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CFTR dysfunction in smooth muscle drives TGFβ dependent airway hyperreactivity

BACKGROUND: The primary underlying defect in cystic fibrosis (CF) is disrupted ion transport in epithelia throughout the body. It is unclear if symptoms such as airway hyperreactivity (AHR) and increased airway smooth muscle (ASM) volume in people with CF are due to inherent abnormalities in smooth...

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Autores principales: Kramer, Elizabeth L., Hudock, Kristin M., Davidson, Cynthia R., Clancy, John P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10416378/
https://www.ncbi.nlm.nih.gov/pubmed/37568151
http://dx.doi.org/10.1186/s12931-023-02495-2
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author Kramer, Elizabeth L.
Hudock, Kristin M.
Davidson, Cynthia R.
Clancy, John P.
author_facet Kramer, Elizabeth L.
Hudock, Kristin M.
Davidson, Cynthia R.
Clancy, John P.
author_sort Kramer, Elizabeth L.
collection PubMed
description BACKGROUND: The primary underlying defect in cystic fibrosis (CF) is disrupted ion transport in epithelia throughout the body. It is unclear if symptoms such as airway hyperreactivity (AHR) and increased airway smooth muscle (ASM) volume in people with CF are due to inherent abnormalities in smooth muscle or are secondary to epithelial dysfunction. Transforming Growth Factor beta 1 (TGFβ) is an established genetic modifier of CF lung disease and a known driver of abnormal ASM function. Prior studies have demonstrated that CF mice develop greater AHR, goblet cell hyperplasia, and ASM hypertrophy after pulmonary TGFβ exposure. However, the mechanism driving these abnormalities in CF lung disease, specifically the contribution of CFTR loss in ASM, was unknown. METHODS: In this study, mice with smooth muscle-specific loss of CFTR function (Cftr(fl/fl); SM-Cre mice) were exposed to pulmonary TGFβ. The impact on lung pathology and physiology was investigated through examination of lung mechanics, Western blot analysis, and pulmonary histology. RESULTS: Cftr(fl/fl); SM-Cre mice treated with TGFβ demonstrated greater methacholine-induced AHR than control mice. However, Cftr(fl/fl); SM-Cre mice did not develop increased inflammation, ASM area, or goblet cell hyperplasia relative to controls following TGFβ exposure. CONCLUSIONS: These results demonstrate a direct smooth muscle contribution to CF airway obstruction mediated by TGFβ. Dysfunction in non-epithelial tissues should be considered in the development of CF therapeutics, including potential genetic therapies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-023-02495-2.
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spelling pubmed-104163782023-08-12 CFTR dysfunction in smooth muscle drives TGFβ dependent airway hyperreactivity Kramer, Elizabeth L. Hudock, Kristin M. Davidson, Cynthia R. Clancy, John P. Respir Res Research BACKGROUND: The primary underlying defect in cystic fibrosis (CF) is disrupted ion transport in epithelia throughout the body. It is unclear if symptoms such as airway hyperreactivity (AHR) and increased airway smooth muscle (ASM) volume in people with CF are due to inherent abnormalities in smooth muscle or are secondary to epithelial dysfunction. Transforming Growth Factor beta 1 (TGFβ) is an established genetic modifier of CF lung disease and a known driver of abnormal ASM function. Prior studies have demonstrated that CF mice develop greater AHR, goblet cell hyperplasia, and ASM hypertrophy after pulmonary TGFβ exposure. However, the mechanism driving these abnormalities in CF lung disease, specifically the contribution of CFTR loss in ASM, was unknown. METHODS: In this study, mice with smooth muscle-specific loss of CFTR function (Cftr(fl/fl); SM-Cre mice) were exposed to pulmonary TGFβ. The impact on lung pathology and physiology was investigated through examination of lung mechanics, Western blot analysis, and pulmonary histology. RESULTS: Cftr(fl/fl); SM-Cre mice treated with TGFβ demonstrated greater methacholine-induced AHR than control mice. However, Cftr(fl/fl); SM-Cre mice did not develop increased inflammation, ASM area, or goblet cell hyperplasia relative to controls following TGFβ exposure. CONCLUSIONS: These results demonstrate a direct smooth muscle contribution to CF airway obstruction mediated by TGFβ. Dysfunction in non-epithelial tissues should be considered in the development of CF therapeutics, including potential genetic therapies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-023-02495-2. BioMed Central 2023-08-11 2023 /pmc/articles/PMC10416378/ /pubmed/37568151 http://dx.doi.org/10.1186/s12931-023-02495-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Kramer, Elizabeth L.
Hudock, Kristin M.
Davidson, Cynthia R.
Clancy, John P.
CFTR dysfunction in smooth muscle drives TGFβ dependent airway hyperreactivity
title CFTR dysfunction in smooth muscle drives TGFβ dependent airway hyperreactivity
title_full CFTR dysfunction in smooth muscle drives TGFβ dependent airway hyperreactivity
title_fullStr CFTR dysfunction in smooth muscle drives TGFβ dependent airway hyperreactivity
title_full_unstemmed CFTR dysfunction in smooth muscle drives TGFβ dependent airway hyperreactivity
title_short CFTR dysfunction in smooth muscle drives TGFβ dependent airway hyperreactivity
title_sort cftr dysfunction in smooth muscle drives tgfβ dependent airway hyperreactivity
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10416378/
https://www.ncbi.nlm.nih.gov/pubmed/37568151
http://dx.doi.org/10.1186/s12931-023-02495-2
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