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Chemoattractants and cytokines in primary ciliary dyskinesia and cystic fibrosis: key players in chronic respiratory diseases

Cellular & Molecular Immunology volume 15, pages 312–323 (2018)Cite this article

Abstract

Patients with primary ciliary dyskinesia (PCD) and cystic fibrosis (CF), two inherited disorders, suffer from recurrent airway infections characterized by persistent bacterial colonization and uncontrollable inflammation. Although present in high counts, neutrophils fail to clear infection in the airways. High levels of C-X-C motif chemokine ligand 8/interleukin-8 (CXCL8/IL-8), the most potent chemokine to attract neutrophils to sites of infection, are detected in the sputum of both patient groups and might cause the high neutrophil influx in the airways. Furthermore, in CF, airway neutrophils are highly activated because of the genetic defect and the high levels of proinflammatory chemoattractants and cytokines (e.g., CXCL8/IL-8, tumor necrosis factor-α and IL-17). The overactive state of neutrophils leads to lung damage and fuels the vicious circle of infection, excessive inflammation and tissue damage. The inflammatory process in CF airways is well characterized, whereas the lung pathology in PCD is far less studied. The knowledge of CF lung pathology could be useful to guide molecular investigations of the inflammatory processes in PCD lungs. Current available therapies can not completely remedy the chronic airway infections in these diseases. This review gives an overview of the role that chemoattractants and cytokines play in these neutrophil-dominated lung pathologies. Finally, the most frequently applied treatments in CF and PCD and new experimental therapies to reduce neutrophil-dominated airway inflammation are described.

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References

  1. Munkholm M, Mortensen J. Mucociliary clearance: pathophysiological aspects. Clin Physiol Funct Imaging 2014; 34: 171–177.

    PubMed  Google Scholar 

  2. Boon M, Jorissen M, Proesmans M, De Boeck K. Primary ciliary dyskinesia, an orphan disease. Eur J Pediatr 2013; 172: 151–162.

    PubMed  Google Scholar 

  3. Yonker LM, Cigana C, Hurley BP, Bragonzi A. Host-pathogen interplay in the respiratory environment of cystic fibrosis. J Cyst Fibros 2015; 14: 431–439.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Ratjen F, Waters V, Klingel M, McDonald N, Dell S, Leahy TR et al. Changes in airway inflammation during pulmonary exacerbations in patients with cystic fibrosis and primary ciliary dyskinesia. Eur Respir J 2016; 47: 829–836.

    CAS  PubMed  Google Scholar 

  5. Sagel SD, Kapsner R, Osberg I, Sontag MK, Accurso FJ. Airway inflammation in children with cystic fibrosis and healthy children assessed by sputum induction. Am J Respir Crit Care Med 2001; 164: 1425–1431.

    CAS  PubMed  Google Scholar 

  6. Castellani C, Assael BM. Cystic fibrosis: a clinical view. Cell Mol Life Sci 2017; 74: 129–140.

    CAS  PubMed  Google Scholar 

  7. Shapiro AJ, Zariwala MA, Ferkol T, Davis SD, Sagel SD, Dell SD et al. Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review. Pediatr Pulmonol 2016; 51: 115–132.

    PubMed  Google Scholar 

  8. Ralhan A, Laval J, Lelis F, Ballbach M, Grund C, Hector A et al. Current concepts and controversies in innate immunity of cystic fibrosis lung disease. J Innate Immun 2016; 8: 531–540.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Terheggen-Lagro SW, Rijkers GT, van der Ent CK. The role of airway epithelium and blood neutrophils in the inflammatory response in cystic fibrosis. J Cyst Fibros 2005; 4 (Suppl 2): 15–23.

    CAS  PubMed  Google Scholar 

  10. Brown JM, Witman GB. Cilia and diseases. Bioscience 2014; 64: 1126–1137.

    PubMed  PubMed Central  Google Scholar 

  11. Noone PG, Leigh MW, Sannuti A, Minnix SL, Carson JL, Hazucha M et al. Primary ciliary dyskinesia: diagnostic and phenotypic features. Am J Respir Crit Care Med 2004; 169: 459–467.

    PubMed  Google Scholar 

  12. Knowles MR, Daniels LA, Davis SD, Zariwala MA, Leigh MW. Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Am J Respir Crit Care Med 2013; 188: 913–922.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Satir P, Christensen ST. Overview of structure and function of mammalian cilia. Annu Rev Physiol 2007; 69: 377–400.

