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      Effects of Low-Dose and Long-Term Treatment with Erythromycin on Interleukin-17 and Interleukin-23 in Peripheral Blood and Induced Sputum in Patients with Stable Chronic Obstructive Pulmonary Disease

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          Abstract

          Objective. To study the effects of low-dose and long-term treatment with erythromycin on IL-17 and IL-23, in peripheral blood and induced sputum, in patients with stable chronic obstructive pulmonary disease (COPD). Methods. Patients were randomly divided into placebo-treated group, group A (12 months of additive treatment with erythromycin, N = 18), and group B (6 months of additive treatment with erythromycin followed by 6 months of follow-up, N = 18). Inflammatory cells in induced sputum, pulmonary function, and the 6-minute walk distance (6MWD) were analyzed. Concentrations of IL-17 and IL-23 in peripheral blood and sputum were measured using enzyme-linked immunosorbent assays. Results. After treatment, sputum and peripheral blood concentrations of IL-17 and IL-23 significantly decreased in groups A and B compared with placebo-treated group. There were no significant differences after erythromycin withdrawal at months 9 and 12 in group B compared with placebo-treated group. An increase in 6MWD was observed after treatment. Conclusions. Erythromycin was beneficial and reduced airway inflammation in COPD patients. Underlying mechanisms may involve inhibition of IL-17 and IL-23 mediated airway inflammation. COPD patients treated with erythromycin for 6 months experienced improved exercise capacity. Finally, treatment for 12 months may be more effective than treatment for 6 months.

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          Most cited references26

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          T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients.

          There are increased numbers of activated T lymphocytes in the bronchial mucosa of stable chronic obstructive pulmonary disease (COPD) patients. T helper type 17 (Th17) cells release interleukin (IL)-17 as their effector cytokine under the control of IL-22 and IL-23. Furthermore, Th17 numbers are increased in some chronic inflammatory conditions. To investigate the expression of interleukin (IL)-17A, IL-17F, IL-21, IL-22 and IL-23 and of retinoic orphan receptor RORC2, a marker of Th17 cells, in bronchial biopsies from patients with stable COPD of different severity compared with age-matched control subjects. The expression of IL-17A, IL-17F, IL-21, IL-22, IL-23 and RORC2 was measured in the bronchial mucosa using immunohistochemistry and/or quantitative polymerase chain reaction. The number of IL-22(+) and IL-23(+) immunoreactive cells is increased in the bronchial epithelium of stable COPD compared with control groups. In addition, the number of IL-17A(+) and IL-22(+) immunoreactive cells is increased in the bronchial submucosa of stable COPD compared with control non-smokers. In all smokers, with and without disease, and in patients with COPD alone, the number of IL-22(+) cells correlated significantly with the number of both CD4(+) and CD8(+) cells in the bronchial mucosa. RORC2 mRNA expression in the bronchial mucosa was not significantly different between smokers with normal lung function and COPD. Further, we report that endothelial cells express high levels of IL-17A and IL-22. Increased expression of the Th17-related cytokines IL-17A, IL-22 and IL-23 in COPD patients may reflect their involvement, and that of specific IL-17-producing cells, in driving the chronic inflammation seen in COPD.
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            Clarithromycin targets neutrophilic airway inflammation in refractory asthma.

            Patients with refractory asthma have persistent symptoms despite maximal treatment with inhaled corticosteroids and long-acting bronchodilators. The availability of add-on therapies is limited, and effective add-on therapies that target noneosinophilic airway inflammation are needed. Macrolide antibiotics, such as clarithromycin, have in vitro efficacy against IL-8 and neutrophils, key inflammatory mediators in noneosinophilic asthma. To determine the efficacy of clarithromycin in patients with severe refractory asthma and specifically in a subgroup of patients with noneosinophilic asthma. Subjects with severe refractory asthma (n = 45) were randomized to receive clarithromycin (500 mg twice daily) or placebo for 8 weeks. The primary outcome for this study was sputum IL-8 concentration. Other inflammatory outcomes assessed included sputum neutrophil numbers and concentrations of neutrophil elastase and matrix metalloproteinase (MMP)-9. Clinical outcomes were also assessed, including lung function, airway hyperresponsiveness to hypertonic saline, asthma control, quality of life, and symptoms. Clarithromycin therapy significantly reduced airway concentrations of IL-8 and neutrophil numbers and improved quality-of-life scores compared with placebo. Reductions in neutrophil elastase and MMP-9 concentrations were also observed. These reductions in inflammation were most marked in those with refractory noneosinophilic asthma. Clarithromycin therapy can modulate IL-8 levels and neutrophil accumulation and activation in the airways of patients with refractory asthma. Macrolide therapy may be an important additional therapy that could be used to reduce noneosinophilic airway inflammation, particularly neutrophilic inflammation, in asthma. Clinical trial registered with the Australian Clinical Trials Registry www.actr.org.au (No. 12605000318684).
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              Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations.

              Frequent chronic obstructive pulmonary disease (COPD) exacerbations are a major cause of hospital admission and mortality and are associated with increased airway inflammation. Macrolides have airway antiinflammatory actions and may reduce the incidence of COPD exacerbations. To determine whether regular therapy with macrolides reduces exacerbation frequency. We performed a randomized, double-blind, placebo-controlled study of erythromycin administered at 250 mg twice daily to patients with COPD over 12 months, with primary outcome variable being the number of moderate and/or severe exacerbations (treated with systemic steroids, treated with antibiotics, or hospitalized). We randomized 109 outpatients: 69 (63%) males, 52 (48%) current smokers, mean (SD) age 67.2 (8.6) years, FEV1 1.32 (0.53) L, FEV1% predicted 50 (18)%. Thirty-eight (35%) of the patients had three or more exacerbations in the year before recruitment, with no differences between treatment groups. There were a total of 206 moderate to severe exacerbations: 125 occurred in the placebo arm. Ten in the placebo group and nine in the macrolide group withdrew. Generalized linear modeling showed that the rate ratio for exacerbations for the macrolide-treated patients compared with placebo-treated patients was 0.648 (95% confidence interval: 0.489, 0.859; P = 0.003) and that these patients had shorter duration exacerbations compared with placebo. There were no differences between the macrolide and placebo arms in terms of stable FEV1, sputum IL-6, IL-8, myeloperoxidase, bacterial flora, serum C-reactive protein, or serum IL-6 or in changes in these parameters from baseline to first exacerbation over the 1-year study period. Macrolide therapy was associated with a significant reduction in exacerbations compared with placebo and may be useful in decreasing the excessive disease burden in this important patient population. Clinical trial registered with www.clinicaltrials.gov (NCT 00147667).
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                Author and article information

                Journal
                Mediators Inflamm
                Mediators Inflamm
                MI
                Mediators of Inflammation
                Hindawi Publishing Corporation
                0962-9351
                1466-1861
                2016
                3 April 2016
                : 2016
                : 4173962
                Affiliations
                Department of Respiratory Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
                Author notes

                Academic Editor: Helen C. Steel

                Article
                10.1155/2016/4173962
                4834156
                27127346
                77272dc9-d7d7-4739-8c12-1e3dd7370283
                Copyright © 2016 Caimei Tan et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 January 2016
                : 10 March 2016
                Categories
                Clinical Study

                Immunology
                Immunology

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