The management of COPD has improved markedly over recent years with the combination of more effective drug treatments and non-pharmacological interventions such as pulmonary rehabilitation . Nevertheless, no drug has convincingly shown its ability to reduce disease progression or mortality.
New applications of currently used treatments, based on a better understanding of their mode of action, may improve management in the near future. In the longer term, research into the basic mechanisms of COPD is leading to therapies targeting the inflammatory process and parenchymal destruction that leads to emphysema (Figure 1) , as well as the systemic effects of the disease [3,4].
| || Figure 1. Targets for COPD therapy based on current understanding of pathogenesis. Irritants activate macrophages, which leads to release of cytokines and influx of neutrophils. These cells release proteases, which break down elastic tissue, thus causing emphysema. Oxygen radicals directly from the irritant stimulus, and released by leukocytes, lead to further tissue damage. Activated epithelial cells and alternatively activated macrophages promote tissue repair, which may be disordered and lead to small airway fibrosis. |
However, drug development in COPD is a challenge because few satisfactory animal models can be used in early drug testing and there is uncertainty as to the best outcome measures to use in clinical trials [5,6]. In addition, clinical trial recruitment may be problematic due to patient comorbidities. Despite these difficulties, evidence of progress in the field of COPD management justifies an optimistic attitude regarding the future for patients with the condition. This review is not meant to be extensive but it nevertheless outlines some of the potential strategies that are currently being explored in the management of COPD.
NEW APPLICATIONS FOR CURRENT TREATMENTS
There has been considerable interest in the mechanism of action of long-acting β2-agonists (LABAs), particularly with respect to their anti-inflammatory potential . Salmeterol has been shown to reduce neutrophil numbers in bronchial biopsies, suggesting a possible effect on neutrophil chemotaxis, and to reduce the amount of airway eosinophilic infiltrate [8,9]. However, a clinical trial did not show any major change in sputum eosinophil counts with salmeterol, even though clinical measures did improve . The authors proposed that salmeterol caused increased size selectivity of the respiratory membrane, a property that is lost when inflammation is present . This is in keeping with animal models that show anti-exudative properties of LABAs [12,13]. LABAs may thus reduce inflammation through their effect on microvascular leakage, and a possible reduction in neutrophil and eosinophil infiltration.
Other potential non-bronchodilatory actions include increased mucociliary clearance [14-17] and reduction in the damage caused by Pseudomonas spp [18,19]. A reduction in both the loss of ciliated cells and cell damage was seen when using salmeterol on Haemophilus influenzae-infected mucosa . These effects might account for the reduction in exacerbations with salmeterol [21,22]. These concepts are outlined in Figure 2.
| || Figure 2. Non-bronchodilatory actions of LABAs. |
There is some evidence that this class of drugs also has anti-inflammatory properties due to its effects on neutrophils, macrophages and T-lymphocytes . One study describes a lymphoid cholinergic system that may influence immune function and which could explain these observations . The enzyme choline acetyltransferase is expressed by non-neuronal cells, including airway epithelial cells; it synthesizes acetylcholine, which is increased in inflammatory disease , possibly because inflammatory mediators such as TNF-α amplify the expression of choline acetyltransferase . This may partly explain the efficacy of long-acting anti-cholinergic drugs in preventing exacerbations when inflammation increases .
Recent interest in this drug has centered on possible anti inflammatory effects and the potential to restore steroid responsiveness . It has been used primarily for bronchodilation, which occurs at concentrations greater than 10 mg/L. There is evidence of a beneficial effect below 10 mg/L, particularly in patients with COPD, where lowdose theophylline reduces the neutrophil content of induced sputum, the neutrophil chemotactic response and the concentration of interleukin (IL)-8 - all of which reflect airway inflammation . A similar study in Japan showed a decrease in sputum concentrations of neutrophil elastase and myeloperoxidase after 4 weeks of treatment with 400mg/day of theophylline . However, both of these studies were small and the clinical benefits of these changes in inflammation have yet to be determined.
