Inhaled hypertonic saline as a therapy for cystic fibrosis

Current Opinion in Pulmonary Medicine

Volumn 12, Issue 6, 2006, Pages 445-452

  Elkins, Mark R ^a,b,c   Bye, Peter T P ^a,b,c  

^a ROYAL PRINCE ALFRED HOSPITAL   (Australia)

^b UNIVERSITY OF SYDNEY   (Australia)

^c WOOLCOCK INSTITUTE OF MEDICAL RESEARCH   (Australia)

Author keywords

Cystic fibrosis; Hypertonic saline; Mucolytic therapy

Indexed keywords

SODIUM CHLORIDE;

ABSENTEEISM; AIRWAY OBSTRUCTION; CILIATED EPITHELIUM; COUGHING; CYSTIC FIBROSIS; DISEASE EXACERBATION; HUMAN; LIQUID; LONG TERM CARE; MUCUS SECRETION; PATHOPHYSIOLOGY; QUALITY OF LIFE; RESPIRATORY EPITHELIUM; RESPIRATORY TRACT INFECTION; RESPIRATORY TRACT INFLAMMATION; REVIEW;

ADMINISTRATION, INHALATION; CYSTIC FIBROSIS; HUMANS; LUNG; LUNG DISEASES; MODELS, BIOLOGICAL; SALINE SOLUTION, HYPERTONIC;

EID: 33750372715     PISSN: 10705287     EISSN: 15316971     Source Type: Journal    
DOI: 10.1097/01.mcp.0000245714.89632.b2     Document Type: Review

References (60)

