Review Article | Published:

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

Cellular & Molecular Immunologyvolume 15pages312323 (2018) | Download Citation

Subjects

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

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

  2. 2

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

  3. 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.

  4. 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.

  5. 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.

  6. 6

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

  7. 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.

  8. 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.

  9. 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.

  10. 10

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

  11. 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.

  12. 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.

  13. 13

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

  14. 14

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

  15. 15

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

  16. 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.

  17. 17

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

  18. 18

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

  19. 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.

  20. 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.

  21. 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.

  22. 22

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

  23. 23

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

  24. 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.

  25. 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.

  26. 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.

  27. 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.

  28. 28

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

  29. 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.

  30. 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.

  31. 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.

  32. 32

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

  33. 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.

  34. 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.

  35. 35

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

  36. 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.

  37. 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.

  38. 38

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

  39. 39

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

  40. 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.

  41. 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.

  42. 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.

  43. 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.

  44. 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.

  45. 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.

  46. 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.

  47. 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.

  48. 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.

  49. 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.

  50. 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.

  51. 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.

  52. 52

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

  53. 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.

  54. 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.

  55. 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.

  56. 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.

  57. 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.

  58. 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.

  59. 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.

  60. 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.

  61. 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.

  62. 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.

  63. 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.

  64. 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.

  65. 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.

  66. 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.

  67. 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.

  68. 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.

  69. 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.

  70. 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.

  71. 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.

  72. 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.

  73. 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.

  74. 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.

  75. 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.

  76. 76

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

  77. 77

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

  78. 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.

  79. 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.

  80. 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.

  81. 81

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

  82. 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.

  83. 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.

  84. 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.

  85. 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.

  86. 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.

  87. 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.

  88. 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.

  89. 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.

  90. 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.

  91. 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.

  92. 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.

  93. 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.

  94. 94

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

  95. 95

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

  96. 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.

  97. 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.

  98. 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.

  99. 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.

  100. 100

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

  101. 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.

  102. 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.

  103. 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.

  104. 104

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

  105. 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.

  106. 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.

  107. 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.

  108. 108

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

  109. 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.

  110. 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.

  111. 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.

  112. 112

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

  113. 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.

  114. 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.

  115. 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.

  116. 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.

  117. 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.

  118. 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.

  119. 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.

  120. 120

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

  121. 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.

  122. 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.

  123. 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.

  124. 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.

  125. 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.

  126. 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.

  127. 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.

Download references

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’).

Author information

Affiliations

  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

Authors

  1. Search for Maaike Cockx in:

  2. Search for Mieke Gouwy in:

  3. Search for Jo Van Damme in:

  4. Search for Sofie Struyf in:

Conflict of interest

The authors declare no conflict of interest.

Corresponding author

Correspondence to Jo Van Damme.

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/cmi.2017.118