Antibiotics as immunomodulant agents in COPD

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It is widely accepted that some antibiotics have activities beyond their direct antibacterial effects. Macrolide is the antibiotic class with more convincing studies and evidence on its immunomodulatory and anti-inflammatory activities. Different clinical studies have shown that macrolide prophylaxis in patients with moderate-severe chronic obstructive pulmonary disease (COPD) can have a significant impact on the exacerbation rate reducing morbidity and, potentially, mortality of the disease. Other antibiotics, such as fluoroquinolones, demonstrate a variety of immunomodulatory effects but only few clinical data are available in COPD. New macrolide derivatives devoid of antibacterial activity have been synthetized. This review analyses the relevance of immunomodulatory and anti-inflammatory effects of antibiotics in the management of COPD.

Highlights

► Immunomodulatory effects of antibiotics related to their proper antibacterial activity. ► Activity of macrolides on innate and adaptive immunities important in COPD. ► Antibiotic prophylaxis in COPD patients with severe disease and chronic bronchitis phenotype. ► Side effects and antibiotic resistance critical in antibiotic prophylaxis. ► New opportunities from new antibiotic-derived drugs devoid of anti-bacterial activity.

Introduction

Chronic obstructive pulmonary disease (COPD) affects more than 210 million people worldwide, with a prevalence of over 10% in people over age of 40 years, accounting for 3–8% of total deaths in high-income countries and 4–9% of total deaths in low-income and middle-income countries [1]. The estimated direct and indirect costs of COPD were around US$ 2.1 trillion in 2010 with a foreseen economic burden rising to US$ 4.8 trillion in 2030 [2].

Notwithstanding this important health and social impact there have been few major advances in the drug management of the disease, mainly due to the still incomplete understanding of the pathogenesis and basic mechanisms of COPD.

Inflammation and immune response seem to play an important role in the pathogenesis of COPD particularly in the late phase of the disease and in the chronic bronchitis phenotype [3, 4]. COPD is characterised by an alteration of cell populations in the airways and in the deep lung that correlates with abnormal tissue repair and remodelling processes and with lung function decline [5, 6, 7].

Moreover, COPD, and particularly its chronic bronchitis phenotype, has mucus hypersecretion as a key presenting symptom playing a possible role in the natural history of the disease and actually being one of the drug targets in COPD management [8].

Aim of this review is to analyse the evidence on the possible role of antibiotics in modulating the immune responses in COPD, reducing inflammatory responses and exacerbation rate.

Inflammation in COPD is relatively steroid-resistant with a poor response of airway inflammation to steroids probably related to a decreased histone deacetylase activity [9, 10], even if some effects of steroids on vascular remodelling has been recently reported [11].

Both innate and adaptive immune responses play a role in the pathogenesis of COPD. Macrophages and neutrophils are the primary causes of pulmonary damage in COPD. The release of metalloproteinases by these cells correlates with the degradation of extracellular matrix and lung parenchyma damage. Neutrophil production of chemokines, like CXCL8, induces an increase of mucus production [12]. Adaptive immune responses including activation of B-cells and T-cells have been demonstrated in COPD and a possible autoimmune process, generated by the response to antigen derived from elastin degradation, is under scrutiny [13, 14•].

New approaches alternative to steroids for the control of inflammation in COPD are currently in development [15].

Chronic mucus production is a well-known risk factor favouring bacterial colonization and infection in COPD. Moreover, chronic bronchitis phenotype is related to a worse outcome. Vestbo et al. demonstrated, in a large epidemiologic study, that mucus hyperproduction was significantly associated with a faster pulmonary function decline and increase number of exacerbations [16]. These results were lately confirmed by other studies showing that chronic bronchitis phenotype, in different subset of patients, was related to higher incidence of the disease and a worsening of the natural history of chronic airflow obstruction [17, 18].

Recently, different trials have shown that chronic bronchitis phenotype correlates with a better response to antibiotic prophylaxis [19, 20•, 21, 22••, 23].

These data confirm the need to better elucidate the pathophysiology of COPD and open new insights in the possible role of antibiotic activity both antibacterial and non-antibacterial in the natural history of the disease.

Macrolides have direct antibacterial activity that includes Gram positive and negative bacteria and atypicals, like Legionella spp., Mycoplasma and Chlamydia spp. The antimicrobial activity of macrolides results from the inhibition of RNA-dependent protein synthesis by reversibly binding to the P site on the 50S subunit of bacterial ribosomes and inhibiting transpeptidation or translocation of nascent peptides.

Both Haemophilus influenzae and Chlamydophila pneumoniae chronic infections have been linked to COPD severity and exacerbation rate [24, 25, 26, 27, 28].

Macrolide antimicrobial coverage, with possible bacteria eradication or bacterial load reduction, may explain part of the anti-inflammatory activity and the long-term effects on exacerbation rate demonstrated by the clinical studies. However, macrolides have many other non-antibiotic effects ranging from anti-inflammatory activity and immune response modulation to reduction of mucus hypersecretion (Table 1).

