Ivacaftor-induced sweat chloride reductions correlate with increases in airway surface liquid pH in cystic fibrosis.

Autor:	Abou Alaiwa MH; Department of Internal Medicine and Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA., Launspach JL; Department of Internal Medicine and Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA., Grogan B; National Referral Centre for Adult Cystic Fibrosis, St. Vincent's University Hospital and University College Dublin School of Medicine, Dublin, Ireland., Carter S; National Referral Centre for Adult Cystic Fibrosis, St. Vincent's University Hospital and University College Dublin School of Medicine, Dublin, Ireland., Zabner J; Department of Internal Medicine and Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA., Stoltz DA; Department of Internal Medicine and Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.; Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA., Singh PK; Departments of Medicine and Microbiology, University of Washington, Seattle, Washington, USA., McKone EF; National Referral Centre for Adult Cystic Fibrosis, St. Vincent's University Hospital and University College Dublin School of Medicine, Dublin, Ireland., Welsh MJ; Department of Internal Medicine and Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.; Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.; Howard Hughes Medical Institute, University of Iowa, Iowa City, Iowa, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2018 Aug 09; Vol. 3 (15). Date of Electronic Publication: 2018 Aug 09 (Print Publication: 2018).
DOI:	10.1172/jci.insight.121468
Abstrakt:	Background: Disruption of cystic fibrosis transmembrane conductance regulator (CFTR) anion channel function causes cystic fibrosis (CF), and lung disease produces most of the mortality. Loss of CFTR-mediated HCO3- secretion reduces the pH of airway surface liquid (ASL) in vitro and in neonatal humans and pigs in vivo. However, we previously found that, in older children and adults, ASL pH does not differ between CF and non-CF. Here, we tested whether the pH of CF ASL increases with time after birth. Finding that it did suggested that adaptations by CF airways increase ASL pH. This conjecture predicted that increasing CFTR activity in CF airways would further increase ASL pH and also that increasing CFTR activity would correlate with increases in ASL pH. Methods: To test for longitudinal changes, we measured ASL pH in newborns and then at 3-month intervals. We also studied people with CF (bearing G551D or R117H mutations), in whom we could acutely stimulate CFTR activity with ivacaftor. To gauge changes in CFTR activity, we measured changes in sweat Cl- concentration immediately before and 48 hours after starting ivacaftor. Results: Compared with that in the newborn period, ASL pH increased by 6 months of age. In people with CF bearing G551D or R117H mutations, ivacaftor did not change the average ASL pH; however reductions in sweat Cl- concentration correlated with elevations of ASL pH. Reductions in sweat Cl- concentration also correlated with improvements in pulmonary function. Conclusions: Our results suggest that CFTR-independent mechanisms increase ASL pH in people with CF. We speculate that CF airway disease, which begins soon after birth, is responsible for the adaptation. Funding: Vertex Inc., the NIH (P30DK089507, 1K08HL135433, HL091842, HL136813, K24HL102246), the Cystic Fibrosis Foundation (SINGH17A0 and SINGH15R0), and the Burroughs Wellcome Fund.
Databáze:	MEDLINE
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