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01-12-2014

Low-Dose Clarithromycin Therapy Modulates Th17 Response In Non-Cystic Fibrosis Bronchiectasis Patients

Authors: Evangelia Fouka, Eleftheria Lamprianidou, Konstantinos Arvanitidis, Eirini Filidou, George Kolios, Paraskevi Miltiades, Emmanouil Paraskakis, Antonios Antoniadis, Ioannis Kotsianidis, Demosthenes Bouros

Published in: Lung | Issue 6/2014

Abstract

Introduction

Th17 cells play a crucial role in neutrophilic inflammation and tissue injury in non-cystic fibrosis (non-CF) bronchiectasis. Clarithromycin demonstrates anti-inflammatory and immunomodulatory properties but the effect of long-term clarithromycin prophylaxis on the Th17 response in non-CF bronchiectasis is still unexplored.

Methods

Th17 response was studied in 22 patients with stable non-CF bronchiectasis receiving daily 500-mg clarithromycin for 12 weeks. We analysed IL-17 concentrations in exhaled breath condensate (EBC) and peripheral blood Th17 cells, whereas functional parameters and clinical data were recorded in parallel.

Results

Both, post-treatment absolute counts of CD4+IL17+ cells in peripheral blood and IL-17 levels in EBC decreased significantly (post-treatment CD4+IL17+ mean 2.418 ± 0.414 cells/μl versus pre-treatment 3.202 ± 0.507 cells/μl, p = 0.036 and post-treatment IL-17 mean levels 7.16 ± 0.47 pg/ml versus pre-treatment 9.32 ± 0.47 pg/ml, p < 0.001, respectively). Post-treatment EBC IL-17 levels decreased significantly in both patients who exhibited exacerbations and those who remained stable during the study period (mean 6.72 ± 0.37 versus 9.12 ± 0.64 pg/ml, p = 0.01 and 7.69 ± 0.9 versus 9.53 ± 0.72 pg/ml, p = 0.042, respectively), while pre-treatment and post-treatment levels did not differ between the two groups (p = 0.665 and p = 0.465, respectively). PaO₂ improved significantly (post-treatment mean 77.73 ± 2.23 mmHg versus pre-treatment 73.18 ± 2.22 mmHg, p = 0.025), while PaCO₂, post-bronchodilation FEV1, and post-bronchodilation FVC remained unaltered.

Conclusions

Our results argue for a reduction of both systemic and local Th17 response after prophylactic, low-dose clarithromycin administration in patients with non-CF bronchiectasis, suggestive of a potential anti-inflammatory and/or immunomodulatory action.

Cole PJ (1986) Inflammation: a two-edged sword–the model of bronchiectasis. Eur J Respir Dis Suppl 147:6–15PubMed

Barker AF (2002) Bronchiectasis. N Engl J Med 346(18):1383–1393CrossRefPubMed

Aujla SJ, Dubin PJ, Kolls JK (2007) Interleukin-17 in pulmonary host defense. Exp Lung Res 33(10):507–518CrossRefPubMed

Iwakura Y, Nakae S, Saijo S, Ishigame H (2008) The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol Rev 226:57–79CrossRefPubMed

Bettelli E, Korn T, Oukka M, Kuchroo VK (2008) Induction and effector functions of Th 17 cells. Nature 453(7198):1051–1057CrossRefPubMed

Steinman L (2007) A brief history of Th 17, the first major revision in the Th 1/Th 2 hypothesis of T cell-mediated tissue damage. Nat Med 13(2):139–145CrossRefPubMed

Vanaudenaerde BM, Verleden SE, Vos R et al (2011) Innate and adaptive interleukin-17-producing lymphocytes in chronic inflammatory lung disorders. Am J Respir Crit Care Med 183(8):977–986CrossRefPubMed

Dubin PJ, McAllister F, Kolls JK (2007) Is cystic fibrosis a TH17 disease? Inflamm Res 56(6):221–227CrossRefPubMed

Kolios G, Manousou P, Bourikas L et al (2006) Ciprofloxacin inhibits cytokine-induced nitric oxide production in human colonic epithelium. Eur J Clin Invest 36(10):720–729CrossRefPubMed

10.

