS ALVEOLAR REPAIR ROUTE OF DELIVERY FUTURE DIRECTIONS REFERENCES

Bronchodilators are the mainstay of current management of COPD, but fail to alter the progression of COPD. The major advances have been in the development of long-acting bronchodilators. Both long-acting inhaled ₂ agonists (salmeterol and formoterol) and long-acting oral ₂ agonists (bambuterol) are useful for symptom control in COPD. Anticholinergics have been the most effective bronchodilators in COPD and there have been some important developments on this area. With the recognition that there are different subtypes of muscarinic receptor, there has been a search for more selective antagonists that inhibit M₁ receptors, which facilitate cholinergic reflexes, and M₃ receptors, which mediate bronchoconstriction and secretion of mucus, but avoid blockade of M₂ receptors localized to cholinergic nerve terminals that may increase acetylcholine release and therefore enhance cholinergic reflexes. It has been difficult to find selective M₃ antagonists, but drugs selective for M₁ and M₃ receptors, such as revatropate (UK-112,166), are in development for COPD (3). The most interesting anticholinergic drug in development is tiotropium bromide.

Tiotropium Bromide

Tiotropium bromide (Ba 679) is a quaternary ammonium compound similar in structure to ipratropium bromide, but with the unique property of kinetic selectivity, with rapid dissociation from M₂ receptors and slow dissociation from M₁ and M₃ receptors (4). However, its most interesting property is its long duration of action in vitro and in vivo. A single dose protects against cholinergic challenge for > 72 h and provides bronchodilatation for > 24 h in patients with COPD (5). Tiotropium is in Phase III clinical trials as a once-daily dry powder inhalation and is more effective than ipratropium bromide given three times daily.

	SMOKING CESSATION

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Quitting smoking is the only strategy that has so far been shown to reduce the rate of decline in lung function in patients with COPD. Less than one-third of patients are able to give up smoking even with support. Nicotine replacement therapy may help some patients and transdermal patches and inhaled nicotine may be the most effective delivery systems, but continued administration of the addictive principle of cigarettes is a poor approach to smoking cessation and nicotine itself theoretically may have adverse cardiovascular effects. Another approach is to develop nicotine receptor antagonists. The novel antidepressant bupropion (Zyban), which enhances central noradrenergic activity, helps smoking cessation. In a study of bupropion given for 7 wk, smoking cessation was 44% compared with only 19% in the placebo group (6).

	MEDIATOR ANTAGONISTS

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Several inflammatory mediators are likely to be involved in COPD, as many inflammatory cells and structural cells are activated and there is an ongoing inflammatory process, even in patients who have given up smoking. In asthma there are multiple mediators involved (7) and blocking the synthesis or receptors of a single mediator has almost always been unsuccessful in the development of useful therapies. However, some specific inhibitors, notably leukotriene D₄ (LTD₄) antagonists, have had some clinical benefit. It is clear that the profile of mediators of COPD is likely to be different from that of mediators of asthma, so that different drugs may be effective. Since COPD is characterized by a neutrophilic inflammation, attention has focused on mediators involved in recruitment and activation of neutrophils or on reactive oxygen species in view of the oxidative stress in COPD (Table 1).

LTB₄ Inhibitors

LTB₄ is a potent chemoattractant of neutrophils and is increased in the sputum of patients with COPD (8). It is probably derived from alveolar macrophages as well as neutrophil themselves and may be synergistic with interleukin 8 (IL-8). Selective LTB₄ receptor antagonists have now been developed. A potent LTB₄ antagonist (LY 293111) is ineffective against allergen challenge in patients with asthma, although it is interesting that it inhibits neutrophil recruitment into the airways during the late response, indicating the capacity to inhibit neutrophil chemotaxis in the airways (9). Several other potent LTB₄ antagonists are now in development (including SC-53228, CP-105,696, SB 201146, and BIIL284). LTB₄ is synthesized by 5'-lipoxygenase (5-LO), of which there are now several potent inhibitors. 5-LO inhibitors, such as zileuton, are now available in some countries for the treatment of asthma, since they also inhibit the synthesis of cysteinyl-leukotrienes, but it is not certain whether they are effective in COPD.