    CAS  PubMed  Google Scholar 

  14. Livraghi A, Randell SH. Cystic fibrosis and other respiratory diseases of impaired mucus clearance. Toxicol Pathol 2007; 35: 116–129.

    CAS  PubMed  Google Scholar 

  15. Sagel SD, Chmiel JF, Konstan MW. Sputum biomarkers of inflammation in cystic fibrosis lung disease. Proc Am Thorac Soc 2007; 4: 406–417.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Cantin AM, Hartl D, Konstan MW, Chmiel JF. Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy. J Cyst Fibros 2015; 14: 419–430.

    CAS  PubMed  Google Scholar 

  17. Rada B. Interactions between neutrophils and Pseudomonas aeruginosa in cystic fibrosis. Pathogens 2017; 6.

    PubMed Central  Google Scholar 

  18. Whitsett JA, Alenghat T. Respiratory epithelial cells orchestrate pulmonary innate immunity. Nat Immunol 2015; 16: 27–35.

    CAS  PubMed  Google Scholar 

  19. McCuaig S, Martin JG. How the airway smooth muscle in cystic fibrosis reacts in proinflammatory conditions: implications for airway hyper-responsiveness and asthma in cystic fibrosis. Lancet Respir Med 2013; 1: 137–147.

    PubMed  Google Scholar 

  20. Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 2011; 11: 519–531.

    CAS  PubMed  Google Scholar 

  21. Turner MD, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta 2014; 1843: 2563–2582.

    CAS  PubMed  Google Scholar 

  22. Elizur A, Cannon CL, Ferkol TW. Airway inflammation in cystic fibrosis. Chest 2008; 133: 489–495.

    PubMed  Google Scholar 

  23. Gifford AM, Chalmers JD. The role of neutrophils in cystic fibrosis. Curr Opin Hematol 2014; 21: 16–22.

    CAS  PubMed  Google Scholar 

  24. Petit-Bertron AF, Tabary O, Corvol H, Jacquot J, Clement A, Cavaillon JM et al. Circulating and airway neutrophils in cystic fibrosis display different TLR expression and responsiveness to interleukin-10. Cytokine 2008; 41: 54–60.

    CAS  PubMed  Google Scholar 

  25. Koller B, Kappler M, Latzin P, Gaggar A, Schreiner M, Takyar S et al. TLR expression on neutrophils at the pulmonary site of infection: TLR1/TLR2-mediated up-regulation of TLR5 expression in cystic fibrosis lung disease. J Immunol 2008; 181: 2753–2763.

    CAS  PubMed  Google Scholar 

  26. Brennan S, Cooper D, Sly PD. Directed neutrophil migration to IL-8 is increased in cystic fibrosis: a study of the effect of erythromycin. Thorax 2001; 56: 62–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Dai Y, Dean TP, Church MK, Warner JO, Shute JK. Desensitisation of neutrophil responses by systemic interleukin 8 in cystic fibrosis. Thorax 1994; 49: 867–871.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Lawrence RH, Sorrelli TC. Decreased polymorphonuclear leucocyte chemotactic response to leukotriene B4 in cystic fibrosis. Clin Exp Immunol 1992; 89: 321–324.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Corvol H, Fitting C, Chadelat K, Jacquot J, Tabary O, Boule M et al. Distinct cytokine production by lung and blood neutrophils from children with cystic fibrosis. Am J Physiol Lung Cell Mol Physiol 2003; 284: L997–1003.

    CAS  PubMed  Google Scholar 

  30. Montemurro P, Mariggio MA, Barbuti G, Cassano A, Vincenti A, Serio G et al. Increase in interleukin-8 production from circulating neutrophils upon antibiotic therapy in cystic fibrosis patients. J Cyst Fibros 2012; 11: 518–524.

    CAS  PubMed  Google Scholar 

  31. Voglis S, Quinn K, Tullis E, Liu M, Henriques M, Zubrinich C et al. Human neutrophil peptides and phagocytic deficiency in bronchiectatic lungs. Am J Respir Crit Care Med 2009; 180: 159–166.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Tecchio C, Micheletti A, Cassatella MA. Neutrophil-derived cytokines: facts beyond expression. Front Immunol 2014; 5: 508.

    PubMed  PubMed Central  Google Scholar 

  33. Kim JS, Okamoto K, Rubin BK. Pulmonary function is negatively correlated with sputum inflammatory markers and cough clearability in subjects with cystic fibrosis but not those with chronic bronchitis. Chest 2006; 129: 1148–1154.