The molecular mechanism behind the anti-inflammatory effect of theophylline may be the activation of histone deacetylase (HDAC) . Histone acetylation is associated with activation and transcription of inflammatory genes and is reversed by HDAC, leading to down-regulation of the inflammatory cascade . HDAC activity is reduced in the bronchi, peripheral lung and alveolar macrophages of patients with COPD, but can be restored to normal by theophylline . The same mechanism contributes to the restoration of steroid responsiveness as corticosteroids exert their anti-inflammatory effect by reducing the expression of inflammatory genes, via recruitment of HDAC2 by the glucocorticoid receptor. This in turn reverses histone acetylation, down-regulating inflammatory genes . Thus, when HDAC levels are low, steroid effects will be reduced. However, since theophylline increases HDAC it should also improve the response to steroids.
The reasons for low HDAC levels in COPD are not yet fully understood, but may relate to oxidative and nitrative stress, which leads to increased tyrosine nitration of HDAC2. This process allows them to be broken down by the proteasome, thus reducing HDAC levels . Many studies have shown an increased oxidant burden in patients with COPD, the results of which have been summarized elsewhere .
One limitation to the use of theophylline is side effects, though these usually occur at high doses. Adenosine receptor antagonism causes some adverse events, such as arrhythmias, and can be avoided by the use of selective phosphodiesterase (PDE) inhibitors (we will return to this later) . Nevertheless, the more common side effects of nausea and headache, which are mediated by PDE, still occur with more selective inhibitors, so further research into the use of low-dose theophylline may be of benefit. These concepts are summarized in Figure 3.
| ||Figure 3. The HDAC Pathway. Histone deacetylase-2 (HDAC2) decreases histone acetylation, leading to decreased expression of pro-inflammatory genes, and hence less local damage due to inflammation. In COPD, oxidative stress decreases HDAC2 so more inflammation could occur. Theophylline acts to increase HDAC2, thus restoring the pathway to its usual action. Glucocorticoids also act via HDAC2 to decrease histone acetylation, and theophylline may thus improve the response to steroids. |
Macrolide antibiotics have anti-inflammatory effects in vitro [36,37]. Neutrophil degranulation and the oxidative burst response to particulate matter were enhanced byazithromycin, and a continuous fall in IL-8, IL-6 and human growth related oncogene-α was observed for 28 days after dosing had ended . The latter phase was associated with an increase in neutrophil apoptosis, suggesting a curtailment of local inflammation and clearing of potentially damaging mediators. Some macrolides have also been shown to inhibit neutrophil elastase (NE), a protease implicated in the pathogenesis of emphysema, which means they would also reduce parenchymal destruction .
Clinical studies of diffuse panbronchiolitis and cystic fibrosis have shown a benefit of macrolides beyond that expected from their anti-bacterial action [40,41-43]. A recent study of COPD showed a tendency for inflammatory markers to decrease, though the effect observed was less than in healthy volunteers [38,44]. However, clarithromycin did not change sputum neutrophil count, IL-8 or TNF-α levels, though there was a small reduction in neutrophil chemotaxis . Unfortunately, in a further study by the same group this effect did not translate into a reduction in exacerbations or an improvement in health status . This study was small and other trials will be needed to determine any clinical benefit of long-term macrolide treatment.
TARGETING COPD PATHOGENESIS
It is generally accepted that COPD is associated with an abnormal inflammatory response . Therefore, it is possible to believe that prevention and reduction of progression will occur if this inflammatory response were to be adequately controlled. The main advance in this area has been the development of phosphodiesterase-4 (PDE4) inhibitors, which have shown promising results in initial trials [48-52]. PDE-4 is the predominant isoform expressed in neutrophils, monocytes, CD4+ and CD8+ cells . It is also present in macrophages, airway smooth muscle and epithelial cells, thus presenting many sites for therapeutic inhibition in COPD . Animal models of neutrophilic inflammation have confirmed that PDE-4 inhibitors suppress this process [55-57].
The first large study of patients with COPD used cilomilast, and showed a mean improvement in FEV1 o f 160 mL (p < .0001) after treatment for 6 weeks . A subsequent study examined airway inflammation using induced sputum and bronchial biopsies . Although this did not show any change in sputum, there was a significant decrease in CD8+ (p = .001) and CD68+ (p = .04) cells in the biopsies. A third randomized controlled trial (RCT) of 647 subjects with COPD over 24 weeks showed a stabilization of FEV1 decline, an improvement in health status (p < .001) and a reduction in exacerbations (p = .002) . The largest RCT to date (1157 patients with COPD) showed an increase in FEV1 relative to placebo although there was no improvement in health status or exacerbation rate .
