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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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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. |
format | Online Article Text |
id | pubmed-8445472 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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