Silencing of Carbohydrate Sulfotransferase 15 Hinders Murine Pulmonary Fibrosis Development.
Silencing of Carbohydrate Sulfotransferase 15 Hinders Murine Pulmonary Fibrosis Development.
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DOI：
10.1016/j.omtn.2016.12.008
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发表时间：
2017-03-17
期刊：
影响因子：
--
通讯作者：
Kimura H
中科院分区：
文献类型：
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作者：
Kai Y;Tomoda K;Yoneyama H;Kitabatake M;Nakamura A;Ito T;Yoshikawa M;Kimura H
肺纤维化是一种以间质纤维化为特征的进行性肺部疾病，目前尚无有效的治疗方法。硫酸软骨素蛋白聚糖（CSPG）已被证明是一种介导剂，但CSPG的糖胺聚糖链的具体组分尚未被探索。我们发现，硫酸软骨素E型（CS-E）参与纤维化。设计了针对碳水化合物磺基转移酶15（CHST 15）的小干扰RNA（siRNA），以抑制CHST 15 mRNA及其产物CS-E。CS-E增强细胞收缩，CHST 15 siRNA抑制胶原蛋白产生。我们发现博来霉素处理在第14天增加了间质成纤维细胞中CHST 15的表达。在第1、4、8和11天鼻内注射CHST 15 siRNA，到第14天CHST 15 mRNA被显著抑制。CHST 15 siRNA降低了肺CSPG和纤维化程度。CHST 15 siRNA抑制了成纤维细胞的活化，如通过抑制α平滑肌肌动蛋白（αSMA）、结缔组织生长因子（CTGF）、赖氨酰氧化酶样2（LOXL 2）和CC-趋化因子配体2（CCL 2）/单核细胞趋化蛋白-1（MCP-1）的表达所证明的。CHST 15 siRNA可减少支气管肺泡灌洗液（BALF）和肺泡中的炎性浸润。这些结果表明CHST 15在成纤维细胞介导的肺纤维化中的关键作用，并提示CHST 15 siRNA在肺纤维化中可能的新治疗作用。
Pulmonary fibrosis is a progressive lung disorder characterized by interstitial fibrosis, for which no effective treatments are available. Chondroitin sulfate proteoglycan (CSPG) has been shown to be a mediator, but the specific component of glycosaminoglycan chains of CSPG has not been explored. We show that chondroitin sulfate E-type (CS-E) is involved in fibrogenesis. Small interfering RNA (siRNA) targeting carbohydrate sulfotransferase 15 (CHST15) was designed to inhibit CHST15 mRNA and its product, CS-E. CS-E augments cell contraction and CHST15 siRNA inhibits collagen production. We found that bleomycin treatment increased CHST15 expression in interstitial fibroblasts at day 14. CHST15 siRNA was injected intranasally on days 1, 4, 8, and 11, and CHST15 mRNA was significantly suppressed by day 14. CHST15 siRNA reduced lung CSPG and the grade of fibrosis. CHST15 siRNA repressed the activation of fibroblasts, as evidenced by suppressed expression of α smooth muscle actin (αSMA), connective tissue growth factor (CTGF), lysyl oxidase like 2 (LOXL2), and CC-chemokine ligand 2 (CCL2)/monocyte chemoattractant protein-1 (MCP-1). Inflammatory infiltrates in the bronchoalveolar lavage fluid (BALF) and interstitium were diminished by CHST15 siRNA. These results indicate a pivotal role for CHST15 in fibroblast-mediated lung fibrosis and suggest a possible new therapeutic role for CHST15 siRNA in pulmonary fibrosis.
DOI：
10.1083/jcb.108.3.1165
发表时间：
1989-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
David G;Lories V;Heremans A;Van der Schueren B;Cassiman JJ;Van den Berghe H
通讯作者：
Van den Berghe H