This series of clinical trials suggests that PDE-4 inhibitors may have a role in the treatment of COPD in the future, though it should be noted that many patients experienced side effects. Whether the benefits so far reflect an anti-inflammatory or bronchodilator effect, or both, remains to be determined.
There are many mediators of the inflammatory process in COPD, some of which have been investigated as therapeutic targets .
Leukotriene B4 inhibitors
Leukotriene (LT) B4 attracts and activates neutrophils through its interaction with the high-affinity receptor BLT1. It is present in high concentrations in the sputum of COPD patients , especially during exacerbations [60,61] and acts as the main neutrophil chemoattractant in the airways of COPD patients with α1-antitrypsin deficiency . This pro-inflammatory pathway has been targeted by a BLT1 antagonist (LY293111); an in vitro study showed some benefit by reducing neutrophil chemotaxis . Animal studies showed suppression of pulmonary inflammation , although studies in humans have been limited by dose-related side effects .
LTB4 is synthesized by 5-lipoxygenase (5-LO), therefore drugs that block 5-LO, or its activating protein (FLAP) would also reduce the level of LTB4-induced inflammation. This was evaluated in a trial of several drugsactive within the leukotriene synthesis pathway - SB201146 is an LTB4 antagonist, BWA4C inhibits 5-LO, and MLK886 blocks FLAP - all resulting in decreased neutrophil survival in human blood . A phase II RCT of a 5-LO inhibitor in patients with COPD showed a modest reduction in sputum inflammation, but further large trials are needed to see if this translates into a clinical benefit .
Transforming Growth Factor β inhibitors
Transforming growth factor β1 (TGF-β1) is highly expressed in the epithelium of the small airways in smokers and patients with COPD and has a role in recruiting macrophages and mast cells to the airways in COPD [68,69]. It is both a potent fibrogenic mediator, such that it may contribute to the narrowing of peripheral airways in COPD , and an inducer of the elastolytic enzyme matrix metalloproteinase-9 (MMP-9), which may add to the parenchymal destruction that results in emphysema . Inhibition of TGF-β1 might therefore be a potential therapy for COPD.
Several chemokines are involved in the recruitment of inflammatory cells to the airway; blocking their action might therefore reduce airway inflammation . IL-8 is a chemokine found in the sputum of patients with emphysema that correlates with disease severity . IL-8 binds to a high-affinity receptor (CXCR2) and a low-affinity receptor (CXCR1). The former is expressed on monocytes and is up-regulated during COPD exacerbations . Blockade of this receptor might therefore prove useful in COPD; a new drug (SB225002) has been developed and will soon enter clinical trials . A compound that antagonizes both CXCR1 and 2 has also shown promise in an animal model . However, a phase II RCT of a monoclonal antibody blocking IL-8 in patients with COPD showed no difference in lung function or health status, though there was an improvement in dyspnea .
Nuclear factor kappa β (NFκβ) is a transcription factor that regulates the expression of IL-8, some other chemokines and selected MMPs and hence is thought to be central to the pathogenesis of COPD. Small molecules can block the inhibitor of κβ2 and a rat model has been used to test such a compound (TPCA-1). This reduced inflammatory mediators, with subgroups of responders and non-responders to steroid suppression of inflammation . This approach may be of central importance in preventing the development or progression of COPD. However, mice that lack NFκβ genes die from serious infections, suggesting it is key to immune surveillance, which may affect the safety of this approach .
Oxidative stress is increased in patients with COPD and is believed to contribute to its pathophysiology . N-acetyl cysteine (NAC) is the most widely studied antioxidant in COPD. A systematic review showed a slight reduction in exacerbations  but a large subsequent RCT did not show any significant benefit for lung function or exacerbations . Resveratrol is a component of red wine that has antioxidant properties, and has been shown to reduce cytokine release from macrophages in bronchoalveolar lavage fluid of COPD patients, suggesting a potential benefit . However, its low bioavailability would require that related compounds or an inhaled formulation be developed for it to be clinically useful.
The predominant pathogenic theory in COPD has been the balance between proteases, which digest elastin and otherstructural proteins, and anti-proteases that protect against this process in the lung . Blocking a protease might help to reduce parenchymal destruction, but the involvement of large numbers of different enzymes may indicate that any specific effect would be small. NE is a serine protease which is inhibited by α1-antitrypsin (AAT) in normal lungs. It would be predicted that NE is central to the development of COPD in AAT deficiency (AATD) since AAT is a major inhibitor of this enzyme. Indeed, increasing AAT in these patients does reduce inflammation . However, no suitably powered RCT has yet been completed so the benefits in patients remain unknown . Other inhibitors of NE have been developed and show promise in animal models [83-85]; one of these has progressed to a clinical trial and does not show any effect on markers of lung destruction .
