Treprostinil inhibits proliferation and extracellular matrix deposition by fibroblasts through cAMP activation

Abstract Idiopathic pulmonary fibrosis (IPF) is characterized by peripheral lung fibrosis and increased interstitial extracellular matrix (ECM) deposition. In IPF, tumor growth factor (TGF)-β1 which is the major stimulus of ECM deposition, and platelet derived growth factor (PDGF)-BB is a potent sti...

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Autores principales:	Christopher Lambers, Michael Roth, Peter Jaksch, Gabriella Muraközy, Michael Tamm, Walter Klepetko, Bahil Ghanim, Feng Zhao
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f625fea680f04117816d7088f850d594
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spelling	oai:doaj.org-article:f625fea680f04117816d7088f850d5942021-12-02T15:08:22ZTreprostinil inhibits proliferation and extracellular matrix deposition by fibroblasts through cAMP activation10.1038/s41598-018-19294-12045-2322https://doaj.org/article/f625fea680f04117816d7088f850d5942018-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-19294-1https://doaj.org/toc/2045-2322Abstract Idiopathic pulmonary fibrosis (IPF) is characterized by peripheral lung fibrosis and increased interstitial extracellular matrix (ECM) deposition. In IPF, tumor growth factor (TGF)-β1 which is the major stimulus of ECM deposition, and platelet derived growth factor (PDGF)-BB is a potent stimulus of fibrosis. Thus, the effect of Treprostinil on TGF-ß1 and PDGF-induced fibroblast proliferation and ECM deposition was investigated. Human peripheral lung fibroblasts of seven IPF patients and five lung donors were stimulated by PDGF, or TGF-β1, or the combination. Cells were pre-incubated (30 min) with either Treprostinil, forskolin, di-deoxyadenosine (DDA), or vehicle. Treprostinil time dependently activated cAMP thereby preventing PDGF-BB induced proliferation and TGF-β1 secretion. Cell counts indicated proliferation; α-smooth muscle actin (α-SMA) indicted differentiation, and collagen type-1 or fibronectin deposition remodeling. Myo-fibroblast indicating α-SMA expression was significantly reduced and its formation was altered by Treprostinil. Collagen type-I and fibronectin deposition were also reduced by Treprostinil. The effect of Treprostinil on collagen type-I deposition was cAMP sensitive as it was counteracted by DDA, while the effect on fibronectin was not cAMP mediated. Treprostinil antagonized the pro-fibrotic effects of both PDGF-BB and TGF-β1 in primary human lung fibroblasts. The data presented propose a therapeutic relevant anti-fibrotic effect of Treprostinil in IPF.Christopher LambersMichael RothPeter JakschGabriella MuraközyMichael TammWalter KlepetkoBahil GhanimFeng ZhaoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-10 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Christopher Lambers Michael Roth Peter Jaksch Gabriella Muraközy Michael Tamm Walter Klepetko Bahil Ghanim Feng Zhao Treprostinil inhibits proliferation and extracellular matrix deposition by fibroblasts through cAMP activation
description	Abstract Idiopathic pulmonary fibrosis (IPF) is characterized by peripheral lung fibrosis and increased interstitial extracellular matrix (ECM) deposition. In IPF, tumor growth factor (TGF)-β1 which is the major stimulus of ECM deposition, and platelet derived growth factor (PDGF)-BB is a potent stimulus of fibrosis. Thus, the effect of Treprostinil on TGF-ß1 and PDGF-induced fibroblast proliferation and ECM deposition was investigated. Human peripheral lung fibroblasts of seven IPF patients and five lung donors were stimulated by PDGF, or TGF-β1, or the combination. Cells were pre-incubated (30 min) with either Treprostinil, forskolin, di-deoxyadenosine (DDA), or vehicle. Treprostinil time dependently activated cAMP thereby preventing PDGF-BB induced proliferation and TGF-β1 secretion. Cell counts indicated proliferation; α-smooth muscle actin (α-SMA) indicted differentiation, and collagen type-1 or fibronectin deposition remodeling. Myo-fibroblast indicating α-SMA expression was significantly reduced and its formation was altered by Treprostinil. Collagen type-I and fibronectin deposition were also reduced by Treprostinil. The effect of Treprostinil on collagen type-I deposition was cAMP sensitive as it was counteracted by DDA, while the effect on fibronectin was not cAMP mediated. Treprostinil antagonized the pro-fibrotic effects of both PDGF-BB and TGF-β1 in primary human lung fibroblasts. The data presented propose a therapeutic relevant anti-fibrotic effect of Treprostinil in IPF.
format	article
author	Christopher Lambers Michael Roth Peter Jaksch Gabriella Muraközy Michael Tamm Walter Klepetko Bahil Ghanim Feng Zhao
author_facet	Christopher Lambers Michael Roth Peter Jaksch Gabriella Muraközy Michael Tamm Walter Klepetko Bahil Ghanim Feng Zhao
author_sort	Christopher Lambers
title	Treprostinil inhibits proliferation and extracellular matrix deposition by fibroblasts through cAMP activation
title_short	Treprostinil inhibits proliferation and extracellular matrix deposition by fibroblasts through cAMP activation
title_full	Treprostinil inhibits proliferation and extracellular matrix deposition by fibroblasts through cAMP activation
title_fullStr	Treprostinil inhibits proliferation and extracellular matrix deposition by fibroblasts through cAMP activation
title_full_unstemmed	Treprostinil inhibits proliferation and extracellular matrix deposition by fibroblasts through cAMP activation
title_sort	treprostinil inhibits proliferation and extracellular matrix deposition by fibroblasts through camp activation
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/f625fea680f04117816d7088f850d594
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Treprostinil inhibits proliferation and extracellular matrix deposition by fibroblasts through cAMP activation

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