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: | , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2017
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/256a03a648894ef7bd5c3c950dca5d67 |
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| Sumario: | 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. |
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