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Comparative Variability of Nasal Potential Difference Measurements in Human and Mice

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DOI: 10.4236/ojrd.2012.22007    4,261 Downloads   8,177 Views   Citations

ABSTRACT

Background: Nasal potential difference (NPD) test has long been used to assist in the diagnosis of Cystic Fibrosis (CF) and more recently as an outcome measure in clinical trials of new CF therapies. This test has also been adapted to the mouse nose. Objectives: We aimed at evaluating variability of the NPD measurements in CF patients displaying two severe CFTR mutations and in sex-matched healthy controls. NPD recorded from F508del-CF and normal wild-type mice were also compared. Methods and results: In each setting, tests were performed by a single qualified operator. In the clinical setting, the latest standardized operation protocol of the CF foundation was followed. A total of 80 tracings were obtained from 10 patients (23.2 y; range 14 to 32) and 10 healthy subjects (34 y; range 24 to 53), each tested twice, in both nostrils. Two CF and two controls were excluded from the statistical data analysis due to the presence of a single non interpretable NPD tracing (4/80, 5%). To achieve equal sample size, tests were obtained from 8 CF mice and normal wild-type. Comprehensive multivariate analysis of paired data showed a good reproducibility of NPD parameters in the clinical and the preclinical setting; lower variability was observed in mice. However, 95% repeatability limits of NPD parameters were large indicating a large measurement error, poor precision and low within-subject repeatability. In both settings, chloride secretion was shown to be the most reproducible and repeatable parameter. Conclusion: In human as in mice, NPD showed good reproducibility but limited within-subject repeatability.

Conflicts of Interest

The authors declare no conflicts of interest.

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A. Leonard, B. Lubamba, B. Dhooghe, S. Noel, P. Wallemacq, P. Lebecque and T. Leal, "Comparative Variability of Nasal Potential Difference Measurements in Human and Mice," Open Journal of Respiratory Diseases, Vol. 2 No. 2, 2012, pp. 43-56. doi: 10.4236/ojrd.2012.22007.

