Journal article
Ivacaftor-induced sweat chloride reductions correlate with increases in airway surface liquid pH in cystic fibrosis
JCI insight, Vol.3(15), e121468
08/09/2018
DOI: 10.1172/jci.insight.121468
PMCID: PMC6129116
PMID: 30089726
Abstract
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.
Details
- Title: Subtitle
- Ivacaftor-induced sweat chloride reductions correlate with increases in airway surface liquid pH in cystic fibrosis
- Creators
- Mahmoud H. Abou Alaiwa - Univ Iowa, Dept Internal Med, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52242 USAJan L. Launspach - Roy J. and Lucille A. Carver College of MedicineBrenda Grogan - University College DublinSuzanne Carter - University College DublinJoseph Zabner - Roy J. and Lucille A. Carver College of MedicineDavid A. Stoltz - Roy J. and Lucille A. Carver College of MedicinePradeep K. Singh - University of WashingtonEdward F. McKone - University College DublinMichael J. Welsh - University of Iowa
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.3(15), e121468
- Publisher
- Amer Soc Clinical Investigation Inc
- DOI
- 10.1172/jci.insight.121468
- PMID
- 30089726
- PMCID
- PMC6129116
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Number of pages
- 8
- Grant note
- P30DK089507; 1K08HL135433; HL091842; HL136813; K24HL102246 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P30DK089507 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) P30ES005605 / NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS) SINGH17A0; SINGH15R0 / Cystic Fibrosis Foundation; Italian Cystic Fibrosis Research Foundation Vertex Inc.; Vertex Pharmaceuticals P01HL051670 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) Burroughs Wellcome Fund
- Language
- English
- Date published
- 08/09/2018
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Fraternal Order of Eagles Diabetes Research Center; Neurosurgery; Internal Medicine
- Record Identifier
- 9984259505902771
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