Sialidase inhibitors attenuate pulmonary fibrosis in a mouse model

Abstract Fibrosis involves increasing amounts of scar tissue appearing in a tissue, but what drives this is unclear. In fibrotic lesions in human and mouse lungs, we found extensive desialylation of glycoconjugates, and upregulation of sialidases. The fibrosis-associated cytokine TGF-β1 upregulates...

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Autores principales:	Tejas R. Karhadkar, Darrell Pilling, Nehemiah Cox, Richard H. Gomer
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/256a03a648894ef7bd5c3c950dca5d67
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spelling	oai:doaj.org-article:256a03a648894ef7bd5c3c950dca5d672021-12-02T15:05:43ZSialidase inhibitors attenuate pulmonary fibrosis in a mouse model10.1038/s41598-017-15198-82045-2322https://doaj.org/article/256a03a648894ef7bd5c3c950dca5d672017-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-15198-8https://doaj.org/toc/2045-2322Abstract Fibrosis involves increasing amounts of scar tissue appearing in a tissue, but what drives this is unclear. In fibrotic lesions in human and mouse lungs, we found extensive desialylation of glycoconjugates, and upregulation of sialidases. The fibrosis-associated cytokine TGF-β1 upregulates sialidases in human airway epithelium cells, lung fibroblasts, and immune system cells. Conversely, addition of sialidases to human peripheral blood mononuclear cells induces accumulation of extracellular TGF-β1, forming what appears to be a sialidase - TGF-β1 - sialidase positive feedback loop. Monocyte-derived cells called fibrocytes also activate fibroblasts, and we found that sialidases potentiate fibrocyte differentiation. A sialylated glycoprotein called serum amyloid P (SAP) inhibits fibrocyte differentiation, and sialidases attenuate SAP function. Injections of the sialidase inhibitors DANA and oseltamivir (Tamiflu) starting either 1 day or 10 days after bleomycin strongly attenuate pulmonary fibrosis in the mouse bleomycin model, and by breaking the feedback loop, cause a downregulation of sialidase and TGF-β1 accumulation. Together, these results suggest that a positive feedback loop involving sialidases potentiates fibrosis, and suggest that sialidase inhibitors could be useful for the treatment of fibrosis.Tejas R. KarhadkarDarrell PillingNehemiah CoxRichard H. GomerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tejas R. Karhadkar Darrell Pilling Nehemiah Cox Richard H. Gomer Sialidase inhibitors attenuate pulmonary fibrosis in a mouse model
description	Abstract Fibrosis involves increasing amounts of scar tissue appearing in a tissue, but what drives this is unclear. In fibrotic lesions in human and mouse lungs, we found extensive desialylation of glycoconjugates, and upregulation of sialidases. The fibrosis-associated cytokine TGF-β1 upregulates sialidases in human airway epithelium cells, lung fibroblasts, and immune system cells. Conversely, addition of sialidases to human peripheral blood mononuclear cells induces accumulation of extracellular TGF-β1, forming what appears to be a sialidase - TGF-β1 - sialidase positive feedback loop. Monocyte-derived cells called fibrocytes also activate fibroblasts, and we found that sialidases potentiate fibrocyte differentiation. A sialylated glycoprotein called serum amyloid P (SAP) inhibits fibrocyte differentiation, and sialidases attenuate SAP function. Injections of the sialidase inhibitors DANA and oseltamivir (Tamiflu) starting either 1 day or 10 days after bleomycin strongly attenuate pulmonary fibrosis in the mouse bleomycin model, and by breaking the feedback loop, cause a downregulation of sialidase and TGF-β1 accumulation. Together, these results suggest that a positive feedback loop involving sialidases potentiates fibrosis, and suggest that sialidase inhibitors could be useful for the treatment of fibrosis.
format	article
author	Tejas R. Karhadkar Darrell Pilling Nehemiah Cox Richard H. Gomer
author_facet	Tejas R. Karhadkar Darrell Pilling Nehemiah Cox Richard H. Gomer
author_sort	Tejas R. Karhadkar
title	Sialidase inhibitors attenuate pulmonary fibrosis in a mouse model
title_short	Sialidase inhibitors attenuate pulmonary fibrosis in a mouse model
title_full	Sialidase inhibitors attenuate pulmonary fibrosis in a mouse model
title_fullStr	Sialidase inhibitors attenuate pulmonary fibrosis in a mouse model
title_full_unstemmed	Sialidase inhibitors attenuate pulmonary fibrosis in a mouse model
title_sort	sialidase inhibitors attenuate pulmonary fibrosis in a mouse model
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/256a03a648894ef7bd5c3c950dca5d67
work_keys_str_mv	AT tejasrkarhadkar sialidaseinhibitorsattenuatepulmonaryfibrosisinamousemodel AT darrellpilling sialidaseinhibitorsattenuatepulmonaryfibrosisinamousemodel AT nehemiahcox sialidaseinhibitorsattenuatepulmonaryfibrosisinamousemodel AT richardhgomer sialidaseinhibitorsattenuatepulmonaryfibrosisinamousemodel
_version_	1718388692083539968

Sialidase inhibitors attenuate pulmonary fibrosis in a mouse model

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