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Keywords:

  • chronic obstructive pulmonary disease;
  • exacerbations;
  • macrophage;
  • phagocytosis;
  • macrolides

Chronic obstructive pulmonary disease (COPD) represents one of the major causes of mortality and morbidity worldwide. The pathogenesis of COPD is complex and multifactorial and is mediated by both pulmonary and systemic factors.1 Patients with COPD suffer frequent exacerbations that require medical intervention. Typically, exacerbations manifest as increased sputum production, more purulent sputum, an increase in airway obstruction and worsening of dyspnoea.2 Patients do not fully recover from these events, and the severity of disease progressively deteriorates. Exacerbations of COPD are frequently induced by bacterial and viral infection, and lower airway colonization is associated with increased disease severity and frequency of exacerbations.3 The ability to prevent or treat infectious exacerbations and airway colonization has the potential to substantially improve the disease course and the quality of life of COPD patients.

A number of treatments are used to relieve the symptoms of COPD, which include anticholinergic bronchodilators, short- and long-acting β-agonists, methylxanthines (e.g. theophylline), and glucocorticoids. These treatments can be used singularly or in combination but fail to modify the factors that initiate and drive the long-term progression of disease or infectious exacerbations/colonization.4–6

Macrophages are phagocytic cells that are important in the clearance of pathogens. Macrophages, particularly alveolar macrophages (AM), have reduced function and play an important role in exacerbations of COPD.7 In COPD patients, they have a limited capacity to phagocytose bacteria8–12 and exhibit reduced efferocytosis. Efferocytosis is the process by which apoptotic cells are removed by phagocytic cells, predominantly macrophages, and is a major factor in the resolution of inflammation. Hodge et al. have previously demonstrated an important link between reduced efferocytosis and COPD pathogenesis.13,14 They demonstrated that a reduction in efferocytosis by macrophages leads to an impaired ability to clear cell debris and infection, and thus contributes to COPD exacerbations. However, while they have demonstrated reversal of efferocytosis with procysteine,15 the efficacy of currently used treatments has not been demonstrated. In this issue of Respirology, Hodge and Reynolds16 isolated AM and monocyte-derived macrophages from patients with COPD and demonstrated that both these cell types have reduced phagocytosis and efferocytosis. Importantly, they also showed that this deficiency can be reversed by oral treatment with low doses of the macrolide antibiotic azithromycin, indicating its potential use as an adjunct treatment.

Macrolide antibiotics are effective against bacterial infections and are both bacteriostatic and bacteriolytic. They also have anti-inflammatory properties and exert immunomodulatory effects through a number of different mechanisms, although these have yet to be fully defined. They suppress a number of pro-inflammatory processes including the expression of cytokines, such as interleukin-1β, interleukin-4, interleukin-6, interleukin-8, granulocyte-macrophage-colony stimulating factor, and tumour necrosis factor-α and -γ.17 They also inhibit tissue damage and the destruction of the extracellular matrix through the reduction of the release of superoxides, elastase and matrix metalloproteinase-9 from various cells. They can also attenuate the recruitment of neutrophils and therefore the damage associated with their influx.18–20 Azithromycin also increases transepithelial electrical resistance by changing the processing of tight junction proteins, which was not observed with penicillin or erythromycin treatment.21 Because of these properties, macrolides have also been used in the treatment of lung disease and have shown benefit in diffuse panbronchiolitis,22 cystic fibrosis23 and bronchiolitis obliterans syndrome following lung transplantation.24 Their beneficial effects are due in part to their widespread diffusion in the lung, efficacy in suppressing symptoms and exacerbations,25 and a reduced propensity to induce allergic responses compared with penicillins and cephalosporins.26 Long-term treatment however is not without risk, as continuous use can result in the development of macrolide resistance by bacteria.27 Previous studies that have investigated the use of macrolides in COPD have indicated positive clinical and biological effects. Gomez et al.28 showed that in 94 azithromycin-treated patients, both exacerbations and hospitalizations were reduced. In a larger study by Albert et al.,29 570 subjects received azithromycin (250 mg daily) for 1 year, with no change to their regular treatment, and their disease exacerbations were compared with 572 placebo controls. The median time to the first exacerbation was 266 days among participants receiving azithromycin compared with 174 days among participants receiving placebo (P < 0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group compared with 1.83 per patient-year in the placebo group (P = 0.01). However, previous studies have not indicated a potential mode of action of the beneficial effects of macrolides in COPD.

Hodge et al.14 previously showed that azithromycin improves the ability of AM to phagocytose apoptotic cells and reduce local and systemic inflammation in COPD patients. The study by these authors in this issue demonstrates another important property of azithromycin that may be beneficial in COPD, which it can reverse the reduced ability of both AM and monocyte-derived macrophages to clear bacteria and necrotic cellular debris, which can contribute to inflammation and secondary necrosis. This supports their previous data showing that macrophages from COPD patients have reduced expression of surface molecules important in bacterial clearance, such as the macrophage mannose receptor, and that expression can be increased by azithromycin.14

The current study also demonstrates that azithromycin enhances the ability of systemic macrophages to clear apoptotic bronchial epithelial cells, which was similar to that observed with AM. This shows that assessment of monocyte-derived macrophages rather than airway-derived AM may be an effective way of monitoring potential changes in phagocytosis induced by macrolides. More broadly, this method of testing systemically derived macrophages may be useful as a marker during the course of other COPD treatments in determining the effect on phagocytosis of AM.

Other macrolides have been trialled for various diseases and exhibit differing beneficial effects with azithromycin, for example affecting quorum sensing.30 This highlights the importance of determining the mechanisms of action for individual macrolides, which would indicate their specific applicability for use in different diseases or for treatment of different levels of severity. Because significantly higher levels of bacteria are associated with more acute exacerbations31 and infections are associated with more severe exacerbations,2,3 it is likely that macrolides may have the most benefit in moderate-to-severe disease. Thus, different macrolides may be more effective in different individuals and suggesting that personalized treatment may be the most efficacious use of macrolides in COPD.

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