References

[1] M. Knowles, J. Gatzy and R. Boucher, “Increased Bioelectric Potential Difference across Respiratory Epithelia in Cystic Fibrosis,” The New England Journal of Medicine, Vol. 305, No. 25, 1981, pp. 1489-1495. doi:10.1056/NEJM198112173052502
[2] P. G. Middleton, D. M. Geddes and E. F. W. Alton, “Protocols for In Vivo Measurement of the Ion Transport Defects in Cystic Fibrosis Nasal Epithelium,” European Respiratory Journal, Vol. 7, No. 11, 1994, pp. 2050-2056.
[3] M. R. Knowles, A. M. Paradiso, R. C. Boucher, “In Vivo Nasal Potential Difference: Techniques and Protocols for Assessing Efficacy of Gene Transfer in Cystic Fibrosis,” Human Gene Therapy, Vol. 6, No. 4, 1995, pp. 445-455. doi:10.1089/hum.1995.6.4-445
[4] K. De Boeck, M. Wilschanski, C. Castellani, C. Taylor, H. Cuppens, J. Dodge and M. Sinaasappel, “Cystic Fibrosis: Terminology and Diagnostic Algorithms,” Thorax, Vol. 61, No. 7, 2006, pp. 627-35. doi:10.1136/thx.2005.043539
[5] P. Lebecque, T. Leal, C. De Boeck, M. Jaspers, H. Cuppens and J. J. Cassiman, “Mutations of the Cystic Fibrosis Gene and Intermediate Sweat Chloride Levels in Children,” American Journal of Respiratory and Critical Care Medicine, Vol. 165, No. 6, 2002, pp. 757-61.
[6] M. Wilschanski, C. Famini, H. Blau, J. Rivlin, A. Augarten, A. Avital, B. Kerem and E. Kerem, “A Pilot Study of the Effect of Gentamicin on Nasal Potential Difference Measurements in CF Patients Carrying Stop Mutations,” American Journal of Respiratory and Critical Care Medicine, Vol. 161, No. 3, 2000, pp. 860-865.
[7] J. P. Clancy, Z. Beb?k, F. Ruiz, C. King, J. Jones, L. Walker, H. Greer, J. Hong, L. Wing, M. Macaluso, R. Lyrene, E. J. Sorscher and D. M. Bedwell, “Evidence That Systemic Gentamicin Suppresses Premature Stop Mutations in Patients with CF,” American Journal of Respiratory and Critical Care Medicine, Vol. 163, No. 7, 2001, 1683-1692.
[8] M. Wilschanski, Y. Yahav, Y. Yaacov, H. Blau, L. Bentur, J. Rivlin, M. Aviram, T. Bdolah-Abram, Z. Bebok, L. Shushi, B. Kerem and E. Kerem, “Gentamicin-Induced Correction of CFTR Function in Patients with CF and CFTR Stop Mutations,” The New England Journal of Medicine, Vol. 349, No. 15, 2003, pp. 1433-1441. doi:10.1056/NEJMoa022170
[9] I. Sermet-Gaudelus, M. Renouil, A. Fajac, L. Bidou, B. Parbaille, S. Pierrot, N. Davy, E. Bismuth, P. Reinert, G. Lenoir, J. F. Lesure, J. P. Rousset and A. Edelman, “In Vitro Prediction of Stop-Codon Suppression by Intravenous Gentamicin in Patients with CF: A Pilot Study,” BMC Medicine, Vol. 5, No. 3, 2007, pp. 5. doi:10.1186/1741-7015-5-5
[10] J. P. Clancy, S. M. Rowe, Z. Bebok, M. L. Aitken, R. Gibson, P. Zeitlin, P. Berclaz, R. Moss, M. R. Knowles, R. A. Oster, N. Mayer-Hamblett and B. Ramsey, “No Detectable Improvements in CF Transmembrane Conductance Regulator by Nasal Aminoglycosides in Patients with CF with Stop Mutations,” American Journal of Respiratory Cell and Molecular Biology, Vol. 37, No. 1, 2007, pp. 57-66. doi:10.1165/rcmb.2006-0173OC
[11] E. Kerem, S. Hirawat, S. Armoni, Y. Yaakov, D. Shoseyov, M. Cohen, M. Nissim-Rafinia, H. Blau, J. Rivlin, M. Aviram, G. L. Elfring, V. J. Northcutt, L. L. Miller, B. Kerem and M. Wilschanski, “Effectiveness of PTC124 Treatment of CF Caused by Nonsense Mutations: A Prospective Phase II Trial,” The Lancet, Vol. 372, No. 9640, 2008, pp. 719-727. doi:10.1016/S0140-6736(08)61168-X