1. Donaldson SH, Boucher RC. Update on pathogenesis of cystic fibrosis lung disease. Curr Opin Pulm Med 2003; 9:486-491.
2. Boucher RC. An overview of the pathogenesis of cystic fibrosis lung disease. Adv Drug Deliv Rev 2002; 54:1359-1371.
3. Stutts MJ, Canessa CM, Olsen JC, et al. CFTR as a cAMP-dependent regulator of sodium channels. Science 1995; 269:805-806.
4. Randell SH, Boucher RC. Effective mucus clearance is essential for respiratory health. Am J Respir Cell Mol Biol 2006; 35:20-28. This study highlights the dominant role of adequate hydration for effective mucus clearance, recently identified regulators of airway surface hydration and the pathophysiologic consequences of impaired mucus clearance.
5. Matsui H, Grubb BR, Tarran R, et al. Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell 1998; 95:1005-1015.
6. Effros RM, Peterson B, Casaburi R, et al. Epithelial lining fluid solute concentrations in chronic obstructive lung disease patients and normal subjects. J Appl Physiol 2005; 99:1286-1292.
7. Tarran R, Grubb BR, Parsons D, et al. The CF salt controversy: in vivo observations and therapeutic approaches. Mol Cell 2001; 8:149-158.
8. Jayaraman S, Song Y, Vetrivel L, et al. Noninvasive in vivo fluorescence measurement of airway-surface liquid depth, salt concentration, and pH. J Clin Invest 2001; 107:317-324.
9. Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care Med 1996; 154:1229-1256.
10. Perks B, Shute JK. DNA and actin bind and inhibit interleukin-8 function in cystic fibrosis sputa: in vitro effects of mucolytics. Am J Respir Crit Care Med 2000; 162:1767-1772.
11. Shak S, Capon DJ, Hellmiss R, et al. Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. Proc Natl Acad Sci U S A 1990; 87:9188-9192.
12. Vasconcellos CA, Allen PG, Wohl ME, et al. Reduction in viscosity of cystic fibrosis sputum in vitro by gelsolin. Science 1994; 263:969-971.
13. Kim J-S, 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. This study examines three markers of neutrophilic inflammation in cystic fibrosis sputum. These correlate closely with the degree of airway obstruction and the impairment of sputum transportability, indicating that inflammation may have a key role in mucus stasis.
14. Girod S, Galabert C, Lecuire A, et al. Phospholipid composition and surface-active properties of tracheobronchial secretions from patients with cystic fibrosis and chronic obstructive pulmonary diseases. Pediatr Pulmonol 1992; 13:22-27.
15. Scheffner AL, Medler EM, Jacobs LW, et al. The in vitro reduction in viscosity of human tracheobronchial secretions by acetylcysteine. Am Rev Respir Dis 1964; 90:721-729.
16. King M, Dasgupta B, Tomkiewicz RP, et al. Rheology of cystic fibrosis sputum after in vitro treatment with hypertonic saline alone and in combination with recombinant human deoxyribonuclease I. Am J Respir Crit Care Med 1997; 156:173-177.
17. Wills PJ, Cole PJ. Sodium chloride improves ciliary transportability of sputum. Am J Respir Crit Care Med 1995; A720.
18. Wills PJ, Hall RL, Chan WM, et al. Sodium chloride increases the ciliary transportability of cystic fibrosis and bronchiectasis sputum on the mucus-depleted bovine trachea. J Clin Invest 1997; 99:9-13.
19. Lieberman J, Kurnick NB. Influence of deoxyribonucleic acid content on the proteolysis of sputum and pus. Nature 1962; 196:988-990.
20. Donaldson SH, Bennett WD, Zeman KL, et al. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Engl J Med 2006; 354:241-250. Hypertonic saline produced a sustained increase in mucociliary clearance over a 2-week period in patients with cystic fibrosis. The study confirmed previous research that the addition of amiloride did not increase the effect of hypertonic saline on mucociliary clearance, and extended this to demonstrate that pretreatment with amiloride did not improve the clinical outcomes of hypertonic saline therapy.
21. Tarran R, Grubb BR, Gatzy JT, et al. The relative roles of passive surface forces and active ion transport in the modulation of airway surface liquid volume and composition. J Gen Physiol 2001; 118:223-236.
22. Rodwell LT, Anderson SD. Airway responsiveness to hyperosmolar saline challenge in cystic fibrosis: a pilot study. Pediatr Pulmonol 1996; 21:282-289.
23. Eng PA, Morton J, Douglass JA, et al. Short-term efficacy of ultrasonically nebulized hypertonic saline in cystic fibrosis. Pediatr Pulmonol 1996; 21:77-83.
24. Suri R, Metcalfe C, Lees B, et al. Comparison of hypertonic saline and alternate-day or daily recombinant human deoxyribonuclease in children with cystic fibrosis: a randomised trial. Lancet 2001; 358:1316-1321.
25. Kastelik JA, Aziz I, Morice AH. Sputum induction in young cystic fibrosis patients. Eur Respir J 2001; 17:1.
26. Elkins MR, Robinson M, Rose BR, et al. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med 2006; 354:229-240. The clinical trial provides the longest comparison of hypertonic saline with a control intervention of normal saline inhalations, with treatment arms of 48 weeks.
27. Tarran R, Button B, Picher M, et al. Normal and cystic fibrosis airway surface liquid homeostasis: the effects of phasic shear stress and viral infections. J Biol Chem 2005; 280:35751-35759. These studies demonstrate how dysregulated ion transport pathways fail to maintain ASL volume in the cystic fibrosis airway, the role of phasic motion in regulating key aspects of airways defence and how interventions that increase motion-induced nucleotide release may be therapeutic in cystic fibrosis patients.
28. Robinson M, Bye PT. Mucociliary clearance in cystic fibrosis. Pediatr Pulmonol 2002; 33:293-306.
29. Robinson M, Regnis JA, Bailey DL, et al. Effect of hypertonic saline, amiloride, and cough on mucociliary clearance in patients with cystic fibrosis. Am J Respir Crit Care Med 1996; 153:1503-1509.
30. Robinson M, Hemming AL, Regnis JA, et al. Effect of increasing doses of hypertonic saline on mucociliary clearance in patients with cystic fibrosis. Thorax 1997; 52:900-903.
