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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Main Authors: Tejas R. Karhadkar, Darrell Pilling, Nehemiah Cox, Richard H. Gomer
Format: Article
Language:English
Published: Nature Publishing Group 2017-11-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-017-15198-8
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spelling doaj-256a03a648894ef7bd5c3c950dca5d672020-12-08T00:35:38ZengNature Publishing GroupScientific Reports2045-23222017-11-017111210.1038/s41598-017-15198-8Sialidase inhibitors attenuate pulmonary fibrosis in a mouse modelTejas R. Karhadkar0Darrell Pilling1Nehemiah Cox2Richard H. Gomer3Department of Biology, Texas A&M UniversityDepartment of Biology, Texas A&M UniversityDepartment of Biology, Texas A&M UniversityDepartment of Biology, Texas A&M UniversityAbstract 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.https://doi.org/10.1038/s41598-017-15198-8
collection DOAJ
language English
format Article
sources DOAJ
author Tejas R. Karhadkar
Darrell Pilling
Nehemiah Cox
Richard H. Gomer
spellingShingle Tejas R. Karhadkar
Darrell Pilling
Nehemiah Cox
Richard H. Gomer
Sialidase inhibitors attenuate pulmonary fibrosis in a mouse model
Scientific Reports
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 Publishing Group
series Scientific Reports
issn 2045-2322
publishDate 2017-11-01
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.
url https://doi.org/10.1038/s41598-017-15198-8
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AT richardhgomer sialidaseinhibitorsattenuatepulmonaryfibrosisinamousemodel
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