    CAS  PubMed  Google Scholar 

  34. Mayer-Hamblett N, Aitken ML, Accurso FJ, Kronmal RA, Konstan MW, Burns JL et al. Association between pulmonary function and sputum biomarkers in cystic fibrosis. Am J Respir Crit Care Med 2007; 175: 822–828.

    PubMed  PubMed Central  Google Scholar 

  35. Corkey CW, Minta JO, Turner JA, Biggar WD. Neutrophil function in the immotile cilia syndrome. J Lab Clin Med 1982; 99: 838–844.

    CAS  PubMed  Google Scholar 

  36. Walter RJ, Danielson JR, Reyes HM. Characterization of a chemotactic defect in patients with Kartagener syndrome. Arch Otolaryngol Head Neck Surg 1990; 116: 465–469.

    CAS  PubMed  Google Scholar 

  37. Afzelius BA, Ewetz L, Palmblad J, Uden AM, Venizelos N. Structure and function of neutrophil leukocytes from patients with the immotile-cilia syndrome. Acta Med Scand 1980; 208: 145–154.

    CAS  PubMed  Google Scholar 

  38. Gallin JI, Wright DG, Malech HL, Davis JM, Klempner MS, Kirkpatrick CH. Disorders of phagocyte chemotaxis. Ann Intern Med 1980; 92: 520–538.

    CAS  PubMed  Google Scholar 

  39. Valerius NH, Knudsen BB, Pedersen M. Defective neutrophil motility in patients with primary ciliary dyskinesia. Eur J Clin Invest 1983; 13: 489–494.

    CAS  PubMed  Google Scholar 

  40. Cockx M, Gouwy M, Godding V, De Boeck K, Van Damme J, Boon M et al. Neutrophils from patients with primary ciliary dyskinesia display reduced chemotaxis to CXCR2 ligands. Front Immunol 2017; 8: 1126.

    PubMed  PubMed Central  Google Scholar 

  41. Estell K, Braunstein G, Tucker T, Varga K, Collawn JF, Schwiebert LM. Plasma membrane CFTR regulates RANTES expression via its C-terminal PDZ-interacting motif. Mol Cell Biol 2003; 23: 594–606.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Bozic CR, Gerard NP, Gerard C. Receptor binding specificity and pulmonary gene expression of the neutrophil-activating peptide ENA-78. Am J Respir Cell Mol Biol 1996; 14: 302–308.

    CAS  PubMed  Google Scholar 

  43. Kube D, Sontich U, Fletcher D, Davis PB. Proinflammatory cytokine responses to P. aeruginosa infection in human airway epithelial cell lines. Am J Physiol Lung Cell Mol Physiol 2001; 280: L493–L502.

    CAS  PubMed  Google Scholar 

  44. Raoust E, Balloy V, Garcia-Verdugo I, Touqui L, Ramphal R, Chignard M. Pseudomonas aeruginosa LPS or flagellin are sufficient to activate TLR-dependent signaling in murine alveolar macrophages and airway epithelial cells. PLoS One 2009; 4: e7259.

    PubMed  PubMed Central  Google Scholar 

  45. Page AV, Liles WC. Colony-stimulating factors in the prevention and management of infectious diseases. Infect Dis Clin N Am 2011; 25: 803–817.

    Google Scholar 

  46. Blackwell TS, Stecenko AA, Christman JW. Dysregulated NF-kappaB activation in cystic fibrosis: evidence for a primary inflammatory disorder. Am J Physiol Lung Cell Mol Physiol 2001; 281: L69–L70.

    CAS  PubMed  Google Scholar 

  47. John G, Chillappagari S, Rubin BK, Gruenert DC, Henke MO. Reduced surface toll-like receptor-4 expression and absent interferon-gamma-inducible protein-10 induction in cystic fibrosis airway cells. Exp Lung Res 2011; 37: 319–326.

    CAS  PubMed  Google Scholar 

  48. Hauber HP, Tulic MK, Tsicopoulos A, Wallaert B, Olivenstein R, Daigneault P et al. Toll-like receptors 4 and 2 expression in the bronchial mucosa of patients with cystic fibrosis. Can Respir J 2005; 12: 13–18.