31. Robinson M, Eberl S, Tomlinson C, et al. Regional mucociliary clearance in patients with cystic fibrosis. Journal of Aerosol Medicine 2000; 13:73-86.
32. Alexis NE, Shu-Chieh H, Zeman KL, et al. Induced sputum derives from the central airways: confirmation using a radiolabeled aerosol bolus delivery technique. Am J Respir Crit Care Med 2001; 164:1964-1970.
33. Aitken ML, Greene KE, Tonelli MR, et al. Analysis of sequential aliquots of hypertonic saline solution-induced sputum from clinically stable patients with cystic fibrosis. Chest 2003; 123:792-799.
34. Sagel SD, Kapsner R, Osberg I, et al. Airway inflammation in children with cystic fibrosis and healthy children assessed by sputum induction. Am J Respir Crit Care Med 2001; 164:1425-1431.
35. De Boeck K, Alifier M, Vandeputte S. Sputum induction in young cystic fibrosis patients. Eur Respir J 2000; 16:91-94.
36. Henig NR, Tonelli MR, Pier MV, et al. Sputum induction as a research tool for sampling the airways of subjects with cystic fibrosis. Thorax 2001; 56:306-311.
37. Riedler J, Reade T, Button B, et al. Inhaled hypertonic saline increases sputum expectoration in cystic fibrosis. J Paediatr Child Health 1996; 32:48-50.
38. Fuchs HJ, Borowitz DS, Christiansen DH, et al., The Pulmozyme Study Group. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med 1994; 331:637-642.
39. Ware J, Sherbourne C. The MOS 36-item short-form health survey: conceptual framework and item selection. Med Care 1992; 30:473-481.
40. Quittner AL, Sweeny S, Watrous M, et al. Translation and linguistic validation of a disease-specific quality of life measure for cystic fibrosis. J Pediatr Psychol 2000; 25:403-414.
41. Balfour-Lynn IM, Elborn JS. 'CF asthma': what is it and what do we do about it? Thorax 2002; 57:742-748.
42. Balfour-Lynn IM, Lees B, Hall P, et al. Multicenter randomized controlled trial of withdrawal of inhaled corticosteroids in cystic fibrosis. Am J Respir Crit Care Med 2006; 173:1356-1362. This study shows that stopping inhaled corticosteroids is not harmful for patients with cystic fibrosis who use them regularly. It is likely that the majority of patients taking them no longer need to do so.
43. Ordonez CL, Henig NR, Mayer-Hamblett N, et al. Inflammatory and microbiologic markers in induced sputum after intravenous antibiotics in cystic fibrosis. Am J Respir Crit Care Med 2003; 168:1471-1475.
44. Ballmann M, von der Hardt H. Hypertonic saline and recombinant human DNase: a randomised cross-over pilot study in patients with cystic fibrosis. J Cyst Fibros 2002; 1:35-37.
45. Smith J, Travis S, Greenberg E, et al. Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid. Cell 1996; 85:229-236.
46. Moraes TJ, Plumb J, Martin R, et al. Abnormalities in the pulmonary innate immune system in cystic fibrosis. Am J Respir Cell Mol Biol 2006; 34:364-374. This study provides further support for the ASL volume hypothesis, indicating that the antimicrobial properties of ASL in cystic fibrosis are compromised in a manner independent of the tonicity of the ASL, and the mechanism by which the antimicrobial properties are impaired does not include a direct effect of the ASL on phagocyte function.
47. Bals R, Weiner DJ, Meegalla RL, et al. Salt-independent abnormality of antimicrobial activity in cystic fibrosis airway surface fluid. Am J Respir Cell Mol Biol 2001; 25:21-25.
48. Koehler DR, Downey GP, Sweezey NB, et al. Lung inflammation as a therapeutic target in cystic fibrosis. Am J Respir Cell Mol Biol 2004; 31:377-381.
49. Clayton A, Holland E, Pang L, et al. Interleukin-1b differentially regulates β2 adrenoreceptor and prostaglandin E2-mediated cAMP accumulation and chloride efflux from Calu-3 bronchial epithelial cells: role of receptor changes, adenylyl cyclase, cyclo-oxygenase 2, and protein kinase A. J Biol Chem 2005; 280:23451-23463. This study indicated that chronic exposure to interleukin-1β significantly impaired chloride efflux. This might further impair the already defective chloride flux in cystic fibrosis and exacerbate the abnormalities in the composition of the airway surface liquid that occur as a result of CFTR dysfunction, promoting further mucociliary dysfunction, infection and inflammation.
50. de Rose V. Mechanisms and markers of airway inflammation in cystic fibrosis. Eur Respir J 2002; 19:333-340.
51. Tabary O, Escotte S, Couetil JP, et al. High susceptibility for cystic fibrosis human airway gland cells to produce IL-8 through the IkB kinase a pathway in response to extracellular NaCl content. J Immunol 2000; 164:3377-3384.
52. Suri R, Marshall LJ, Wallis C, et al. 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.
53. Luk CKA, Dulfano MJ. Effect of pH, viscosity and ionic strength changes on ciliary beating frequency of human bronchial explants. Clin Sci 1983; 64:449-451.
54. Boek WM, Keles N, Graamans K, et al. Physiologic and hypertonic saline solutions impair ciliary activity in vitro. Laryngoscope 1999; 109:396-399.
55. Silber G, Proud D, Warner J, et al. In vivo release of inflammatory mediators by hyperosmolar solutions. Am Rev Respir Dis 1988; 137:606-612.
56. Folkesson HG, Kheradmand F, Matthay MA. The effect of salt water on alveolar epithelial barrier function. Am J Respir Crit Care Med 1994; 150:1555-1563.
57. Konig P, Gayer D, Barbero GJ, et al. Short-term and long-term effects of albuterol aerosol therapy in cystic fibrosis: a preliminary report. Pediatr Pulmonol 1995; 20:205-214.
58. Büscher R, Eilmes KJ, Grasemann H, et al. Beta-2 adrenoceptor gene polymorphisms in cystic fibrosis lung disease. Pharmacogenetics 2002; 12:347-353.
59. Elkins MR, Tingpej P, Moriarty C, et al. Tolerability of hypertonic saline when delivered rapidly via the eFlow® nebulizer in subjects with cystic fibrosis. Pediatr Pulmonol (in press), Suppl 29, 2006.
60. Wark PAB, McDonald V. Nebulised hypertonic saline for cystic fibrosis (Cochrane Review). The Cochrane Database of Systematic Reviews 2005. This systematic review comprehensively summarizes all the clinical trials of hypertonic saline for cystic fibrosis.