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Pan-Phosphodiesterase Inhibitors Attenuate TGF-β-Induced Pro-Fibrotic Phenotype in Alveolar Epithelial Type II Cells by Downregulating Smad-2 Phosphorylation

Airway remodeling is a pathological process that accompanies many chronic lung diseases. One of the important players in this process are epithelial cells, which under the influence of pro-inflammatory and pro-fibrotic factors present in the airway niche, actively participate in the remodeling proce...

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Autores principales: Wójcik-Pszczoła, Katarzyna, Chłoń-Rzepa, Grażyna, Jankowska, Agnieszka, Ferreira, Bruno, Koczurkiewicz-Adamczyk, Paulina, Pękala, Elżbieta, Wyska, Elżbieta, Pociecha, Krzysztof, Gosens, Reinoud
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9024446/
https://www.ncbi.nlm.nih.gov/pubmed/35455420
http://dx.doi.org/10.3390/ph15040423
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author Wójcik-Pszczoła, Katarzyna
Chłoń-Rzepa, Grażyna
Jankowska, Agnieszka
Ferreira, Bruno
Koczurkiewicz-Adamczyk, Paulina
Pękala, Elżbieta
Wyska, Elżbieta
Pociecha, Krzysztof
Gosens, Reinoud
author_facet Wójcik-Pszczoła, Katarzyna
Chłoń-Rzepa, Grażyna
Jankowska, Agnieszka
Ferreira, Bruno
Koczurkiewicz-Adamczyk, Paulina
Pękala, Elżbieta
Wyska, Elżbieta
Pociecha, Krzysztof
Gosens, Reinoud
author_sort Wójcik-Pszczoła, Katarzyna
collection PubMed
description Airway remodeling is a pathological process that accompanies many chronic lung diseases. One of the important players in this process are epithelial cells, which under the influence of pro-inflammatory and pro-fibrotic factors present in the airway niche, actively participate in the remodeling process by increasing extracellular matrix secretion, acquiring migration properties, and overproducing pro-fibrotic transducers. Here, we investigated the effect of three new 8-arylalkylamino- and 8-alkoxy-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl-N-(5-(tert-butyl)-2-hydroxyphenyl)butanamides (1, 2, and 3), representing prominent pan-phosphodiesterase (pan-PDE) inhibitors on transforming growth factor type β (TGF-β)-induced alveolar epithelial type II cells (A549 cell line) of a pro-fibrotic phenotype. Our results demonstrate for the first time the strong activity of pan-PDE inhibitors in the prevention of TGF-β-induced mesenchymal markers’ expression and A549 cells’ migration. We also showed an increased p-CREB and decreased p-Smad-2 phosphorylation in TGF-β-induced A549 cells treated with 1, 2, and 3 derivatives, thereby confirming a pan-PDE inhibitor mesenchymal phenotype reducing effect in alveolar epithelial type II cells via suppression of the canonical Smad signaling pathway. Our observations confirmed that PDE inhibitors, and especially those active against various isoforms involved in the airway remodeling, constitute an interesting group of compounds modulating the pro-fibrotic response of epithelial cells.
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spelling pubmed-90244462022-04-23 Pan-Phosphodiesterase Inhibitors Attenuate TGF-β-Induced Pro-Fibrotic Phenotype in Alveolar Epithelial Type II Cells by Downregulating Smad-2 Phosphorylation Wójcik-Pszczoła, Katarzyna Chłoń-Rzepa, Grażyna Jankowska, Agnieszka Ferreira, Bruno Koczurkiewicz-Adamczyk, Paulina Pękala, Elżbieta Wyska, Elżbieta Pociecha, Krzysztof Gosens, Reinoud Pharmaceuticals (Basel) Article Airway remodeling is a pathological process that accompanies many chronic lung diseases. One of the important players in this process are epithelial cells, which under the influence of pro-inflammatory and pro-fibrotic factors present in the airway niche, actively participate in the remodeling process by increasing extracellular matrix secretion, acquiring migration properties, and overproducing pro-fibrotic transducers. Here, we investigated the effect of three new 8-arylalkylamino- and 8-alkoxy-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl-N-(5-(tert-butyl)-2-hydroxyphenyl)butanamides (1, 2, and 3), representing prominent pan-phosphodiesterase (pan-PDE) inhibitors on transforming growth factor type β (TGF-β)-induced alveolar epithelial type II cells (A549 cell line) of a pro-fibrotic phenotype. Our results demonstrate for the first time the strong activity of pan-PDE inhibitors in the prevention of TGF-β-induced mesenchymal markers’ expression and A549 cells’ migration. We also showed an increased p-CREB and decreased p-Smad-2 phosphorylation in TGF-β-induced A549 cells treated with 1, 2, and 3 derivatives, thereby confirming a pan-PDE inhibitor mesenchymal phenotype reducing effect in alveolar epithelial type II cells via suppression of the canonical Smad signaling pathway. Our observations confirmed that PDE inhibitors, and especially those active against various isoforms involved in the airway remodeling, constitute an interesting group of compounds modulating the pro-fibrotic response of epithelial cells. MDPI 2022-03-30 /pmc/articles/PMC9024446/ /pubmed/35455420 http://dx.doi.org/10.3390/ph15040423 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wójcik-Pszczoła, Katarzyna
Chłoń-Rzepa, Grażyna
Jankowska, Agnieszka
Ferreira, Bruno
Koczurkiewicz-Adamczyk, Paulina
Pękala, Elżbieta
Wyska, Elżbieta
Pociecha, Krzysztof
Gosens, Reinoud
Pan-Phosphodiesterase Inhibitors Attenuate TGF-β-Induced Pro-Fibrotic Phenotype in Alveolar Epithelial Type II Cells by Downregulating Smad-2 Phosphorylation
title Pan-Phosphodiesterase Inhibitors Attenuate TGF-β-Induced Pro-Fibrotic Phenotype in Alveolar Epithelial Type II Cells by Downregulating Smad-2 Phosphorylation
title_full Pan-Phosphodiesterase Inhibitors Attenuate TGF-β-Induced Pro-Fibrotic Phenotype in Alveolar Epithelial Type II Cells by Downregulating Smad-2 Phosphorylation
title_fullStr Pan-Phosphodiesterase Inhibitors Attenuate TGF-β-Induced Pro-Fibrotic Phenotype in Alveolar Epithelial Type II Cells by Downregulating Smad-2 Phosphorylation
title_full_unstemmed Pan-Phosphodiesterase Inhibitors Attenuate TGF-β-Induced Pro-Fibrotic Phenotype in Alveolar Epithelial Type II Cells by Downregulating Smad-2 Phosphorylation
title_short Pan-Phosphodiesterase Inhibitors Attenuate TGF-β-Induced Pro-Fibrotic Phenotype in Alveolar Epithelial Type II Cells by Downregulating Smad-2 Phosphorylation
title_sort pan-phosphodiesterase inhibitors attenuate tgf-β-induced pro-fibrotic phenotype in alveolar epithelial type ii cells by downregulating smad-2 phosphorylation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9024446/
https://www.ncbi.nlm.nih.gov/pubmed/35455420
http://dx.doi.org/10.3390/ph15040423
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