Rubin BK, Henke MO (2004) Immunomodulatory activity and effectiveness of macrolides in chronic airway disease. Chest 125(2 Suppl):70S–78SCrossRefPubMed

11.

Shinkai M, Tamaoki J, Kobayashi H et al (2006) Clarithromycin delays progression of bronchial epithelial cells from G1 phase to S phase and delays cell growth via extracellular signal-regulated protein kinase suppression. Antimicrob Agents Chemother 50(5):1738–1744PubMedCentralCrossRefPubMed

12.

Tsang WK, Bilton D (2009) Clinical challenges in managing bronchiectasis. Respirology 14(5):637–650CrossRefPubMed

13.

Banerjee D, Honeybourne D, Khair OA (2004) The effect of oral clarithromycin on bronchial airway inflammation in moderate-to-severe stable COPD: a randomized controlled trial. Treat Respir Med 3(1):59–65CrossRefPubMed

14.

Horváth I, Hunt J, Barnes PJ et al (2005) ATS/ERS task force on exhaled breath condensate. exhaled breath condensate: methodological recommendations and unresolved questions. Eur Respir J 26(3):523–548CrossRefPubMed

15.

Miller MR, Crapo R, Hankinson J et al (2005) ATS/ERS task force. General considerations for lung function testing. Eur Respir J 26(1):153–161CrossRefPubMed

16.

Sun YC, Zhou QT, Yao WZ (2005) Sputum interleukin-17 is increased and associated with airway neutrophilia in patients with severe asthma. Chin Med J (Engl) 118(11):953–956

17.

Di Stefano A, Caramori G, Gnemmi I et al (2009) T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients. Clin Exp Immunol 157:316–324PubMedCentralCrossRefPubMed

18.

McAllister F, Henry A, Kreindler JL et al (2005) Role of IL-17A, IL-17F, and the IL-17 receptor in regulating growth-related oncogene-alpha and granulocyte colony-stimulating factor in bronchial epithelium: implications for airway inflammation in cystic fibrosis. J Immunol 175(1):404–412PubMedCentralCrossRefPubMed

19.

Tan HL, Regamey N, Brown S et al (2011) The Th17 pathway in cystic fibrosis lung disease. Am J Respir Crit Care Med 184(2):252–258PubMedCentralCrossRefPubMed

20.

Ding FM, Zhu SL, Shen C et al (2012) Low-dose clarithromycin therapy modulates CD4(+) T-cell responses in a mouse model of chronic Pseudomonas aeruginosa lung infection. Respirology 17(4):727–734CrossRefPubMed

21.

Tiringer K, Treis A, Fucik P et al (2013) A Th17- and Th2-skewed cytokine profile in cystic fibrosis lungs represents a potential risk factor for Pseudomonas aeruginosa infection. Am J Respir Crit Care Med 187(6):621–629CrossRefPubMed

22.

Wong C, Jayaram L, Karalus N et al (2012) Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 380(9842):660–667CrossRefPubMed

23.

Altenburg J, de Graaff CS, Stienstra Y et al (2013) Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA 309(12):1251–1259CrossRefPubMed

24.

Kushwah R, Gagnon S, Sweezey NB (2013) Intrinsic predisposition of naïve cystic fibrosis T cells to differentiate towards a Th17 phenotype. Respir Res 14:138PubMedCentralCrossRefPubMed

25.

Ishimatsu Y, Kadota J, Iwashita T et al (2004) Macrolide antibiotics induce apoptosis of human peripheral lymphocytes in vitro. Int J Antimicrob Agents 24(3):247–253CrossRefPubMed

26.