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    Effects on airways inflammation

Macrolides act on the inflammatory cascade modulating/reducing the production and concentrations of different pro-inflammatory cytokines, including IL-1, IL-6, IL-8 and TNFα. This activity seems to be mainly related to a suppressive activity of transcription factors such as activator protein 1 (AP1) and nuclear factor-kB (NFkB) [29, 30].

Reduced exposure of the airways epithelial cells to inflammatory mediators leads to protective effects against epithelial damage and ciliary dysfunction that can be important in improving the epithelial ‘mechanical’ barrier against exogenous attacks [31, 32, 33].

Macrolides also induce a reduction of epithelial and endothelial expression of adhesion molecules, like ICAM-1 and VCAM-1, decreasing the leukocytes adhesion and recruitment. This reduction can have an indirect effect on inflammatory responses [34, 35].

Few data also indicate that macrolide can influence the toll-like receptors, mainly TLR4, expression and activity, even if it is still unclear if and how this activity can determine a reduction of inflammation or have an impact on the immune response [36].

COPD is a disease where several disruptions of innate and adaptive lung defences occur: impairment of mucociliary clearance, reduction in airway antimicrobial polypeptides, and impaired alveolar macrophage, neutrophil and lymphocyte functions. In this situation chronic infection of the airways becomes a frequent finding, and bacteria and microbial antigens can perpetuate, either directly or indirectly, inflammation of the airways and lung parenchyma, inducing the so called vicious circle of infection and inflammation [37].

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    Macrophages

Alveolar macrophages play an important role in the innate immune response to infections and are also involved in the removal of debris and apoptotic cells after inflammatory injury. Macrolides have different activities on these cells: enhance phagocytosis of apoptotic cells, thus reducing further inflammatory responses related to cell necrosis; alter macrophage phenotype and pulmonary compartmentalization during lung infection, leading to a reduced inflammatory response, maintaining the bacterial clearance; and promote monocyte-to-macrophage differentiation, increasing the number of active macrophages with an enhancement of their cytocidal activity, as demonstrated in COPD [38, 39•, 40].

Emphysema is one of the distinct features of COPD and macrophages are directly involved in the degradation of extracellular matrix components and induction of emphysema by the production of metalloproteinases, such as MMP-9 and MMP-12, and other proteases [41, 42, 43].

In an animal model of smoke-induced emphysema, macrolides prevent emphysema by modulating lung inflammation in mice [44]. Clarithromycin, at low dose for six months, suppresses chemotactic factor production and proteases, including MMPs, elastases and cathepsins, that promote the destruction of alveolar walls. These results support the possibility that macrolides may provide a new therapeutic approach for pulmonary emphysema. This conclusion is also supported by the fact that macrolide treatment slows and stabilizes the ongoing process of inflammation more effectively than smoking cessation in smoke-exposed mice.

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    Neutrophils

Neutrophil is the other key cell determining the inflammatory and immune responses in COPD patients. As for macrophages, cytotoxic products of neutrophils can damage both airways structure and lung parenchyma. Macrolides modulate different functions of neutrophils, reducing chemotactic responses to citokines, neutrophil-derived elastolytic activity and neutrophil accumulation in the tissue [45]. Macrolides also reduce the expression of neutrophil adhesion molecules Mac-1 and the serum concentration of soluble adhesion molecules, like sL-selectin, sE-selectin and sP-selectin [46].

Moreover, superoxide anion production by neutrophils is inhibited and superoxide dismutase activity is enhanced by macrolides even at very low concentrations [47, 48].

Macrolide treatment has an impact on B-cell and T-cell activities. Long-term therapy with erythromycin reduces the number of bronchoalveolar lavage fluid lymphocytes in patients with diffuse panbronchiolitis and clarithromycin and azithromycin induce an increase of apoptosis of activated lymphocytes, both these effects may reduce inflammation and may have a role in chronic respiratory diseases [49, 50]. Along with these effects, macrolide can modulate dendritic cell functions. Sugiyama et al. demonstrated that clarithromycin and azithromycin had anti-inflammatory effects through modulation of the functions of dendritic cells, each macrolide affecting cytokines production differently, for example, clarithromycin inhibits IL-6 and IL-2 production whereas azithromycin enhances IL-10 production [51].

Many bacteria including Streptococcus pneumoniae, H. influenzae, Mycoplasma pneumoniae and C. pneumoniae have been shown to induce MUC5AC production by epithelial cells that can be inhibited by macrolide activity [52, 53, 54, 55]. This inhibition may be related both to a pure antibacterial activity and to a non-antibacterial activity like downregulation of MUC5AC mRNA expression and protein secretion through inhibition of transcriptional factors.

Another possible mechanism by which macrolides decrease mucus hypersecretion is related to inhibition of water secretion in the airways lumen through inhibition of chloride secretion [56, 57].

Microaspiration of gastric contents and/or vagal irritation from gastroesophageal reflux may constitute airway irritants and thus represent a potential pathogenic mechanism for acute exacerbations of COPD.

