Sialidase inhibitors attenuate pulmonary fibrosis in a mouse model.
Sialidase inhibitors attenuate pulmonary fibrosis in a mouse model.
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DOI：
10.1038/s41598-017-15198-8
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发表时间：
2017-11-08
影响因子：
4.6
通讯作者：
Gomer RH
中科院分区：
文献类型：
--
作者：
Karhadkar TR;Pilling D;Cox N;Gomer RH
纤维化涉及组织中出现的疤痕组织数量增加，但驱动因素尚不清楚。在人类和小鼠肺纤维化病变中，我们发现糖缀合物的广泛去唾液酸化和唾液酸酶的上调。纤维化相关细胞因子TGF-β1上调人气道上皮细胞、肺成纤维细胞和免疫系统细胞中的唾液酸酶。相反，向人外周血单核细胞中添加唾液酸酶诱导细胞外TGF-β1的积累，形成似乎是唾液酸酶- TGF-β1 -唾液酸酶正反馈环。称为纤维细胞的单核细胞衍生的细胞也激活成纤维细胞，并且我们发现唾液酸酶增强纤维细胞分化。一种称为血清淀粉样蛋白P（SAP）的唾液酸化糖蛋白抑制纤维细胞分化，唾液酸酶减弱SAP功能。在博莱霉素后1天或10天开始注射唾液酸酶抑制剂DANA和奥司他韦（达菲），可强烈减弱小鼠博莱霉素模型中的肺纤维化，并通过打破反馈回路，导致唾液酸酶和TGF-β1蓄积下调。总之，这些结果表明，涉及唾液酸酶的正反馈环增强纤维化，并表明唾液酸酶抑制剂可用于治疗纤维化。
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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DOI：
10.1146/annurev-pathol-020712-163930
发表时间：
2013-01-24
期刊：
Annual review of pathology
影响因子：
--
作者：
Duffield JS;Lupher M;Thannickal VJ;Wynn TA
通讯作者：
Wynn TA
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
32.4
作者：
Fielding, Ceri A.;Jones, Gareth W.;McLoughlin, Rachel M.;McLeod, Louise;Hammond, Victoria J.;Uceda, Javier;Williams, Anwen S.;Lambie, Mark;Foster, Thomas L.;Liao, Chia-Te;Rice, Christopher M.;Greenhill, Claire J.;Colmont, Chantal S.;Hams, Emily;Coles, Barbara;Kift-Morgan, Ann;Newton, Zarabeth;Craig, Katherine J.;Williams, John D.;Williams, Geraint T.;Davies, Simon J.;Humphreys, Ian R.;O'Donnell, Valerie B.;Taylor, Philip R.;Jenkins, Brendan J.;Topley, Nicholas;Jones, Simon A.
通讯作者：
Jones, Simon A.
影响因子：
3
作者：
Amith, Schammim Ray;Jayanth, Preethi;Szewczuk, Myron R.
通讯作者：
Szewczuk, Myron R.
影响因子：
4
作者：
D'Avila, Francesca;Tringali, Cristina;Venerando, Bruno
通讯作者：
Venerando, Bruno