    PubMed  Google Scholar 

  49. John G, Yildirim AO, Rubin BK, Gruenert DC, Henke MO. TLR-4-mediated innate immunity is reduced in cystic fibrosis airway cells. Am J Respir Cell Mol Biol 2010; 42: 424–431.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Greene CM, Carroll TP, Smith SG, Taggart CC, Devaney J, Griffin S et al. TLR-induced inflammation in cystic fibrosis and non-cystic fibrosis airway epithelial cells. J Immunol 2005; 174: 1638–1646.

    CAS  PubMed  Google Scholar 

  51. Muir A, Soong G, Sokol S, Reddy B, Gomez MI, Van Heeckeren A et al. Toll-like receptors in normal and cystic fibrosis airway epithelial cells. Am J Respir Cell Mol Biol 2004; 30: 777–783.

    CAS  PubMed  Google Scholar 

  52. Bogdan C. Nitric oxide and the immune response. Nat Immunol 2001; 2: 907–916.

    CAS  PubMed  Google Scholar 

  53. Wodehouse T, Kharitonov SA, Mackay IS, Barnes PJ, Wilson R, Cole PJ. Nasal nitric oxide measurements for the screening of primary ciliary dyskinesia. Eur Respir J 2003; 21: 43–47.

    CAS  PubMed  Google Scholar 

  54. Manna A, Caffarelli C, Varini M, Povesi Dascola C, Montella S, Maglione M et al. Clinical application of exhaled nitric oxide measurement in pediatric lung diseases. Ital J Pediatr 2012; 38: 74.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Boon M, Meyts I, Proesmans M, Vermeulen FL, Jorissen M, De Boeck K. Diagnostic accuracy of nitric oxide measurements to detect primary ciliary dyskinesia. Eur J Clin Invest 2014; 44: 477–485.

    CAS  PubMed  Google Scholar 

  56. Steagall WK, Elmer HL, Brady KG, Kelley TJ. Cystic fibrosis transmembrane conductance regulator-dependent regulation of epithelial inducible nitric oxide synthase expression. Am J Respir Cell Mol Biol 2000; 22: 45–50.

    CAS  PubMed  Google Scholar 

  57. Sorio C, Montresor A, Bolomini-Vittori M, Caldrer S, Rossi B, Dusi S et al. Mutations of cystic fibrosis transmembrane conductance regulator gene cause a monocyte-selective adhesion deficiency. Am J Respir Crit Care Med 2016; 193: 1123–1133.

    CAS  PubMed  Google Scholar 

  58. Van de Weert-van Leeuwen PB, Van Meegen MA, Speirs JJ, Pals DJ, Rooijakkers SH, Van der Ent CK et al. Optimal complement-mediated phagocytosis of Pseudomonas aeruginosa by monocytes is cystic fibrosis transmembrane conductance regulator-dependent. Am J Respir Cell Mol Biol 2013; 49: 463–470.

    CAS  PubMed  Google Scholar 

  59. Van Damme J, Van Beeumen J, Opdenakker G, Billiau A. A novel, NH2-terminal sequence-characterized human monokine possessing neutrophil chemotactic, skin-reactive, and granulocytosis-promoting activity. J Exp Med 1988; 167: 1364–1376.

    CAS  PubMed  Google Scholar 

  60. Van Damme J, De Ley M, Opdenakker G, Billiau A, De Somer P, Van Beeumen J. Homogeneous interferon-inducing 22 K factor is related to endogenous pyrogen and interleukin-1. Nature 1985; 314: 266–268.

    CAS  PubMed  Google Scholar 

  61. Van Damme J, Van Beeumen J, Decock B, Van Snick J, De Ley M, Billiau A. Separation and comparison of two monokines with lymphocyte-activating factor activity: IL-1 beta and hybridoma growth factor (HGF). Identification of leukocyte-derived HGF as IL-6. J Immunol 1988; 140: 1534–1541.

    CAS  PubMed  Google Scholar 

  62. Kreisel D, Nava RG, Li W, Zinselmeyer BH, Wang B, Lai J et al. In vivo two-photon imaging reveals monocyte-dependent neutrophil extravasation during pulmonary inflammation. Proc Natl Acad Sci USA 2010; 107: 18073–18078.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Maus UA, Waelsch K, Kuziel WA, Delbeck T, Mack M, Blackwell TS et al. Monocytes are potent facilitators of alveolar neutrophil emigration during lung inflammation: role of the CCL2-CCR2 axis. J Immunol 2003; 170: 3273–3278.