Chemokine Inhibitors

Several chemokines are involved in neutrophil chemotaxis (10). These belong to the CXC family of chemokines and the most prominent member is IL-8, which is markedly elevated in the sputum of patients with COPD (11). Blocking antibodies to IL-8 and related chemokines inhibit certain types of neutrophilic inflammation in experimental animals, but may not be suited to long-term therapy in humans, so that there has been a search for IL-8 receptor antagonists. IL-8 attracts neutrophils via a high-affinity G protein-coupled receptor (CXCR1) and a common receptor shared by other members of the CXC family (CXCR2). A nonpeptide inhibitor of CXCR2 (SB225002) has been discovered by screening; it blocks the chemotactic response of neutrophils to IL-8 and other CXC chemokines, such as GRO-, which are also increased in COPD (12).

Other chemokines may be involved in COPD. The recruitment of large numbers of activated macrophages (presumably from blood monocytes) may be dependent on CC chemokines such as monocyte chemoattractive peptides (MCP-1 to MCP-5), which activate CC receptors (CCR2) on macrophages (10).

Tumor Necrosis Factor  Inhibitors

Tumor necrosis factor  (TNF-) levels are raised in the sputum of patients with COPD (11) and induces IL-8 in airway cells (13). Humanized TNF antibodies have been developed for clinical use and are effective in other chronic inflammatory disease, such as rheumatoid arthritis and inflammatory bowel disease. Soluble TNF receptors, which sequester released TNF, have also been developed and have entered clinical trials. There may be problems with long-term administration because of the development of blocking antibodies and repeated injections are inconvenient. TNF convertase, which prevents the release of active TNF-, may be a more attractive target because it is possible to discover small molecule inhibitors, some of which are also matrix metalloprotease inhibitors.

Antioxidants

Oxidative stress is increased in patients with COPD, particularly during exacerbations, and reactive oxygen species contribute to its pathophysiology (14). Oxidants are present in cigarette smoke (10¹⁴ molecules per puff) and are produced endogenously by activated inflammatory cells, including neutrophils and alveolar macrophages. This suggests that antioxidants may be of use in the therapy of COPD. N-Acetylcysteine (NAC) provides cysteine for enhanced production of glutathione (GSH) and has antioxidant effects in vitro and in vivo. In clinical studies NAC reduces the number of exacerbations of COPD and in an uncontrolled study appeared to reduce the rate of decline in FEV₁ over a 2-yr period (15). Although epidemiological studies have linked COPD to poor intake of dietary antioxidants, such as vitamins C and E, there have been no controlled trials of these vitamins in COPD. It is likely that more effective antioxidants will be developed for clinical use in future. Spin-trap antioxidants, such as -phenyl- N-tert-butyl nitrone, are much more potent and inhibit intracellular reactive oxygen species formation by forming stable compounds (16).

Prostanoid Inhibitors

Oxidative stress may result in the nonenzymatic formation of prostanoid mediators, isoprostanes, directly from arachidonic acid without the involvement of cyclooxygenase. There is increased formation of isoprostanes in COPD (17). The most abundant isoprostane, 8-iso-prostaglandin F₂, is a potent constrictor of human airways in vitro, acting partly via stimulation of thromboxane prostanoid (TP) receptors (18). This suggests that thromboxane receptor antagonists, such as seratrodast and Bay u3405, might be beneficial in COPD. The role of prostaglandins in COPD is unknown. In patients with bronchiectasis indomethacin has an inhibitory effect on chemotaxis of peripheral neutrophils, but no effect on neutrophils in sputum (19).