[12] I. Sermet-Gaudelus, K. D. Boeck, G. J. Casimir, F. Vermeulen, T. Leal, A. Mogenet, D. Roussel, J. Fritsch, L. Hanssens, S. Hirawat, N. L. Miller, S. Constantine, A. Reha, T. Ajayi, G. L. Elfring and L. L. Miller, “Ataluren (PTC124) Induces CF Transmembrane Conductance Regulator Protein Expression and Activity in Children with Nonsense Mutation CF,” American Journal of Respiratory and Critical Care Medicine, Vol. 182, No. 10, 2010, pp. 1262-1272. doi:10.1164/rccm.201001-0137OC
[13] F. J. Accurso, S. M. Rowe, J. P. Clancy, M. P. Boyle, J. M. Dunitz, P. R. Durie, S. D. Sagel, D. B. Hornick, M. W. Konstan, S. H. Donaldson, R. B. Moss, J. M. Pilewski, R. C. Rubenstein, A. Z. Uluer, M. L. Aitken, S. D. Freedman, L. M. Rose, N. Mayer-Hamblett, Q. Dong, J. Zha, A. J. Stone, E. R. Olson, C. L. Ordo?ez, P. W. Campbell, M. A. Ashlock and B. W. Ramsey, “Effect of VX-770 in Persons with CF and the G551D-CFTR Mutation,” The New England Journal of Medicine, Vol. 363, No. 21, 2010, pp. 1991-2003. do
[14] M. Wilschanski, L. L. Miller, D. Shoseyov, H. Blau, J. Rivlin, M. Aviram, M. Cohen, S. Armoni, Y. Yaakov, T. Pugatch, M. Cohen-Cymberknoh, N. L. Miller, A. Reha, V. J. Northcutt, S. Hirawat, K. Donnelly, G. L. Elfring, T. Ajayi and E. Kerem, “Chronic Ataluren (PTC124) Treatment of Nonsense Mutation CF,” European Respiratory Journal, Vol. 38, No. 1, 2011, pp. 59-69. doi:10.1183/09031936.00120910
[15] J. P. Clancy, S. M. Rowe, F. J. Accurso, M. L. Aitken, R. S. Amin, M. A. Ashlock, M. Ballmann, M. P. Boyle, I. Bronsveld, P. W. Campbell, K. De Boeck, S. H. Donaldson, H. L. Dorkin, J. M. Dunitz, P. R. Durie, M. Jain, A. Leonard, K. S. McCoy, R. B. Moss, J. M. Pilewski, D. B. Rosenbluth, R. C. Rubenstein, M. S. Schechter, M. Botfield, C. L. Ordo?ez, G. T. Spencer-Green, L. Vernillet, S. Wisseh, K. Yen and M. W. Konstan, “Results of a Phase IIa Study of VX-809, an Investigational CFTR Corrector Compound, in
[16] A. Leonard, P. Lebecque and T. Leal, “A Randomized Placebo-Controlled Trial of Miglustat in Cystic Fibrosis Based on Nasal Potential Difference,” Journal of Cystic Fibrosis, 2012, in press.
[17] G. M. Solomon, M. W. Konstan, M. Wilschanski, J. Billings, I. Sermet, F. Accurso, F. Vermeulen, E. Levin, H. Hathorne, G. Reeves, G. Sabbatini, A. Hill, N. MayerHamblett, M. Ashlock, J. P. Clancy and S. M. Rowe, “An International Randomized Multicenter Comparison of Nasal Potential Difference Techniques,” Chest, Vol. 1384, No. 4, 2010, pp. 919-928. doi:10.1378/chest.10-0179
[18] T. Leal, J. Lebacq, R. Vanbinst, Ch Lederman, M. De Kock and P. Wallemacq, “Successful Protocol of Anaesthesia for Measuring Transepithelial Nasal Potential Difference in Spontaneously Breathing Mice,” Laboratory Animals, Vol. 40, No. 1, 2006, pp. 43-52. doi:10.1258/002367706775404480
[19] B. Lubamba, H. Lecourt, J. Lebacq, P. Lebecque, H. De Jonge, P. Wallemacq and T. Leal, “Preclinical Evidence that Sildenafil and Vardenafil Activate Chloride Transport in Cystic Fibrosis,” American Journal of Respiratory and Critical Care Medicine, Vol. 177, No. 5, 2008, pp. 506-515. doi:10.1164/rccm.200703-344OC