    CAS  PubMed  Google Scholar 

  64. Sturges NC, Wikstrom ME, Winfield KR, Gard SE, Brennan S, Sly PD et al. Monocytes from children with clinically stable cystic fibrosis show enhanced expression of Toll-like receptor 4. Pediatr Pulmonol 2010; 45: 883–889.

    PubMed  Google Scholar 

  65. Brennan S, Sly PD, Gangell CL, Sturges N, Winfield K, Wikstrom M et al. Alveolar macrophages and CC chemokines are increased in children with cystic fibrosis. Eur Respir J 2009; 34: 655–661.

    CAS  PubMed  Google Scholar 

  66. Moser C, Kjaergaard S, Pressler T, Kharazmi A, Koch C, Hoiby N. The immune response to chronic Pseudomonas aeruginosa lung infection in cystic fibrosis patients is predominantly of the Th2 type. APMIS 2000; 108: 329–335.

    CAS  PubMed  Google Scholar 

  67. Struyf S, Proost P, Van Damme J. Regulation of the immune response by the interaction of chemokines and proteases. Adv Immunol 2003; 81: 1–44.

    CAS  PubMed  Google Scholar 

  68. McAllister F, Henry A, Kreindler JL, Dubin PJ, Ulrich L, Steele C et al. 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 2005; 175: 404–412.

    CAS  PubMed  Google Scholar 

  69. Osika E, Cavaillon JM, Chadelat K, Boule M, Fitting C, Tournier G et al. Distinct sputum cytokine profiles in cystic fibrosis and other chronic inflammatory airway disease. Eur Respir J 1999; 14: 339–346.

    CAS  PubMed  Google Scholar 

  70. Saba S, Soong G, Greenberg S, Prince A. Bacterial stimulation of epithelial G-CSF and GM-CSF expression promotes PMN survival in CF airways. Am J Respir Cell Mol Biol 2002; 27: 561–567.

    CAS  PubMed  Google Scholar 

  71. Sagel SD, Wagner BD, Anthony MM, Emmett P, Zemanick ET. Sputum biomarkers of inflammation and lung function decline in children with cystic fibrosis. Am J Respir Crit Care Med 2012; 186: 857–865.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Rao S, Wright AK, Montiero W, Ziegler-Heitbrock L, Grigg J. Monocyte chemoattractant chemokines in cystic fibrosis. J Cyst Fibros 2009; 8: 97–103.

    CAS  PubMed  Google Scholar 

  73. Gouwy M, Struyf S, Catusse J, Proost P, Van Damme J. Synergy between proinflammatory ligands of G protein-coupled receptors in neutrophil activation and migration. J Leukoc Biol 2004; 76: 185–194.

    CAS  PubMed  Google Scholar 

  74. Williams AE, Jose RJ, Mercer PF, Brealey D, Parekh D, Thickett DR et al. Evidence for chemokine synergy during neutrophil migration in ARDS. Thorax 2017; 72: 66–73.

    PubMed  Google Scholar 

  75. Jorens PG, Van Damme J, De Backer W, Bossaert L, De Jongh RF, Herman AG et al. Interleukin 8 (IL-8) in the bronchoalveolar lavage fluid from patients with the adult respiratory distress syndrome (ARDS) and patients at risk for ARDS. Cytokine 1992; 4: 592–597.

    CAS  PubMed  Google Scholar 

  76. Bruscia EM, Bonfield TL. Innate and adaptive immunity in cystic fibrosis. Clin Chest Med 2016; 37: 17–29.

    PubMed  Google Scholar 

  77. Tan HL, Rosenthal M. IL-17 in lung disease: friend or foe? Thorax 2013; 68: 788–790.

    PubMed  Google Scholar 

  78. Cunningham S, McColm JR, Mallinson A, Boyd I, Marshall TG. Duration of effect of intravenous antibiotics on spirometry and sputum cytokines in children with cystic fibrosis. Pediatr Pulmonol 2003; 36: 43–48.

    PubMed  Google Scholar 

  79. Salva PS, Doyle NA, Graham L, Eigen H, Doerschuk CM. TNF-alpha, IL-8, soluble ICAM-1, and neutrophils in sputum of cystic fibrosis patients. Pediatr Pulmonol 1996; 21: 11–19.

    CAS  PubMed  Google Scholar 

  80. Wolter JM, Rodwell RL, Bowler SD, McCormack JG. Cytokines and inflammatory mediators do not indicate acute infection in cystic fibrosis. Clin Diagn Lab Immunol 1999; 6: 260–265.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Sagel SD, Accurso FJ. Monitoring inflammation in CF. Cytokines. Clin Rev Allergy Immunol 2002; 23: 41–57.