	NEW ANTIINFLAMMATORY TREATMENTS

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COPD is characterized by chronic inflammation of the respiratory tract, even in ex-smokers. Bronchoalveolar lavage and induced sputum in patients with COPD demonstrate increased numbers of neutrophils and macrophages (11). At sites of lung destruction in the lung parenchyma there are increased numbers of macrophages and CD8⁺ (cytotoxic) T lymphocytes and similar changes are seen in the airway walls (20). The mechanisms of the neutrophilic inflammation in COPD are not yet certain, but it is likely that neutrophil chemotactic factors are released into the airways from activated macrophages and possibly from epithelial cells and CD8⁺ T lymphocytes. It is important to elucidate more precisely the molecular and cellular mechanisms of COPD in order to identify novel targets for therapy. Our current superficial understanding of COPD suggests that there may be several approaches (Figure 1).

View larger version (36K): [in this window] [in a new window]   Figure 1.   Targets for COPD therapy, based on current understanding of the inflammatory mechanisms. Cigarette smoke (and other irritants) activate macrophages in the respiratory tract that release neutrophil chemotactic factors, including interleukin 8 (IL-8) and leukotriene B4 (LTB4). Macrophages may recruit and activate other macrophages via other chemokines such as macrophage chemoattractant peptide 1 (MCP-1). These cells then release proteases, such as neutrophil elastase (NE) and matrix metalloproteinases (MMP), that break down connective tissue in the lung parenchyma, resulting in emphysema, and also stimulate hypersecretion of mucus. These enzymes are normally counteracted by protease inhibitors, including 1-antitrypsin (1-AT) and secretory leukoprotease inhibitor (SLPI). Cytotoxic T cells (CD8+) may also be involved in the inflammatory cascade.

The Disappointment of Corticosteroid Therapy

Because there is chronic inflammation in COPD airways it was argued that inhaled corticosteroids might prevent the progression of the disease. The efficacy of corticosteroids in COP is still uncertain, but this very uncertainty implied that they are of little benefit (21). There is little evidence that inhaled corticosteroids are beneficial in COPD, although there may be a minority of patients (~ 10%) who have some response to steroids and these patients should probably be regarded as having concomitant asthma. Several studies of the long-term use of inhaled corticosteroids in slowing disease progression have been reported, confirming that there is no significant benefit. This might be predicted by the demonstration that neither inhaled nor oral corticosteroids have any significant effect on neutrophil counts, granule proteins, or inflammatory cytokines in induced sputum (22). A trivial inhibitory effect on neutrophil chemotaxis and neutrophil elastase activity has been reported, but in another study there was no effect on proteases or antiproteases in induced sputum. This is in marked contrast to the efficacy of corticosteroids in asthma and their ability to reduce eosinophil counts in induced sputum (22). However, corticosteroids are effective in treating acute exacerbations in COPD, presumably via some as yet undefined antiinflammatory effect (23), but possibly related to the fact that there is an increase in eosinophils in the airways during acute exacerbations of COPD. The disappointing action of corticosteroids in COPD suggests that novel types of nonsteroidal antiinflammatory treatment may be needed. One of the reasons that corticosteroids may be ineffective is that they are usually ineffective in neutrophilic inflammation and prolong the survival of neutrophils by delaying apoptosis. Furthermore, corticosteroids fail to inhibit the elevated IL-8 and TNF- levels in induced sputum in patients with COPD, although synthesis of these cytokines would be expected (22). This may indicate that there is an element of corticosteroid resistance in COPD that may be a part of the disease process.

There are several new approaches to antiinflammatory treatment in COPD (Table 2).