Kadota J, Mizunoe S, Kishi K et al (2005) Antibiotic-induced apoptosis in human activated peripheral lymphocytes. Int J Antimicrob Agents 25(3):216–220CrossRefPubMed

27.

Loukides S, Kontogianni K, Hillas G et al (2011) Exhaled breath condensate in asthma: from bench to bedside. Curr Med Chem 18(10):1432–1443CrossRefPubMed

28.

Borrill ZL, Roy K, Singh D (2008) Exhaled breath condensate biomarkers in COPD. Eur Respir J 32(2):472–486CrossRefPubMed

29.

Robroeks CM, Roozeboom MH, de Jong PA et al (2010) Structural lung changes, lung function, and non-invasive inflammatory markers in cystic fibrosis. Pediatr Allergy Immunol 21(3):493–500CrossRefPubMed

30.

Karakoc GB, Inal A, Yilmaz M et al (2009) Exhaled breath condensate MMP-9 levels in children with bronchiectasis. Pediatr Pulmonol 44(10):1010–1016CrossRefPubMed

31.

Zihlif N, Paraskakis E, Tripoli C et al (2006) Markers of airway inflammation in primary ciliary dyskinesia studied using exhaled breath condensate. Pediatr Pulmonol 41(6):509–514CrossRefPubMed

32.

Brodlie M, McKean MC, Johnson GE et al (2011) Raised interleukin-17 is immunolocalised to neutrophils in cystic fibrosis lung disease. Eur Respir J 37(6):1378–1385CrossRefPubMed

33.

Eustace A, Smyth LJ, Mitchell L et al (2011) Identification of cells expressing IL-17A and IL-17F in the lungs of patients with COPD. Chest 139(5):1089–1100CrossRefPubMed

34.

Loukides S, Bouros D, Papatheodorou G et al (2002) Exhaled H₂O₂ in steady-state bronchiectasis: relationship with cellular composition in induced sputum, spirometry, and extent and severity of disease. Chest 121(1):81–88CrossRefPubMed

35.

Tsang KW, Ho PI, Chan KN et al (1999) A pilot study of low-dose erythromycin in bronchiectasis. Eur Respir J 13(2):361–364CrossRefPubMed

36.

Feldman C, Anderson R, Theron AJ et al (1997) Roxithromycin, clarithromycin, and azithromycin attenuate the injurious effects of bioactive phospholipids on human respiratory epithelium in vitro. Inflammation 21(6):655–665CrossRefPubMed

37.

Pukhalsky AL, Shmarina GV, Kapranov NI et al (2004) Anti-inflammatory and immunomodulating effects of clarithromycin in patients with cystic fibrosis lung disease. Mediat Inflamm 13(2):111–117CrossRef

38.

Yalçin E, Kiper N, Ozçelik U et al (2006) Effects of claritromycin on inflammatory parameters and clinical conditions in children with bronchiectasis. J Clin Pharm Ther 31(1):49–55CrossRefPubMed

39.

Altenburg J, de Graaff CS, van der Werf TS et al (2011) Immunomodulatory effects of macrolide antibiotics—part 2: advantages and disadvantages of long-term, low-dose macrolide therapy. Respiration 81(1):75–87CrossRefPubMed

Title: Low-Dose Clarithromycin Therapy Modulates Th17 Response In Non-Cystic Fibrosis Bronchiectasis Patients
Authors: Evangelia Fouka
Eleftheria Lamprianidou
Konstantinos Arvanitidis
Eirini Filidou
George Kolios
Paraskevi Miltiades
Emmanouil Paraskakis
Antonios Antoniadis
Ioannis Kotsianidis
Demosthenes Bouros
Publication date: 01-12-2014
Publisher: Springer US
Published in: Lung / Issue 6/2014
Print ISSN: 0341-2040
Electronic ISSN: 1432-1750
DOI: https://doi.org/10.1007/s00408-014-9619-0

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