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

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 s...

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Autores principales: Meyerholz, David K., Stoltz, David A., Gansemer, Nick D., Ernst, Sarah E., Cook, Daniel P., Strub, Matthew D., LeClair, Erica N., Barker, Carrie K., Adam, Ryan J., Leidinger, Mariah R., Gibson-Corley, Katherine N., Karp, Philip H., Welsh, Michael J., McCray, Paul B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019641/
https://www.ncbi.nlm.nih.gov/pubmed/29467455
http://dx.doi.org/10.1038/s41374-018-0026-7
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author Meyerholz, David K.
Stoltz, David A.
Gansemer, Nick D.
Ernst, Sarah E.
Cook, Daniel P.
Strub, Matthew D.
LeClair, Erica N.
Barker, Carrie K.
Adam, Ryan J.
Leidinger, Mariah R.
Gibson-Corley, Katherine N.
Karp, Philip H.
Welsh, Michael J.
McCray, Paul B.
author_facet Meyerholz, David K.
Stoltz, David A.
Gansemer, Nick D.
Ernst, Sarah E.
Cook, Daniel P.
Strub, Matthew D.
LeClair, Erica N.
Barker, Carrie K.
Adam, Ryan J.
Leidinger, Mariah R.
Gibson-Corley, Katherine N.
Karp, Philip H.
Welsh, Michael J.
McCray, Paul B.
author_sort Meyerholz, David K.
collection PubMed
description 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 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.
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spelling pubmed-60196412018-08-21 Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs Meyerholz, David K. Stoltz, David A. Gansemer, Nick D. Ernst, Sarah E. Cook, Daniel P. Strub, Matthew D. LeClair, Erica N. Barker, Carrie K. Adam, Ryan J. Leidinger, Mariah R. Gibson-Corley, Katherine N. Karp, Philip H. Welsh, Michael J. McCray, Paul B. Lab Invest Article 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 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. 2018-02-21 2018-06 /pmc/articles/PMC6019641/ /pubmed/29467455 http://dx.doi.org/10.1038/s41374-018-0026-7 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Meyerholz, David K.
Stoltz, David A.
Gansemer, Nick D.
Ernst, Sarah E.
Cook, Daniel P.
Strub, Matthew D.
LeClair, Erica N.
Barker, Carrie K.
Adam, Ryan J.
Leidinger, Mariah R.
Gibson-Corley, Katherine N.
Karp, Philip H.
Welsh, Michael J.
McCray, Paul B.
Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs
title Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs
title_full Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs
title_fullStr Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs
title_full_unstemmed Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs
title_short Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs
title_sort lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019641/
https://www.ncbi.nlm.nih.gov/pubmed/29467455
http://dx.doi.org/10.1038/s41374-018-0026-7
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