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GED-0507 attenuates lung fibrosis by counteracting myofibroblast transdifferentiation in vivo and in vitro

The development of more effective, better tolerated drug treatments for progressive pulmonary fibrosis (of which idiopathic pulmonary fibrosis is the most common and severe form) is a research priority. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a key regulator of inflammation...

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Autores principales: Speca, Silvia, Dubuquoy, Caroline, Rousseaux, Christel, Chavatte, Philippe, Desreumaux, Pierre, Spagnolo, Paolo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445472/
https://www.ncbi.nlm.nih.gov/pubmed/34529707
http://dx.doi.org/10.1371/journal.pone.0257281
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author Speca, Silvia
Dubuquoy, Caroline
Rousseaux, Christel
Chavatte, Philippe
Desreumaux, Pierre
Spagnolo, Paolo
author_facet Speca, Silvia
Dubuquoy, Caroline
Rousseaux, Christel
Chavatte, Philippe
Desreumaux, Pierre
Spagnolo, Paolo
author_sort Speca, Silvia
collection PubMed
description The development of more effective, better tolerated drug treatments for progressive pulmonary fibrosis (of which idiopathic pulmonary fibrosis is the most common and severe form) is a research priority. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a key regulator of inflammation and fibrosis and therefore represents a potential therapeutic target. However, the use of synthetic PPAR-γ agonists may be limited by their potentially severe adverse effects. In a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, we have demonstrated that the non-racemic selective PPAR-γ modulator GED-0507 is able to reduce body weight loss, ameliorate clinical and histological features of pulmonary fibrosis, and increase survival rate without any safety concerns. Here, we focused on the biomolecular effects of GED-0507 on various inflammatory/fibrotic pathways. We demonstrated that preventive and therapeutic administration of GED-0507 reduced the BLM-induced mRNA expression of several markers of fibrosis, including transforming growth factor (TGF)-β, alpha-smooth muscle actin, collagen and fibronectin as well as epithelial-to-mesenchymal transition (EMT) and expression of mucin 5B. The beneficial effect of GED-0507 on pulmonary fibrosis was confirmed in vitro by its ability to control TGFβ-induced myofibroblast activation in the A549 human alveolar epithelial cell line, the MRC-5 lung fibroblast line, and primary human lung fibroblasts. Compared with the US Food and Drug Administration-approved antifibrotic drugs pirfenidone and nintedanib, GED-0507 displayed greater antifibrotic activity by controlling alveolar epithelial cell dysfunction, EMT, and extracellular matrix remodeling. In conclusion, GED-0507 demonstrated potent antifibrotic properties and might be a promising drug candidate for the treatment of pulmonary fibrosis.
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spelling pubmed-84454722021-09-17 GED-0507 attenuates lung fibrosis by counteracting myofibroblast transdifferentiation in vivo and in vitro Speca, Silvia Dubuquoy, Caroline Rousseaux, Christel Chavatte, Philippe Desreumaux, Pierre Spagnolo, Paolo PLoS One Research Article The development of more effective, better tolerated drug treatments for progressive pulmonary fibrosis (of which idiopathic pulmonary fibrosis is the most common and severe form) is a research priority. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a key regulator of inflammation and fibrosis and therefore represents a potential therapeutic target. However, the use of synthetic PPAR-γ agonists may be limited by their potentially severe adverse effects. In a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, we have demonstrated that the non-racemic selective PPAR-γ modulator GED-0507 is able to reduce body weight loss, ameliorate clinical and histological features of pulmonary fibrosis, and increase survival rate without any safety concerns. Here, we focused on the biomolecular effects of GED-0507 on various inflammatory/fibrotic pathways. We demonstrated that preventive and therapeutic administration of GED-0507 reduced the BLM-induced mRNA expression of several markers of fibrosis, including transforming growth factor (TGF)-β, alpha-smooth muscle actin, collagen and fibronectin as well as epithelial-to-mesenchymal transition (EMT) and expression of mucin 5B. The beneficial effect of GED-0507 on pulmonary fibrosis was confirmed in vitro by its ability to control TGFβ-induced myofibroblast activation in the A549 human alveolar epithelial cell line, the MRC-5 lung fibroblast line, and primary human lung fibroblasts. Compared with the US Food and Drug Administration-approved antifibrotic drugs pirfenidone and nintedanib, GED-0507 displayed greater antifibrotic activity by controlling alveolar epithelial cell dysfunction, EMT, and extracellular matrix remodeling. In conclusion, GED-0507 demonstrated potent antifibrotic properties and might be a promising drug candidate for the treatment of pulmonary fibrosis. Public Library of Science 2021-09-16 /pmc/articles/PMC8445472/ /pubmed/34529707 http://dx.doi.org/10.1371/journal.pone.0257281 Text en © 2021 Speca et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Speca, Silvia
Dubuquoy, Caroline
Rousseaux, Christel
Chavatte, Philippe
Desreumaux, Pierre
Spagnolo, Paolo
GED-0507 attenuates lung fibrosis by counteracting myofibroblast transdifferentiation in vivo and in vitro
title GED-0507 attenuates lung fibrosis by counteracting myofibroblast transdifferentiation in vivo and in vitro
title_full GED-0507 attenuates lung fibrosis by counteracting myofibroblast transdifferentiation in vivo and in vitro
title_fullStr GED-0507 attenuates lung fibrosis by counteracting myofibroblast transdifferentiation in vivo and in vitro
title_full_unstemmed GED-0507 attenuates lung fibrosis by counteracting myofibroblast transdifferentiation in vivo and in vitro
title_short GED-0507 attenuates lung fibrosis by counteracting myofibroblast transdifferentiation in vivo and in vitro
title_sort ged-0507 attenuates lung fibrosis by counteracting myofibroblast transdifferentiation in vivo and in vitro
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445472/
https://www.ncbi.nlm.nih.gov/pubmed/34529707
http://dx.doi.org/10.1371/journal.pone.0257281
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