[20] B. Lubamba, J. Lebacq, P. Lebecque, R. Vanbever, A. Leonard, P. Wallemacq and T. Leal, “Airway Delivery of Low-Dose Miglustat Normalizes Nasal Potential Difference in F508del Cystic Fibrosis Mice,” American Journal of Respiratory and Critical Care Medicine, Vol. 179, No. 11, 2009, pp. 1022-1028. doi:10.1164/rccm.200901-0049OC
[21] B. Lubamba, J. Lebacq, G. Reychler, E. Marbaix, P. Wallemacq, P. Lebecque and T. Leal, “Inhaled PDE5 Inhibitors Restore Chloride Transport in Cystic Fibrosis Mice,” European Respiratory Journal, Vol. 37, No. 1, 2011, pp. 72-78. doi:10.1183/09031936.00013510
[22] J. H. van Doorninck, P. J. French, E. Verbeek, R. H. Peters, H. Morreau, J. Bijman and B. J. Scholte, “A Mouse Model for the Cystic Fibrosis Delta F508 Mutation,” The EMBO Journal, Vol. 14, No. 18, 1995, pp. 4403-4411.
[23] L. E. Gibson and R. E. Cooke, “A Test for Concentration of Electrolytes in Sweat in Cystic Fibrosis of the Pancreas Utilizing Pilocarpine by Iontophoresis,” Pediatrics, Vol. 23, No. 3, 1959, pp. 545-549.
[24] R. J. Knudson, M. D. Lebowitz, C. J. Holberg and B. Burrows, “Changes in the Normal Maximal Expiratory Flow-Volume Curve with Growth and Aging,” The American Review of Respiratory Disease, Vol. 127, No. 6, 1983, pp. 725-734.
[25] X. Pepermans, M. Philippe and T. Leal, “New Molecular Screening Assay for Increased Detection Rate of CFTR Mutations in European Populations,” European Respiratory Disease, Vol. 6, No. 1, 2010, pp. 62-65.
[26] W. Nicklas, P. Baneux, R. Boot, T. Decelle, A. A. Deeny, M. Fumanelli and B. Illgen-Wilcke, “Recommendations for the Health Monitoring of Rodent and Rabbit Colonies in Breeding and Experimental Units,” Laboratory Animals, Vol. 36, No. 1, 2002, pp. 20-42. doi:10.1258/0023677021911740
[27] J. M. Bland and D. G. Altman, “Statistical Methods for Assessing Agreement between Two Methods of Clinical Measurement,” The Lancet, Vol. 327, No. 8476, 1986, pp. 307-310. doi:10.1016/S0140-6736(86)90837-8
[28] S. M. Rowe, J. P. Clancy and M. Wilschanski, “Nasal Potential Difference Measurements to Assess CFTR Ion Channel Activity,” Methods in Molecular Biology, Vol. 741, No. 1, 2011, pp. 69-86. doi:10.1007/978-1-61779-117-8_6
[29] F. Vermeulen, M. Proesmans, N. Feyaerts and K. De Boeck, “Nasal Potential Measurements on the Nasal Floor and under the Inferior Turbinate: Does It Matter?” Pediatric Pulmonology, Vol. 46, No. 2, 2011, pp. 145-152. doi:10.1002/ppul.21333
[30] G. M. Solomon, H. R. Young, G. Reeves, R. A. Oster, L. Fan, J. P. Clancy and S. M. Rowe, “Comparison of Commonly Employed Nasal Potential Difference Techniques in Human Subjects,” Pediatric Pulmonology, Vol. 42, No. S30, 2007, p. 248.
[31] Y. Yaakov, E. Kerem, Y. Yahav, J. Rivlin, H. Blau, L. Bentur, M. Aviram, E. Picard, T. Bdolah-Abram and M. Wilschanski, “Reproducibility of Nasal Potential Difference Measurements in CF,” Chest, Vol. 132, No. 4, 2007, pp. 1219-1226. doi:10.1378/chest.06-2975
[32] N. Simmonds, L. D’Souza, M. Roughton, E. Alton, J. C. Davies and M. E. Hodson, “CF and Survival to 40 Years: A Study of CFTR Function,” European Respiratory Journal, Vol. 37, No. 5, 2011, pp. 1076-1082. doi:10.1183/09031936.00079010
[33] J. P. Clancy, S. M. Rowe, Z. Bebok, M. L. Aitken, R. Gibson, P. Zeitlin, P. Berclaz, R. Moss, M. R. Knowles, R. A. Oster, N. Mayer-Hamblett and B. Ramsey, “No Detectable Improvements in Cystic Fibrosis Transmembrane Conductance Regulator by Nasal Aminoglycosides in Patients with Cystic Fibrosis with Stop Mutations,” American Journal of Respiratory Cell and Molecular Biology, Vol. 37, No. 1, 2007, pp. 57-66. doi:10.1165/rcmb.2006-0173OC
