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:	Silvia Speca, Caroline Dubuquoy, Christel Rousseaux, Philippe Chavatte, Pierre Desreumaux, Paolo Spagnolo
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4e14e0a06e454dd7afa2c0687228310a
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spelling	oai:doaj.org-article:4e14e0a06e454dd7afa2c0687228310a2021-12-02T20:06:15ZGED-0507 attenuates lung fibrosis by counteracting myofibroblast transdifferentiation in vivo and in vitro.1932-620310.1371/journal.pone.0257281https://doaj.org/article/4e14e0a06e454dd7afa2c0687228310a2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0257281https://doaj.org/toc/1932-6203The 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.Silvia SpecaCaroline DubuquoyChristel RousseauxPhilippe ChavattePierre DesreumauxPaolo SpagnoloPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 9, p e0257281 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Silvia Speca Caroline Dubuquoy Christel Rousseaux Philippe Chavatte Pierre Desreumaux Paolo Spagnolo GED-0507 attenuates lung fibrosis by counteracting myofibroblast transdifferentiation in vivo and in vitro.
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	article
author	Silvia Speca Caroline Dubuquoy Christel Rousseaux Philippe Chavatte Pierre Desreumaux Paolo Spagnolo
author_facet	Silvia Speca Caroline Dubuquoy Christel Rousseaux Philippe Chavatte Pierre Desreumaux Paolo Spagnolo
author_sort	Silvia Speca
title	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_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_sort	ged-0507 attenuates lung fibrosis by counteracting myofibroblast transdifferentiation in vivo and in vitro.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/4e14e0a06e454dd7afa2c0687228310a
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GED-0507 attenuates lung fibrosis by counteracting myofibroblast transdifferentiation in vivo and in vitro.

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