Phosphodiesterase 4 Inhibitors

Inhibition of phosphodiesterases (PDEs) increases cyclic AMP content of neutrophils, resulting in reduced chemotaxis, activation, degranulation, and adherence (24). Theophylline is a weak and nonselective PDE inhibitor and has inhibitory effects on neutrophil function in vitro. Unlike corticosteroid treatment in patients with COPD, theophylline reduces neutrophil counts in induced sputum (25). The predominant isoenzyme in inflammatory cells is PDE4, and several PDE4 inhibitors are now in clinical development for asthma. PDE4 inhibitors also inhibit the function of macrophages and CD8⁺ T lymphocytes, which are also involved in the inflammatory process in COPD (Figure 2). Many of the first-generation PDE4 inhibitors have been limited by side effects, particularly nausea. In second-generation PDE4 inhibitors, such as SB 207499, this may be less of a problem and a trial of this drug has shown an improvement in lung function and symptoms of patients with moderate COPD.

View larger version (27K): [in this window] [in a new window]   Figure 2.   Effect of phosphodiesterase 4 (PDE4) inhibitors on the inflammatory process in COPD. PDE4 inhibitors inhibit the activation of macrophages, neutrophils, and CD8+ T lymphocytes.

NF-B Inhibitors

The transcription factor NF-B regulates the expression of IL-8 and TNF- and its inhibition therefore inhibits neutrophilic inflammation (26). There are several possible approaches to inhibition of NF-B, including gene transfer of the inhibitor of NF-B (I-B), a search for inhibitors of I-B kinases (IKK), NF-B-inducing kinase (NIK), and I-B ubiquitin ligase, which regulate the activity of NF-B, and the development of drugs that inhibit the degradation of I-B (27). One concern about this approach is that effective inhibitors of NF-B may result in immune suppression and impair host defenses, since knockout mice who lack NF-B proteins succumb to septicemia.

Adhesion Molecule Blockers

Neutrophil recruitment into the lungs and respiratory tract is dependent on adhesion molecules expressed on neutrophils and endothelial cells in the pulmonary and bronchial circulations. Neutrophil adhesion in response to chemotactic factors is characterized by expression of the ₂ integrins CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1) on the surface of the neutrophil and their interaction with their counterreceptors, including intercellular adhesion molecule 1 (ICAM-1), on endothelial cells. E-selectin on endothelial cells also interacts with sialyl-Lewis^x on neutrophils. Bronchial biopsies of patients with COPD have demonstrated increased expression of E-selectin on vessels and ICAM-1 on epithelial cells (28). Drugs that interfere with these adhesion molecules should therefore inhibit neutrophil inflammation in COPD. Monoclonal antibodies to CD18, ICAM-1, and E-selectin inhibit neutrophil accumulation in animal models of lung inflammation. Small molecule inhibitors of adhesion molecules are now in clinical development. However, there are concerns about this therapeutic approach for a chronic disease, as an impaired neutrophilic response may increase the susceptibility to infection. Indeed, a congenital deficiency of ₂ integrins results in leukocyte adhesion deficiency syndrome, characterized by recurrent septicemia.

Interleukin 10

IL-10 is a cytokine with a wide spectrum of antiinflammatory actions. It inhibits the secretion of TNF- and IL-8 from macrophages, but tips the balance in favor of antiproteases by decreasing the expression of matrix metalloproteinases, while increasing the expression of tissue inhibitors of matrix metalloproteinases (TIMPs) (29). IL-10 is currently in clinical trials for other chronic inflammatory diseases (inflammatory bowel disease, rheumatoid arthritis, and psoriasis), including patients with steroid resistance. Treatment with daily injections of IL-10 over several weeks has been remarkably well tolerated. IL-10 may have therapeutic potential in COPD, especially if a selective activator of IL-10 receptors or signal transduction pathways can be developed. Some currently available drugs, including theophylline and PDE4 inhibitors, may also increase the secretion of IL-10.

p38 MAP Kinase Inhibitors

Mitogen-activated protein (MAP) kinases play a key role in chronic inflammation and several complex enzyme cascades have not been defined (30). One of the p38 MAP kinase pathways is involved in secretion of cytokines, including IL-8 and TNF-. Nonpeptide inhibitors of p38 MAP kinase, such as SB 203580, SB 220025, and RWJ 67657, have now been developed and these drugs have a broad range of antiinflammatory effects.

