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Dysregulated Proinflammatory and Fibrogenic Phenotype of Fibroblasts in Cystic Fibrosis

Morbi-mortality in cystic fibrosis (CF) is mainly related to chronic lung infection and inflammation, uncontrolled tissue rearrangements and fibrosis, and yet the underlying mechanisms remain largely unknown. We evaluated inflammatory and fibrosis responses to bleomycin in F508del homozygous and wil...

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Autores principales: Huaux, François, Noel, Sabrina, Dhooghe, Barbara, Panin, Nadtha, Lo Re, Sandra, Lison, Dominique, Wallemacq, Pierre, Marbaix, Etienne, Scholte, Bob J., Lebecque, Patrick, Leal, Teresinha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667188/
https://www.ncbi.nlm.nih.gov/pubmed/23734196
http://dx.doi.org/10.1371/journal.pone.0064341
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author Huaux, François
Noel, Sabrina
Dhooghe, Barbara
Panin, Nadtha
Lo Re, Sandra
Lison, Dominique
Wallemacq, Pierre
Marbaix, Etienne
Scholte, Bob J.
Lebecque, Patrick
Leal, Teresinha
author_facet Huaux, François
Noel, Sabrina
Dhooghe, Barbara
Panin, Nadtha
Lo Re, Sandra
Lison, Dominique
Wallemacq, Pierre
Marbaix, Etienne
Scholte, Bob J.
Lebecque, Patrick
Leal, Teresinha
author_sort Huaux, François
collection PubMed
description Morbi-mortality in cystic fibrosis (CF) is mainly related to chronic lung infection and inflammation, uncontrolled tissue rearrangements and fibrosis, and yet the underlying mechanisms remain largely unknown. We evaluated inflammatory and fibrosis responses to bleomycin in F508del homozygous and wild-type mice, and phenotype of fibroblasts explanted from mouse lungs and skin. The effect of vardenafil, a cGMP-specific phosphodiesterase type 5 inhibitor, was tested in vivo and in culture. Responses of proinflammatory and fibrotic markers to bleomycin were enhanced in lungs and skin of CF mice and were prevented by treatment with vardenafil. Purified lung and skin fibroblasts from CF mice proliferated and differentiated into myofibroblasts more prominently and displayed higher sensitivity to growth factors than those recovered from wild-type littermates. Under inflammatory stimulation, mRNA and protein expression of proinflammatory mediators were higher in CF than in wild-type fibroblasts, in which CFTR expression reached similar levels to those observed in other non-epithelial cells, such as macrophages. Increased proinflammatory responses in CF fibroblasts were reduced by half with submicromolar concentrations of vardenafil. Proinflammatory and fibrogenic functions of fibroblasts are upregulated in CF and are reduced by vardenafil. This study provides compelling new support for targeting cGMP signaling pathway in CF pharmacotherapy.
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spelling pubmed-36671882013-06-03 Dysregulated Proinflammatory and Fibrogenic Phenotype of Fibroblasts in Cystic Fibrosis Huaux, François Noel, Sabrina Dhooghe, Barbara Panin, Nadtha Lo Re, Sandra Lison, Dominique Wallemacq, Pierre Marbaix, Etienne Scholte, Bob J. Lebecque, Patrick Leal, Teresinha PLoS One Research Article Morbi-mortality in cystic fibrosis (CF) is mainly related to chronic lung infection and inflammation, uncontrolled tissue rearrangements and fibrosis, and yet the underlying mechanisms remain largely unknown. We evaluated inflammatory and fibrosis responses to bleomycin in F508del homozygous and wild-type mice, and phenotype of fibroblasts explanted from mouse lungs and skin. The effect of vardenafil, a cGMP-specific phosphodiesterase type 5 inhibitor, was tested in vivo and in culture. Responses of proinflammatory and fibrotic markers to bleomycin were enhanced in lungs and skin of CF mice and were prevented by treatment with vardenafil. Purified lung and skin fibroblasts from CF mice proliferated and differentiated into myofibroblasts more prominently and displayed higher sensitivity to growth factors than those recovered from wild-type littermates. Under inflammatory stimulation, mRNA and protein expression of proinflammatory mediators were higher in CF than in wild-type fibroblasts, in which CFTR expression reached similar levels to those observed in other non-epithelial cells, such as macrophages. Increased proinflammatory responses in CF fibroblasts were reduced by half with submicromolar concentrations of vardenafil. Proinflammatory and fibrogenic functions of fibroblasts are upregulated in CF and are reduced by vardenafil. This study provides compelling new support for targeting cGMP signaling pathway in CF pharmacotherapy. Public Library of Science 2013-05-29 /pmc/articles/PMC3667188/ /pubmed/23734196 http://dx.doi.org/10.1371/journal.pone.0064341 Text en © 2013 Huaux et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Huaux, François
Noel, Sabrina
Dhooghe, Barbara
Panin, Nadtha
Lo Re, Sandra
Lison, Dominique
Wallemacq, Pierre
Marbaix, Etienne
Scholte, Bob J.
Lebecque, Patrick
Leal, Teresinha
Dysregulated Proinflammatory and Fibrogenic Phenotype of Fibroblasts in Cystic Fibrosis
title Dysregulated Proinflammatory and Fibrogenic Phenotype of Fibroblasts in Cystic Fibrosis
title_full Dysregulated Proinflammatory and Fibrogenic Phenotype of Fibroblasts in Cystic Fibrosis
title_fullStr Dysregulated Proinflammatory and Fibrogenic Phenotype of Fibroblasts in Cystic Fibrosis
title_full_unstemmed Dysregulated Proinflammatory and Fibrogenic Phenotype of Fibroblasts in Cystic Fibrosis
title_short Dysregulated Proinflammatory and Fibrogenic Phenotype of Fibroblasts in Cystic Fibrosis
title_sort dysregulated proinflammatory and fibrogenic phenotype of fibroblasts in cystic fibrosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667188/
https://www.ncbi.nlm.nih.gov/pubmed/23734196
http://dx.doi.org/10.1371/journal.pone.0064341
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