    CAS  PubMed  Google Scholar 

  82. Bush A, Payne D, Pike S, Jenkins G, Henke MO, Rubin BK. Mucus properties in children with primary ciliary dyskinesia: comparison with cystic fibrosis. Chest 2006; 129: 118–123.

    PubMed  Google Scholar 

  83. Korkmaz B, Horwitz MS, Jenne DE, Gauthier F. Neutrophil elastase, proteinase 3, and cathepsin G as therapeutic targets in human diseases. Pharmacol Rev 2010; 62: 726–759.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Sly PD, Gangell CL, Chen L, Ware RS, Ranganathan S, Mott LS et al. Risk factors for bronchiectasis in children with cystic fibrosis. N Engl J Med 2013; 368: 1963–1970.

    CAS  PubMed  Google Scholar 

  85. Sagel SD, Sontag MK, Wagener JS, Kapsner RK, Osberg I, Accurso FJ. Induced sputum inflammatory measures correlate with lung function in children with cystic fibrosis. J Pediatr 2002; 141: 811–817.

    PubMed  Google Scholar 

  86. Yeh CY, Yeh TH, Jung CJ, Chen PL, Lien HT, Chia JS. Activated human nasal epithelial cells modulate specific antibody response against bacterial or viral antigens. PLoS ONE 2013; 8: e55472.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. McKenzie CW, Klonoski JM, Maier T, Trujillo G, Vitiello PF, Huber VC et al. Enhanced response to pulmonary Streptococcus pneumoniae infection is associated with primary ciliary dyskinesia in mice lacking Pcdp1 and Spef2. Cilia 2013; 2: 18.

    PubMed  PubMed Central  Google Scholar 

  88. Zihlif N, Paraskakis E, Tripoli C, Lex C, Bush A. Markers of airway inflammation in primary ciliary dyskinesia studied using exhaled breath condensate. Pediatr Pulmonol 2006; 41: 509–514.

    PubMed  Google Scholar 

  89. Husson MO, Wizla-Derambure N, Turck D, Gosset P, Wallaert B. Effect of intermittent inhaled tobramycin on sputum cytokine profiles in cystic fibrosis. J Antimicrob Chemother 2005; 56: 247–249.

    CAS  PubMed  Google Scholar 

  90. Kobbernagel HE, Buchvald FF, Haarman EG, Casaulta C, Collins SA, Hogg C et al. Study protocol, rationale and recruitment in a European multi-centre randomized controlled trial to determine the efficacy and safety of azithromycin maintenance therapy for 6 months in primary ciliary dyskinesia. BMC Pulm Med 2016; 16: 104.

    PubMed  PubMed Central  Google Scholar 

  91. Conway S, Balfour-Lynn IM, De Rijcke K, Drevinek P, Foweraker J, Havermans T et al. European Cystic Fibrosis Society Standards of Care: framework for the cystic fibrosis centre. J Cyst Fibros 2014; 13 (Suppl 1): S3–22.

    PubMed  PubMed Central  Google Scholar 

  92. Cohen-Cymberknoh M, Shoseyov D, Kerem E. Managing cystic fibrosis: strategies that increase life expectancy and improve quality of life. Am J Respir Crit Care Med 2011; 183: 1463–1471.

    PubMed  Google Scholar 

  93. Hoiby N, Krogh Johansen H, Moser C, Song Z, Ciofu O, Kharazmi A. Pseudomonas aeruginosa and the in vitro and in vivo biofilm mode of growth. Microbes Infect 2001; 3: 23–35.

    CAS  PubMed  Google Scholar 

  94. Fauroux B, Tamalet A, Clement A. Management of primary ciliary dyskinesia: the lower airways. Paediatr Respir Rev 2009; 10: 55–57.

    PubMed  Google Scholar 

  95. Polineni D, Davis SD, Dell SD. Treatment recommendations in primary ciliary dyskinesia. Paediatr Respir Rev 2016; 18: 39–45.

    PubMed  Google Scholar 

  96. Barbato A, Frischer T, Kuehni CE, Snijders D, Azevedo I, Baktai G et al. Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children. Eur Respir J 2009; 34: 1264–1276.

    CAS  PubMed  Google Scholar 

  97. Moss RB, Mayer-Hamblett N, Wagener J, Daines C, Hale K, Ahrens R et al. Randomized, double-blind, placebo-controlled, dose-escalating study of aerosolized interferon gamma-1b in patients with mild to moderate cystic fibrosis lung disease. Pediatr Pulmonol 2005; 39: 209–218.