Other Neutrophil Inhibitors

Prostaglandin E₂ (PGE₂) is a potent inhibitor of the oxidative burst in neutrophils and its effects are mediated via EP₂ receptors. Selective EP₂ agonists, such as misoprostil and butaprost, may therefore be effective in suppressing neutrophil activation, but have not been studied in COPD.

Colchicine potently inhibits neutrophil activation, enzyme release, and chemotaxis by disrupting cyctoskeletal microtubule structure. A controlled trial of colchicine in COPD showed some reduction in neutrophil elastase activity (31).

	PROTEASE INHIBITORS

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There is compelling evidence for an imbalance between proteases that digest elastin (and other structural proteins) and antiproteases that protect against this in COPD. This suggests that either inhibiting these proteolytic enzymes or increasing antiproteases may be beneficial and theoretically should prevent the progression of airflow obstruction in COPD (Table 3). Considerable progress has been made in identifying the enzymes involved in elastolytic activity in emphysema and in characterizing the endogenous antiproteases that counteract this activity.

Neutrophil Elastase Inhibitors

Neutrophil elastase (NE), a neutral serine protease, is a major constituent of lung elastolytic activity. In addition, it potently stimulates secretion of mucus and induces IL-8 release from epithelial cells and therefore may perpetuate the inflammatory state. This has led to a search for neutrophil elastase inhibitors. Peptide NE inhibitors, such as ICI 200355, and nonpeptide inhibitors, such as ONO-5046, have been developed and have high potency (32, 33). These drugs inhibit neutrophil elastase-induced lung injury in experimental animals, whether given by inhalation or systemically (32), and inhibit neutrophil elastase-induced secretion of mucus in vitro. There are few clinical studies of neutrophil elastase in COPD. A clinical study of oral MR889 administered for 4 wk showed no overall effect on plasma elastin-derived peptides or urinary desmosine (markers of elastolytic activity), but these may not be sensitive markers (34). These inhibitors act extracellularly and may not inhibit the enzyme at the site of release when neutrophils adhere to connective tissue. Intracellular NE inhibitors might therefore be more effective, at least in preventing lung destruction. Although neutrophil elastase is likely to be the major mechanism mediating elastolysis in patients with ₁-antitrypsin (₁-AT) deficiency, it may well not be the major elastolytic enzyme in smoking-related COPD, and it is important to consider other enzymes as targets for inhibition.

Cathepsin Inhibitors

Neutrophil elastase is not the only proteolytic enzyme secreted by neutrophils. Cathepsin G and proteinase 3 have elastolytic activity and may need to be inhibited together with neutrophil elastase. Cathepsins (cathepsins B, L, and S) are also released from macrophages. Suramin, a hexasulfonated naphthylurea that has been used as an antitumor drug, is a potent inhibitor of cathepsin G, proteinase 3, and neutrophil elastase (35). Novel and more specific cathepsin inhibitors and now in development.

Matrix Metalloproteinase Inhibitors

Matrix metalloproteinases (MMPs) are a group of more than 20 closely related endopeptidases that are capable of degrading all of the components of the extracellular matrix of lung parenchyma, including elastin, collagen, proteoglycans, laminin, and fibronectin. They are produced by neutrophils, alveolar macrophages, and airway epithelial cells. Increased levels of collagenase (MMP-1) and gelatinase B (MMP-9) have been detected in bronchoalveolar lavage fluid of patients with emphysema. Lavaged macrophages from patients with emphysema express more MMP-9 and MMP-1 than do cells from control subjects, suggesting that these cells, rather than neutrophils, may be the major cellular source (36). Alveolar macrophages also express a unique MMP, macrophage metalloelastase (MMP-12) (37). MMP-12 knockout mice do not develop emphysema and do not show the expected increases in lung macrophages after long-term exposure to cigarette smoke (38). Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of these potent enzymes and several TIMPS have now been characterized. There are several approaches to inhibiting MMPs (39). One approach is to enhance the secretion of TIMPs and another is to inhibit the induction of MMPs in COPD. MMPs may show increased expression with cigarette smoking through induction in response to inflammatory cytokines, oxidants, and other enzymes, such as neutrophil elastase. It may be possible to prevent this induction with specific transcription inhibitors. Another approach is to develop specific enzyme inhibitors. Tetracyclines and hydroxamates, such as batimastat (BB-94) and the orally active marimastat (BB-2516), are nonselective MMP inhibitors. Side effects of such drugs may be a problem in long-term use, however. More selective inhibitors of individual MMPs, such as MMP-9 and MMP-12, are now in development and are likely to be better tolerated in chronic therapy. However, it is still not clear whether there is one predominant MMP in COPD or whether a broad-spectrum inhibitor will be necessary.

