Low-molecular-weight fucoidan attenuates bleomycin-induced pulmonary fibrosis: possible role in inhibiting TGF-β1-induced epithelial-mesenchymal transition through ERK pathway
Low-molecular-weight fucoidan attenuates bleomycin-induced pulmonary fibrosis: possible role in inhibiting TGF-β1-induced epithelial-mesenchymal transition through ERK pathway
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低分子量岩藻依聚糖减弱博莱霉素诱导的肺纤维化：通过 ERK 途径抑制 TGF-β1 诱导的上皮间质转化的可能作用
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通讯作者：
王辰
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作者：
王璐;张盼;李新鹏;张祎;詹庆元;王辰
翻译后摘要：肺纤维化（PF），进行性肺间质疾病的治疗选择是非常有限的。研究表明，转化生长因子-β1（TGF-β1）诱导的上皮-间质转化（EMT）是导致肾纤维化的一个重要介导过程。低分子量褐藻多糖硫酸酯（LMWF）具有抗纤维化作用，可抑制TGF-β1介导的EMT，从而减轻肾纤维化。因此，我们假设LMWF可能是一个有吸引力的候选人，以减轻PF。80 C57 BL/6小鼠和A549细胞分别参与了我们的体内和体外实验。采用HE染色、Masson三色染色、肺湿重/干重比、羟脯氨酸含量等指标评价肺纤维化程度。采用酶联免疫吸附试验（ELISA）和免疫荧光法检测TGF-β1水平，免疫组化染色、实时荧光定量PCR和Western blot法检测EMT标志物和细胞外信号调节激酶（ERK）信号通路的表达。正如预期的那样，我们的体内模型显示LMWF与改善的肺纤维化组织病理学和显著降低的肺羟脯氨酸含量相关。支气管肺泡灌洗液（BALF）和肺组织中TGF-β1表达水平较治疗前下降。免疫染色、实时PCR和蛋白质印迹表明，给予LMWF后，肺EMT表型减弱，ERK信号转导下调。体外实验结果表明，TGF-β1诱导的EMT具有类似的药理学抑制作用，并下调ERK信号转导。以上结果初步表明，LMWF可通过ERK信号通路抑制TGF-β1诱导的EMT，从而减轻博莱霉素诱导的PF。
Abstract: The therapeutic options for pulmonary fibrosis (PF), a progressive interstitial disease of the lung, are extremely limited. Studies have shown that transforming growth factor-β1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) functions as a central mediating process that contributes to PF. Also, low-molecular-weight fucoidan (LMWF), a sulfated polysaccharide extracted from brown seaweed, has been reported to have antifibrotic characteristics that can help to alleviate kidney fibrosis by inhibiting TGF-β1-mediated EMT. Thus we hypothesized that LMWF might be an attractive candidate for alleviating PF. Eighty C57BL/6 mice and A549 cells were respectively involved in our vivo and vitro experiments. The lung fibrosis was primarily assessed by hematoxylin and eosin (H&E), Masson’s trichrome stain, lung wet-to-dry weight ratio and hydroxyproline content. TGF-β1 levels were determined by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence, and the expression of EMT markers and extracellular signal-regulated kinase (ERK) signaling were mainly based on immunostaining, real-time PCR and Western blot. As expected, our vivo models showed that LMWF was associated with improved lung fibrotic histopathology and significantly reduced lung hydroxyproline content. Levels of TGF-β1 expression in bronchoalveolar lavage fluid (BALF) and lung tissue decreased than it had been before treatment. Immunostaining, real-time PCR, and Western blot demonstrated that the lung EMT phenotype was attenuated and ERK signaling downregulated after LMWF administration. The vitro experiments resulted in a similar pharmacologic inhibitory effect of TGF-β1-induced EMT with downregulated ERK signaling. Collectively, our results preliminary suggested that LMWF could attenuate bleomycin-induced PF by inhibiting TGF-β1-induced EMT through ERK signaling.