    PubMed  Google Scholar 

  98. Ordonez CL, Stulbarg M, Grundland H, Liu JT, Boushey HA. Effect of clarithromycin on airway obstruction and inflammatory markers in induced sputum in cystic fibrosis: a pilot study. Pediatr Pulmonol 2001; 32: 29–37.

    CAS  PubMed  Google Scholar 

  99. Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2003; 290: 1749–1756.

    CAS  PubMed  Google Scholar 

  100. Chmiel JF, Konstan MW, Elborn JS. Antibiotic and anti-inflammatory therapies for cystic fibrosis. Cold Spring Harb Perspect Med 2013; 3: a009779.

    PubMed  PubMed Central  Google Scholar 

  101. Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet 2002; 360: 978–984.

    CAS  PubMed  Google Scholar 

  102. Itoh M, Kishi K, Nakamura H, Hatao H, Kioi K, Sudou A et al. A case of immotile-dyskinetic cilia syndrome responding to clenbuterol hydrochloride and azithromycin. Nihon Kokyuki Gakkai Zasshi 2002; 40: 617–621.

    PubMed  Google Scholar 

  103. Keshari RS, Jyoti A, Dubey M, Kothari N, Kohli M, Bogra J et al. Cytokines induced neutrophil extracellular traps formation: implication for the inflammatory disease condition. PLoS One 2012; 7: e48111.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Kearney CE, Wallis CE. Deoxyribonuclease for cystic fibrosis. Cochrane Database Syst Rev 2000; 3: CD001127.

    Google Scholar 

  105. Suri R, Marshall LJ, Wallis C, Metcalfe C, Bush A, Shute JK. Effects of recombinant human DNase and hypertonic saline on airway inflammation in children with cystic fibrosis. Am J Respir Crit Care Med 2002; 166: 352–355.

    PubMed  Google Scholar 

  106. Konstan MW, Ratjen F. Effect of dornase alfa on inflammation and lung function: potential role in the early treatment of cystic fibrosis. J Cyst Fibros 2012; 11: 78–83.

    CAS  PubMed  Google Scholar 

  107. Paul K, Rietschel E, Ballmann M, Griese M, Worlitzsch D, Shute J et al. Effect of treatment with dornase alpha on airway inflammation in patients with cystic fibrosis. Am J Respir Crit Care Med 2004; 169: 719–725.

    PubMed  Google Scholar 

  108. Desai M, Weller PH, Spencer DA. Clinical benefit from nebulized human recombinant DNase in Kartagener's syndrome. Pediatr Pulmonol 1995; 20: 307–308.

    CAS  PubMed  Google Scholar 

  109. El-Abiad NM, Clifton S, Nasr SZ. Long-term use of nebulized human recombinant DNase1 in two siblings with primary ciliary dyskinesia. Respir Med 2007; 101: 2224–2226.

    PubMed  Google Scholar 

  110. ten Berge M, Brinkhorst G, Kroon AA, de Jongste JC. DNase treatment in primary ciliary dyskinesia—assessment by nocturnal pulse oximetry. Pediatr Pulmonol 1999; 27: 59–61.

    CAS  PubMed  Google Scholar 

  111. Amirav I, Cohen-Cymberknoh M, Shoseyov D, Kerem E. Primary ciliary dyskinesia: prospects for new therapies, building on the experience in cystic fibrosis. Paediatr Respir Rev 2009; 10: 58–62.

    PubMed  Google Scholar 

  112. Grommes J, Soehnlein O. Contribution of neutrophils to acute lung injury. Mol Med 2011; 17: 293–307.

    CAS  PubMed  Google Scholar 

  113. Konstan MW, Krenicky JE, Finney MR, Kirchner HL, Hilliard KA, Hilliard JB et al. Effect of ibuprofen on neutrophil migration in vivo in cystic fibrosis and healthy subjects. J Pharmacol Exp Ther 2003; 306: 1086–1091.

    CAS  PubMed  Google Scholar 

  114. Bertolotto M, Contini P, Ottonello L, Pende A, Dallegri F, Montecucco F. Neutrophil migration towards C5a and CXCL8 is prevented by non-steroidal anti-inflammatory drugs via inhibition of different pathways. Br J Pharmacol 2014; 171: 3376–3393.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Lands LC, Milner R, Cantin AM, Manson D, Corey M. High-dose ibuprofen in cystic fibrosis: Canadian safety and effectiveness trial. J Pediatr 2007; 151: 249–254.