Rascon-Aguilar et al. demonstrated that COPD patients who have reflux symptoms at least once a week are more likely to have an increased number of exacerbations [58].

Among non-antibiotic activities, macrolides show effects on gastroesophageal reflux potentially reducing microaspiration of gastric content that can be involved in airways inflammation and hyperreactivity [59].

Quorum sensing is a mechanism, used by many Gram-positive and Gram-negative bacteria, to regulate gene induction in a population-dependent manner [60]. It triggers the formation of biofilms, tissue damaging exoproducts and virulence factors that contribute directly and indirectly to the pathogenesis of bacterial infections [61, 62, 63, 64]

In COPD bacterial chronic infection is common and contributes to the pathogenesis of the disease in a substantial number of patients. Macrolides show strong activity in reducing quorum sensing in different bacteria including Pseudomonas aeruginosa [65]. Moreover, Imamura et al. demonstrated that macrolides can have a bactericidal activity against P. aeruginosa on stationary phase through interaction with the outer membrane of the bacteria [66]. Mulet et al. not only confirmed this activity but also showed the in vitro potential selection of resistant strains [67].

Indirect antibacterial activities namely inhibition of bacterial quorum sensing, bacterial adhesion and induced bacteriostasis, may explain, at least in part, the efficacy of long-term prophylaxis with macrolides in COPD patients [20•, 21, 22••].

Other classes of antibiotics exert modulatory effects on immune cells and inflammation in the airways.

Most of fluoroquinolones have been shown to inhibit IL-1, IL-6 and TNFα synthesis probably through the inhibition of NFkB activation [68]. Blau et al. showed, in a model of cystic fibrosis cell line, that moxifloxacin inhibits IL-8 and MAPK activation in monocytic and respiratory epithelial cells with a TNF-α and IL-1β inhibition induced by moxifloxacin higher than that induced by ciprofloxacin and azithromycin [69].

Dalhoff et al. in their elegant review on the immunomodulatory effects of quinolones hypothesize different mechanisms leading to non-antibiotic activities of quinolones including modulation of intracellular cyclic adenosine-3,5-monophosphate and phosphodiesterases and transcription factors [70••].

Fluoroquinolones (e.g. ciprofloxacin) and cephalosporins (e.g. ceftazidime) have also been shown to influence quorum sensing in P. aeruginosa in vitro and inhaled tobramycin showed antibacterial and anti-inflammatory effects in severe COPD patients chronically infected by P. aeruginosa [71, 72].

Pulsed use of moxifloxacin in preventing exacerbation of COPD showed a positive effect mainly in moderate-severe patients with chronic production of mucopurulent sputum [23]. Further studies are needed to unravel the real role of immunomodulatory/anti-inflammatory effects of non-macrolide antibiotics in managing COPD.

Aside from its beneficial effects, possible side effects of any long-term treatment with antibiotic should be taken into account. Both macrolide and quinolone trials in COPD demonstrated a higher incidence of side effects in the active treatment arms [20•, 21, 22••, 23]. Development of antibiotic resistance among respiratory pathogens has been reported during long-term macrolide treatment. In the azithromycin study, patients in the active treatment arm were more likely to become colonized with macrolide-resistant organisms; however, there was no evidence suggesting that colonization increased the incidence of acute exacerbations of COPD or pneumonia [22••]. In the Pulse study, a regular monitoring of sputum flora and of faecal flora identified a transient increase in MIC of few strains of S. pneumoniae and Staphylococcus aureus. However, these isolates did not persist or cause exacerbations [23]. The results of the COPD trials did not indicate a clinically significant resistance emergence.

However, as the risk may emerge if this kind of prophylaxis should be applied to a large number of patients, new approaches are actually in development such as novel tetracyclines and macrolides with potent anti-inflammatory and/or immunomodulatory activity, without any anti-bacterial property [73, 74, 75, 76, 77•].

Several non-antibiotic macrolide derivatives, which can also be called immunolides, have been proposed. EM703 and EM900 are erythromycin derivatives. EM703 has a potent anti-inflammatory activity and promotes monocyte-to-macrophage differentiation in vitro [74]. EM900 suppresses IL-1 and TNF-α expression, and inhibits IL-1β-induced MUC5AC expression. These effects seem to be mediated by the suppression of NF-κB activation [75, 76].

A non-antibiotic derivative of azithromycin, CSY0073, has been recently synthetized [77]. This drug retains the anti-inflammatory and immunomodulatory activity of conventional macrolides through a highly effective inhibition of nuclear translocation of the p65 subunit of NF-κB.

Section snippets

Conclusions

In pulmonary practice, long-term antibiotic prophylaxis is becoming increasingly popular for the treatment of patients with chronic airways diseases, such as COPD.

This approach is based on the results of different studies, mainly in vitro and in animal models, showing a beneficial effect of antibiotics on modulation of immune response and inflammation. Recent clinical trials showed positive results of antibiotic prophylaxis in reducing COPD exacerbation frequency, sputum volume and inflammatory

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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