₁-Antitrypsin

The association of ₁-AT deficiency with early onset emphysema suggested that this endogenous inhibitor of NE may be of therapeutic benefit in COPD. Cigarette smoking inactivates ₁-AT, resulting in unopposed activity of NE and cathepsins. Extraction of ₁-AT from human plasma is expensive and extracted ₁-antitrypsin is available only in a few countries. This treatment must be given intravenously and has a half-life of only 5 d. This has led to the development of inhaled formulations, but these are inefficient and expensive (40). Recombinant ₁-AT with amino acid substitutions to increase stability may result in a more stable product. Gene therapy is another possibility, using a adenovirus vector or liposomes, but there have been major problems in developing efficient delivery systems. There is a particular problem with gene transfer in ₁-AT deficiency in that large amounts of protein (1-2 g) need to be synthesized each day. Human ₁-AT has now been available for more than 10 yr, but even in patients with severe ₁-AT deficiency and emphysema there is only a marginal effect on the rate of decline in FEV₁ (41). There is no evidence that ₁-AT treatment would halt the progression of COPD and emphysema in patients who have normal plasma concentrations.

Serpins

Other serum protease inhibitors (serpins), such as elafin, may also be important in counteracting elastolytic activity in the lung. Elafin, an elastase-specific inhibitor, is found in bronchoalveolar lavage and is synthesized by epithelial cells in response to inflammatory stimuli (42). Serpins may not be able to inhibit NE at the sites of elastin destruction, owing to tight adherence of the inflammatory cell to connective tissue. Furthermore, these proteins may become inactivated by the inflammatory process and the action of oxidants, so that they may not be able to adequately counteract elastolytic activity in the lung unless used in conjunction with other therapies.

Secretory Leukoprotease Inhibitor

Secretory leukoprotease inhibitor (SLPI) is a 12-kD serpin that appears to be a major inhibitor of elastase activity in the airways. It is secreted by epithelial cells (42) and its secretion is increased by corticosteroids in vitro (43). In vitro recombinant human SLPI is more effective at inhibiting neutrophil-mediated proteolysis than ₁-AT (44). Recombinant human SLPI given by aerosolization increases anti-neutrophil elastase activity in epithelial lining fluid for more than 12 h, indicating potential therapeutic use (45).

	MUCOREGULATORS

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Increased secretion of mucus is found in all patients who smoke heavily, irrespective of airflow obstruction. However, epidemiological data suggest that hypersecretion of mucus is significantly associated with a more rapid decline in FEV₁ and increased hospitalization of patients with COPD (46). This suggests that it may be important to develop drugs that inhibit the hypersecretion of mucus, although it is important to find drugs that do not suppress normal mucous secretion or impair mucociliary clearance. There are several types of mucoregulatory drug in development.

