Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs

David K Meyerholz; David A Stoltz; Nick D Gansemer; Sarah E Ernst; Daniel P Cook; Matthew D Strub; Erica N LeClair; Carrie K Barker; Ryan J Adam; Mariah R Leidinger; Katherine N Gibson-Corley; Philip H Karp; Michael J Welsh; Paul B McCray Jr

doi:10.1038/s41374-018-0026-7

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Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs

Journal article

Open access

Peer reviewed

Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs

David K Meyerholz, David A Stoltz, Nick D Gansemer, Sarah E Ernst, Daniel P Cook, Matthew D Strub, Erica N LeClair, Carrie K Barker, Ryan J Adam, Mariah R Leidinger, …

Laboratory investigation, Vol.98(6), pp.825-838

06/2018

DOI: 10.1038/s41374-018-0026-7

PMCID: PMC6019641

PMID: 29467455

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Abstract

Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function causes cystic fibrosis (CF), predisposing the lungs to chronic infection and inflammation. In young infants with CF, structural airway defects are increasingly recognized before the onset of significant lung disease, which suggests a developmental origin and a possible role in lung disease pathogenesis. The role(s) of CFTR in lung development is unclear and developmental studies in humans with CF are not feasible. Young CF pigs have structural airway changes and develop spontaneous postnatal lung disease similar to humans; therefore, we studied lung development in the pig model (non-CF and CF). CF trachea and proximal airways had structural lesions detectable as early as pseudoglandular development. At this early developmental stage, budding CF airways had smaller, hypo-distended lumens compared to non-CF airways. Non-CF lung explants exhibited airway lumen distension in response to forskolin/IBMX as well as to fibroblast growth factor (FGF)-10, consistent with CFTR-dependent anion transport/secretion, but this was lacking in CF airways. We studied primary pig airway epithelial cell cultures and found that FGF10 increased cellular proliferation (non-CF and CF) and CFTR expression/function (in non-CF only). In pseudoglandular stage lung tissue, CFTR protein was exclusively localized to the leading edges of budding airways in non-CF (but not CF) lungs. This discreet microanatomic localization of CFTR is consistent with the site, during branching morphogenesis, where airway epithelia are responsive to FGF10 regulation. In summary, our results suggest that the CF proximal airway defects originate during branching morphogenesis and that the lack of CFTR-dependent anion transport/liquid secretion likely contributes to these hypo-distended airways.

Morphogenesis

Cyclic AMP - physiology

Fibroblast Growth Factor 10 - physiology

Animals

Swine

Humans

Cells, Cultured

Cystic Fibrosis Transmembrane Conductance Regulator - physiology

Female

Lung - embryology

Cystic Fibrosis Transmembrane Conductance Regulator - analysis

Trachea - abnormalities

Details

Title: Subtitle: Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs
Creators: David K Meyerholz - Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA. david-meyerholz@uiowa.edu
David A Stoltz - Department of Biomedical Engineering, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Nick D Gansemer - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Sarah E Ernst - Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Daniel P Cook - Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Matthew D Strub - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Erica N LeClair - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Carrie K Barker - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Ryan J Adam - Department of Biomedical Engineering, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Mariah R Leidinger - Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Katherine N Gibson-Corley - Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Philip H Karp - Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Michael J Welsh - Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Paul B McCray Jr - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Laboratory investigation, Vol.98(6), pp.825-838
DOI: 10.1038/s41374-018-0026-7
PMID: 29467455
PMCID: PMC6019641
NLM abbreviation: Lab Invest
ISSN: 0023-6837
eISSN: 1530-0307
Publisher: United States
Grant note: T32 GM008629 / NIGMS NIH HHS P30 ES005605 / NIEHS NIH HHS P01 HL091842 / NHLBI NIH HHS T32 HL007638 / NHLBI NIH HHS T32 GM007337 / NIGMS NIH HHS P01 HL051670 / NHLBI NIH HHS P30 DK054759 / NIDDK NIH HHS
Language: English
Date published: 06/2018
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Pathology; Neurosurgery; Internal Medicine; Ophthalmology and Visual Sciences
Record Identifier: 9984025368302771

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