[34] M. Mall, B. R. Grubb, J. R. Harkema, W. K. O’Neal and R. C. Boucher, “Increased Airway Epithelial Na+ Absorption Produces Cystic Fibrosis-Like Lung Disease in Mice,” Nature Medicine, Vol. 10, No. 5, 2004, pp. 487-493. doi:10.1038/nm1028
[35] Z. Zhou, D. Treis, S. C. Schubert, M. Harm, J. Schattemy, S. Hirtz, J. Duerr, R. C. Boucher and M. A. Mall, “Precentive but Not Late Amiloride Therapy Reduces Morbidity and Mortality of Lung Disease in βENaC-Overexpressing Mice,” American Journal of Respiratory and Critical Care Medicine, Vol. 178, No. 12, 2008, pp. 1245-1256. doi:10.1164/rccm.200803-442OC
[36] G. R. Cutting, “Modifier Genes in Mendelian Disorders: The Example of Cystic Fibrosis,” Annals of the New York Academy Sciences, Vol. 1214, 2010, pp. 57-69. doi:10.1111/j.1749-6632.2010.05879.x
[37] S. M. Graham, S. N. Scott, J. Launspach and J. Zabner, “The Effects of Fluticasone Propionate on Nasal Epithelial Potential Difference,” American Journal of Rhinology, Vol. 16, No. 3, 2002, pp. 145-149.
[38] P. M. Barker, D. J. Gillie, M. S. Schechter and B. K. Rubin, “Effect of Macrolides on In Vivo Ion Transport across CF Nasal Epithelium,” American Journal of Respiratory and Critical Care Medicine, Vol. 171, No. 8, 2005, pp. 868-871. doi:10.1164/rccm.200311-1508OC
[39] I. Oliynyk, G. Varelogianni, M. Schalling, M. S. Asplund, G. M. Roomans and M. Johannesson, “Azithromycin Increases Chloride Efflux from CF Airway Epithelial Cells,” Experimental Lung Research, Vol. 35, No. 3, 2009, pp. 210-221. doi:10.1080/01902140802534967
[40] F. Delavoie, M. Molinari, M. Milliot, J. M. Zahm, C. Coraux, J. Michel and G. Balossier, “Salmeterol Restores Secretory Functions in CF Airway Submucosal Gland Serous Cells,” American Journal of Respiratory and Cell Molecular Biology, Vol. 40, No. 4, 2009, pp. 388-397. doi:10.1165/rcmb.2008-0037OC
[41] J. M. Zahm, F. Delavoie, F. Toumi, B. Nawrocki-Raby, C Kileztky, J. Michel, G. Balossier, M. Johnson, C. Coraux and P. Birembaut, “Long Acting β2-Agonist and Corticosteroid Restore Airway Glandular Cell Function Altered by Bacterial Supernatant,” Respiratory Research, Vol. 11, No. 1, 2010, p. 16. doi:10.1186/1465-9921-11-6
[42] M. K?ttgen, A. E. Busch, M. J. Hug, R. Greger and K. Kunzelmann, “N-Acetyl-L-Cysteine and Its Derivatives Activate a Cl-Conductance in Epithelial Cells,” Pflugers Archiv European Journal of Physiology, Vol. 431, No. 4, 1996, pp. 549-555. doi:10.1007/BF02191902
[43] T. Leal, J. Lebacq, P. Lebecque, J. Cumps and P. Wallemacq, “Modified Method to Measure Nasal Potential Difference,” Clinical Chemistry and Laboratory Medicine, Vol. 41, No. 1, 2003, pp. 61-67. doi:10.1515/CCLM.2003.011
[44] T. Leal, I. Fajac, H. L. Wallace, P. Lebecque, J. Lebacq, D. Hubert, J. Dall’Ava, D. Dusser, A. P. Ganesan, C. Knoop, J. Cumps, P. Wallemacq and K. W. Southern, “Airway Ion Transport Impacts on Disease Presentation and Severity in Cystic Fibrosis,” Clinical Biochemiatry, Vol. 41, No. 10-11, 2008, pp. 764-772. doi:10.1016/j.clinbiochem.2008.03.013

  
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