beta-Elemene inhibits the proliferation of primary human airway granulation fibroblasts by down-regulating canonical Wnt/beta-catenin pathway
beta-Elemene inhibits the proliferation of primary human airway granulation fibroblasts by down-regulating canonical Wnt/beta-catenin pathway
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β-榄香烯通过下调经典 Wnt/β-catenin 通路抑制原代人气道颗粒成纤维细胞的增殖
DOI：
10.1042/bsr20171386
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发表时间：
2018
影响因子：
4
通讯作者：
Zeng Yi Ming
中科院分区：
文献类型：
--
作者：
Xue Cheng;Hong Ling Ling;Lin Jun Sheng;Yao Xiang Yang;Wu Ding Hui;Lin Xiao Ping;Zhang Jia Min;Zhang Xiao Bin;Zeng Yi Ming
由于肉芽组织复发，良性气道狭窄是一个临床挑战。我们前期的研究证明，一种中药β-榄香烯可以有效抑制增生性人气道肉芽组织中培养的成纤维细胞的生长，从而减缓该病的进展。本研究的目的是找出这种效应的机制。我们从正常人气道组织和人气道肉芽组织中培养成纤维细胞。这些细胞与 160 μg/ml 生理盐水 (NS)、不同剂量的 β-榄香烯或 10 ng/ml 经典 Wnt/β-catenin 通路抑制剂（Dickkopf-1、DKK-1）一起培养。测量细胞的增殖率以及参与经典Wnt/β-连环蛋白途径的六种分子的表达，即Wnt3a、糖原合成酶激酶-3β（GSK-3β）、β-连环蛋白、α-平滑肌肌动蛋白（α-SMA）、转化生长因子-β（TGF-β）和胶原蛋白I（Col-I）。最后，我们使用经典的Wnt/β-catenin通路激活剂（LiCl）进一步确定了β-榄香烯的作用机制。经典 Wnt/β-连环蛋白途径在人气道肉芽成纤维细胞中被激活。 β-榄香烯不影响正常人气道成纤维细胞；然而，它对人气道颗粒成纤维细胞的Wnt3a、非活性GSK-3β、β-连环蛋白、α-SMA、TGF-β和Col-I的增殖和表达具有剂量反应性抑制作用。更重要的是，它对活性β-连环蛋白的表达和核转位具有相同的作用。所有这些效应与 10 ng/ml DKK-1 相似，并且可以被 10 mM LiCl 减弱。因此，β-榄香烯通过下调经典 Wnt/β-catenin 通路来抑制原代人气道肉芽成纤维细胞的增殖。该通路可能是治疗良性气管支气管狭窄的有希望的靶标。
Benign airway stenosis is a clinical challenge because of recurrent granulation tissues. Our previous study proved that a Chinese drug, β-elemene, could effectively inhibit the growth of fibroblasts cultured from hyperplastic human airway granulation tissues, which could slow down the progression of this disease. The purpose of the present study is to find out the mechanism for this effect. We cultured fibroblasts from normal human airway tissues and human airway granulation tissues. These cells were cultured with 160 μg/ml normal saline (NS), different doses of β-elemene, or 10 ng/ml canonical Wnt/β-catenin pathway inhibitor (Dickkopf-1, DKK-1). The proliferation rate of cells and the expression of six molecules involved in canonical Wnt/β-catenin pathway, Wnt3a, glycogen synthase kinase-3β (GSK-3β), β-catenin, α-smooth muscle actin (α-SMA), transforming growth factor-β (TGF-β), and Collagen I (Col-I), were measured. At last, we used canonical Wnt/β-catenin pathway activator (LiCl) to further ascertain the mechanism of β-elemene. Canonical Wnt/β-catenin pathway is activated in human airway granulation fibroblasts. β-Elemene didn’t affect normal human airway fibroblasts; however, it had a dose–responsive inhibitive effect on the proliferation and expression of Wnt3a, non-active GSK-3β, β-catenin, α-SMA, TGF-β, and Col-I of human airway granulation fibroblasts. More importantly, it had the same effect on the expression and nuclear translocation of active β-catenin. All these effects were similar to 10 ng/ml DKK-1 and could be attenuated by 10 mM LiCl. Thus, β-elemene inhibits the proliferation of primary human airway granulation fibroblasts by down-regulating canonical Wnt/β-catenin pathway. This pathway is possibly a promising target to treat benign tracheobronchial stenosis.