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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2017-11-01
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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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