Tachykinin Antagonists

Tachykinins are potent stimulants of mucous secretion from submucosal glands and goblet cells in human and animal airways and act via NK₁ receptors. In animal studies cigarette smoke induces airway secretion of mucus via release of tachykinins from sensory nerves through a local axon reflex mechanism (47). NK₁ antagonists markedly inhibit neurogenic secretion of mucus and may therefore have potential as mucoregulators in cigarette smoke-induced chronic bronchitis. Several potent nonpeptide NK₁ receptor antagonists, such as CP-99,994 and SR 140333, are now in clinical development, and while it is unlikely that they will be useful in asthma, they might have a role as regulators of hypersecretion of mucus in COPD.

Sensory Neuropeptide Release Inhibitors

Another approach to blocking tachykinin-mediated effects is to inhibit the release of tachykinins from sensory nerve endings, via activation of prejunctional receptors (48). Of these receptors, µ-opioid receptors are most effective and the µ-opioid agonist morphine potently inhibits cigarette smoke-induced secretion of mucus in animal airways. In human airways in vitro morphine inhibits secretion of mucus activated via stimulation of sensory nerves. While morphine itself may not be useful as a therapeutic agent because of addiction, peripherally acting opioid agonists that do not cross the blood-brain barrier, such as BW443, might be of use.

Many prejunctional receptors appear to operate via the opening of a common potassium (K⁺) channel, suggesting that K⁺ channel openers may be useful in blocking the secretion of mucus. Openers of ATP-dependent K⁺ channels, such as levcromakalim, have an inhibitory effect on cigarette smoke-induced secretion of mucus in animals.

Mediator and Enzyme Inhibitors

Many mediators stimulate secretion of mucus from submucosal glands and/or goblet cells and may therefore contribute to increased secretion of mucus in COPD. It is unlikely, however, that any mediator antagonists (e.g., anti-leukotrienes) would have a major effect on secretion of mucus. NE and other proteases are potent stimulants of submucosal gland and goblet cell secretion, suggesting that protease inhibitors may have inhibitory effects on secretion of mucus, as well as inhibiting lung destruction. Inhalation of the cyclooxygenase inhibitor indomethacin is reported to reduce hypersecretion of mucus in patients with COPD (49), but long-term trials of COX inhibitors have not yet been undertaken.

MUC Gene Suppressors

Nine MUC genes that encode mucin proteins have already been cloned and many are expressed in human airways. MUC5AC (particularly in goblet cells), MUC5B (particularly in submucosal glands), MUC4, and MUC8 appear to be important in airway mucus. MUC5AC may be upregulated by inflammatory cytokines and inhibited by glucocorticoids (50). It is possible that drugs may be developed that inhibit the abnormally increased expression of MUC genes in COPD, while preserving baseline secretion of MUC2. Such drugs, other than corticosteroids, have not yet been developed.

Mucolytic Agents

Several drugs were developed to reduce viscosity of mucus, thus aiding clearance from the respiratory tract. These drugs include cysteine derivatives such as N-acetylcysteine, methylcysteine, and carbocisteine, which are effective in reducing the viscosity of mucus in vitro, but there is little convincing evidence that they increase clearance of mucus in patients with COPD. DNase also reduces sputum viscosity, particularly when sputum is infected, as DNA is a major determinant of sputum viscosity. Although nebulized recombinant human DNase (dornase alfa) appears to improve the rheological properties of mucus in patients with cystic fibrosis, this has not been reported in COPD. It is possible that more effective mucolytic agents will be developed in future.

Macrolide Antibiotics

Erythromycin inhibits mucin secretion from human airways in vitro and appears to be interactive with corticosteroids (51). This property does not appear to be related to its antibiotic activity and is consistent with other studies demonstrating an inhibitory action of erythromycin on cell secretion. The molecular mechanisms involved in these effects need to be defined and controlled studies in COPD may be indicated.