    CAS  PubMed  Google Scholar 

  116. Chmiel JF, Konstan MW, Knesebeck JE, Hilliard JB, Bonfield TL, Dawson DV et al. IL-10 attenuates excessive inflammation in chronic Pseudomonas infection in mice. Am J Respir Crit Care Med 1999; 160: 2040–2047.

    CAS  PubMed  Google Scholar 

  117. Lore NI, Cigana C, Riva C, De Fino I, Nonis A, Spagnuolo L et al. IL-17A impairs host tolerance during airway chronic infection by Pseudomonas aeruginosa. Sci Rep 2016; 6: 25937.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Hsu D, Taylor P, Fletcher D, van Heeckeren R, Eastman J, van Heeckeren A et al. Interleukin-17 pathophysiology and therapeutic intervention in cystic fibrosis lung infection and inflammation. Infect Immun 2016; 84: 2410–2421.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Moss RB, Mistry SJ, Konstan MW, Pilewski JM, Kerem E, Tal-Singer R et al. Safety and early treatment effects of the CXCR2 antagonist SB-656933 in patients with cystic fibrosis. J Cyst Fibros 2013; 12: 241–248.

    CAS  PubMed  Google Scholar 

  120. Jundi K, Greene CM. Transcription of interleukin-8: how altered regulation can affect cystic fibrosis lung disease. Biomolecules 2015; 5: 1386–1398.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Konstan MW, Doring G, Heltshe SL, Lands LC, Hilliard KA, Koker P et al. A randomized double blind, placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis. J Cyst Fibros 2014; 13: 148–155.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Milani R, Marcellini A, Montagner G, Baldisserotto A, Manfredini S, Gambari R et al. Phloridzin derivatives inhibiting pro-inflammatory cytokine expression in human cystic fibrosis IB3-1 cells. Eur J Pharm Sci 2015; 78: 225–233.

    CAS  PubMed  Google Scholar 

  123. Kirsten AM, Forster K, Radeczky E, Linnhoff A, Balint B, Watz H et al. The safety and tolerability of oral AZD5069, a selective CXCR2 antagonist, in patients with moderate-to-severe COPD. Pulm Pharmacol Ther 2015; 31: 36–41.

    CAS  PubMed  Google Scholar 

  124. Rennard SI, Dale DC, Donohue JF, Kanniess F, Magnussen H, Sutherland ER et al. CXCR2 Antagonist MK-7123. A phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015; 191: 1001–1011.

    CAS  PubMed  Google Scholar 

  125. Patel DD, Lee DM, Kolbinger F, Antoni C. Effect of IL-17A blockade with secukinumab in autoimmune diseases. Ann Rheum Dis 2013; 72 (Suppl 2): ii116–ii123.

    CAS  PubMed  Google Scholar 

  126. Valenti P, Frioni A, Rossi A, Ranucci S, De Fino I, Cutone A et al. Aerosolized bovine lactoferrin reduces neutrophils and pro-inflammatory cytokines in mouse models of Pseudomonas aeruginosa lung infections. Biochem Cell Biol 2017; 95: 41–47.

    CAS  PubMed  Google Scholar 

  127. Strippoli MP, Frischer T, Barbato A, Snijders D, Maurer E, Lucas JS et al. Management of primary ciliary dyskinesia in European children: recommendations and clinical practice. Eur Respir J 2012; 39: 1482–1491.

    PubMed  Google Scholar 

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Acknowledgements

This work was supported by a C1 grant from KU Leuven, the Fund for Scientific Research of Flanders (FWO-Vlaanderen), the Interuniversity Attraction Poles Program (P7/40)-Belgian Science Policy and the COST Action (BM1407, ‘BEAT-PCD’).

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  1. Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, 3000, Leuven, Belgium

    Maaike Cockx, Mieke Gouwy, Jo Van Damme & Sofie Struyf

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  1. Maaike Cockx
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  2. Mieke Gouwy
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Correspondence to Jo Van Damme.

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Cockx, M., Gouwy, M., Van Damme, J. et al. Chemoattractants and cytokines in primary ciliary dyskinesia and cystic fibrosis: key players in chronic respiratory diseases. Cell Mol Immunol 15, 312–323 (2018). https://doi.org/10.1038/cmi.2017.118

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