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.
Highlights
Fibrosing diseases such as severe asthma, ischemic heart disease, cirrhosis of the liver, end stage kidney disease, and idiopathic pulmonary fibrosis (IPF) involve the inappropriate formation of scar tissue in an internal organ, and are associated with an estimated 45% of all deaths in the US1–4
To determine if desialylation of proteins can be observed in pulmonary fibrosis, we stained tissue sections with Sambucus nigra lectin (SNA) or Maackia amurensis lectin II (Mal II), which detect sialic acids on glycoconjugates, or peanut agglutinin (PNA), which detects a variety of carbohydrates if they are not sialylated[46]
Compared to chronic obstructive pulmonary disease (COPD) patient lungs with relatively normal lung function, or compared to control mouse lungs, fibrotic human lungs and fibrotic mouse lungs showed less staining for sialylated glycoconjugates, and increased staining for desialylated glycoconjugates (Fig. 1a–d)
Summary
Fibrosing diseases such as severe asthma, ischemic heart disease, cirrhosis of the liver, end stage kidney disease, and idiopathic pulmonary fibrosis (IPF) involve the inappropriate formation of scar tissue in an internal organ, and are associated with an estimated 45% of all deaths in the US1–4. Bacteria, protozoa, and all mammals have sialidases ( known as neuraminidases) that remove the sialic acids from glycoconjugates[10,11]. When CRP was mutated to have a glycosylation similar to that of SAP (including a terminal sialic acid), the resulting CRP A32N was essentially indistinguishable from SAP in in vitro assays on neutrophils, monocytes, and macrophages[34]. (c) Mouse lungs at day 21 after saline or bleomycin treatment were stained with MAL II to detect sialic acid on glycoconjugates or with. (f) Total sialic acid from the day 21 lung tissue of saline- or bleomycin-treated mice.
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