	ALVEOLAR REPAIR

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Since a major mechanism of airway obstruction in COPD is loss of elastic recoil due to proteolytic destruction of lung parenchyma, it seems unlikely that this could be reversible by drug therapy, although it might be possible to reduce the rate of progression by preventing the inflammatory and enzymatic disease process. It is even possible that drugs might be developed that will stimulate regrowth of alveoli. Retinoic acid increases the number of alveoli in rats and, remarkably, reverses the histological and physiological changes induced by elastase treatment (52). It is not certain whether such alveolar proliferation is possible in adult human lungs, however. Retinoic acid activates intracellular retinoic acid receptors, which act as transcription factors to regulate the expression of many genes. The molecular mechanisms involved, and whether this can be extrapolated to humans, are not yet known. Several retinoic acid receptor subtype agonists have now been developed that may have a greater selectivity for this effect.

Hepatocyte growth factor (HGF, scatter factor) has a major effect on the growth of alveoli in fetal lung (53) and it is possible that in future drugs might be developed that switch on responsiveness to HGF in adult lung or mimic the action of HGF.

	ROUTE OF DELIVERY

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Bronchodilators are currently given via inhalers, either metered dose inhalers or dry powder inhalers, that have been optimized to deliver drugs to the respiratory tract in asthma. But in emphysema the inflammatory process takes place in the lung parenchyma. This implies that if a drug is to be delivered by inhalation it should have a lower mass median diameter, so that there is preferential deposition in the lung periphery. It may be more appropriate to give therapy parenterally, as it will need to reach the lung parenchyma via the pulmonary circulation, but parenteral administration may increase the risk of systemic side effects.

	FUTURE DIRECTIONS

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New drugs for the treatment of COPD are needed. While preventing and quitting smoking is the obvious preferred approach, this has proved to be difficult in the majority of patients. In addition, it is likely that the inflammatory process initiated by cigarette smoking may continue even when smoking has ceased. Furthermore, approximately 10% of patients with COPD are nonsmokers. COPD may be due to other environmental factors (pollutants, passive smoking, other inhaled toxins) or due to developmental changes in the lungs.

Genetic Risk Factors for COPD

It is important to identify the factors that determine why only 10-20% of smokers develop COPD. So far this is little understood, although it is likely that genetic factors are important (54). A clearly established genetic risk factor for COPD is the ZZ allele of the ₁-antitrypsin gene, although heterozygotes may be at slightly increased risk. There is also an association with a polymorphism of the TNF- gene (TNF2) that is associated with greater inducibility of TNF-. There are also weak associations with ₁-antichymotrypsin, ₂-macroglobulin, and vitamin D-binding protein. A polymorphism in the gene for an enzyme, microsomal epoxide hydrolase, that is responsible for metabolism of reactive epoxide intermediates, which may be generated in tobacco smoke, has been associated with a four- to fivefold increased risk of COPD and emphysema. It is likely that many other genetic polymorphisms will be discovered that will confer risk on smokers for the development of COPD and emphysema, so that it will eventually be possible to identify at-risk patients and focus more effective therapies on these patients before lung function becomes too impaired.

Identification of Novel Therapeutic Targets

Identification of genes that predispose to the development of COPD in smokers may identify novel therapeutic targets. Powerful techniques, including high-density oligonucleotide arrays (gene chips), are able to identify multiple polymorphisms; differential display may identify the expression of novel genes and proteomics of novel proteins expressed.

Early Detection of Disease

Since at the moment COPD is irreversible and slowly progressive it will become ever more important, as effective therapies emerge, to identify early cases before symptoms develop.

Surrogate Markers

Several drugs now in development may be useful in COPD. These include LTB₄ antagonists and 5-LO inhibitors, PDE4 inhibitors, new antioxidants, and NE and MMP inhibitors. It will be difficult to demonstrate the efficacy of such treatments, as determination of the effect of any drug on the rate of decline in lung function will require large studies over at least 2 yr. There is an urgent need to develop surrogate markers, such as in the analysis of sputum parameters (cells, mediators, enzymes), that may predict the clinical usefulness of such drugs. More research on the basic cellular and molecular mechanism of COPD and emphysema is urgently needed to aid the logical development of new therapies for this common and important disease for which no effective preventative treatments currently exist.