Some matrix metalloproteinases (MMPs) also have elastolytic activity and are a potential target for drug development. To date, one non-selective MMP inhibitor (marimastat) has been tested extensively in malignant disease, but frequent musculoskeletal side effects limit its use . A small trial with asthma patients using the same drug showed a reduction in airway hyperresponsiveness but no effect on symptoms or FEV1 . Further investigation and trials will be needed before this class of drug may be considered useful in COPD.
Over the past 10 years there has been increasing interest in strategies directed at alveolar surface area restoration . Retinoids have received the most attention, since they have been shown to repair elastase-induced emphysema in rats . Two small trials of all-trans retinoic acid with this model have been reported, showing beneficial effects on markers of protease/antiprotease balance, but no significant clinical effects because the studies were not appropriately powered [91,92]. However, the drug was well tolerated and larger and more specific trials are now underway.
Interventions affecting systemic disease
Systemic effects of COPD, such as cachexia and muscle wasting, are well recognized as playing a significant role in the morbidity and mortality of affected patients . Factors contributing to such effects include inactivity, malnutrition and hypoxia.
Anti-Tumor Necrosis Factor treatment
Elevated serum tumor necrosis factor α (TNF-α) levels are common in nutritionally depleted COPD patients, and TNF-α is thought to play a central role in both the respiratory and systemic components of the disease [93,94]. Skeletal muscle apoptosis may be related to TNF-α release, hence anti-TNF drugs could block this process . This class of drug is well established in the treatment of other inflammatory diseases, such as rheumatoid arthritis, and infliximab has recently been studied in COPD . However, there were no beneficial effects, though this may have been because all participants were current smokers - smoking attenuates the response to the drug .
Therapies that influence muscle mass and function
Nutritional supplementation increases body weight in COPD , as does megestrol acetate , though it does not improve lean muscle mass. Low androgen levels have been linked to quadriceps muscle weakness in men with COPD . In support of this, an RCT of testosterone injections in men with COPD and low testosterone levels was undertaken as part of a pulmonary rehabilitation program and showed an improvement in muscle mass in the treatment group . A study of subjects with normal testosterone levels but without COPD showed a similar increase in muscle mass, without any significant adverse events . This suggests that androgen supplementation may help to improve muscle mass in male COPD patients, regardless of their testosterone level. Anabolic steroids are used for the same reason by some athletes and have been studied in male patients with COPD, showing slight benefits . Skeletal muscle dysfunction has also been linked to NFκβ activation, so inhibitors of this pathway might also improve this feature of the disease .
Interventions for secondary pulmonary hypertension
Clinically significant pulmonary hypertension (PH) has a prevalence of 1-2 per 1000 patients with severe COPD and is thought to occur due to pulmonary vascular remodeling and vasoconstriction . The latter may occur secondary to hypoxia, but vascular changes are also seen in smokers without evidence of airflow limitation, therefore other mechanisms must be involved . Some of the treatments used for PH associated with idiopathic and connective tissue disease have been tested in COPD.
Inhaled nitric oxide administered alongside oxygen continuously for a period of 3 months reduced PH and improved exercise tolerance in COPD . Prostacyclin infusions have been tested in patients with COPD and acute respiratory failure requiring mechanical ventilation, but this did not demonstrate any benefit . Sildenafil, a PDE5 inhibitor, was used in a pilot study of patients with severe COPD, resulting in an improvement in exercise capacity and a reduction in pulmonary vascular resistance in 6 out of 7 patients . There are theoretical reasons why endothelin-1 (ET-1) receptor antagonists might also help patients with COPD and pulmonary hypertension, since there is increased expression of ET-1 around the pulmonary vasculature of patients with COPD and PH, but these agents have yet to be tested in this patient group .
The expanding research in COPD continues to support the role of inflammation and tissue damage in disease progression. Basic and clinical research studies are dissecting the pathways involved, thus raising the possibility of specific therapeutic strategies. The major deterrent has been the identification of accepted endpoints for phase II and III studies, though this is being addressed for future interventions so that they may evaluate all important aspects in the development and progression of COPD.
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