MMP-3 activation is involved in copper oxide nanoparticle-induced epithelial-mesenchymal transition in human lung epithelial cells.
MMP-3 activation is involved in copper oxide nanoparticle-induced epithelial-mesenchymal transition in human lung epithelial cells.
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DOI：
10.1080/17435390.2022.2030822
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发表时间：
2021-12
期刊：
影响因子：
5
通讯作者：
Zhang, Qunwei
中科院分区：
文献类型：
--
作者：
Zhang, Yuanbao;Mo, Yiqun;Yuan, Jiali;Zhang, Yue;Mo, Luke;Zhang, Qunwei
纳米氧化铜（Nano-CuO）广泛应用于医疗、工业领域以及我们的日常生活用品中。然而，纳米CuO的生物安全性评价远远落后于其快速发展。在这里，我们研究了纳米CuO对正常人支气管上皮BEAS-2B细胞的不利影响，特别是确定纳米CuO暴露是否导致MMP-3（肺纤维化的重要介质）失调，及其在上皮间质转化（EMT）中的潜在作用。我们的结果表明，接触纳米 CuO（而非纳米 TiO2）会导致 ROS 生成、MAPK 激活和 MMP-3 表达增加。在线粒体 DNA 耗尽的 BEAS-2B ρ0 细胞中未观察到纳米 CuO 诱导的 ROS 生成，表明线粒体可能是纳米 CuO 诱导的 ROS 生成的主要来源。用ROS清除剂或抑制剂预处理细胞或消耗线粒体DNA显着减弱纳米CuO诱导的MAPK激活和MMP-3上调，用MAPK抑制剂预处理细胞消除了纳米CuO诱导的MMP-3上调，表明纳米CuO诱导的MMP-3上调是通过纳米CuO诱导的ROS生成和MAPK激活。此外，细胞暴露于 Nano-CuO 48 h 导致 E-钙粘蛋白表达降低，波形蛋白、α-SMA 和纤连蛋白表达增加，MMP-3 siRNA 转染可改善这种情况，表明 MMP-3 在 Nano-CuO 诱导的 EMT 中发挥重要作用。综上所述，我们的研究表明，纳米 CuO 暴露导致线粒体 ROS 生成、MAPK 激活和 MMP-3 上调。纳米 CuO 暴露还导致细胞经历 EMT，这是通过纳米 CuO 诱导 ROS/MAPKs/MMP-3 通路失调而实现的。我们的研究结果将有助于进一步了解金属纳米颗粒诱导的各种毒性作用（包括 EMT 和肺纤维化）的潜在机制。
Copper oxide nanoparticles (Nano-CuO) are wildly used in medical and industrial fields and our daily necessities. However, the biosafety assessment of Nano-CuO is far behind their rapid development. Here, we investigated the adverse effects of Nano-CuO on normal human bronchial epithelial BEAS-2B cells, especially determined whether Nano-CuO exposure caused dysregulation of MMP-3, an important mediator in pulmonary fibrosis, and its potential role in epithelial-mesenchymal transition (EMT). Our results showed that exposure to Nano-CuO, but not Nano-TiO2, caused increased ROS generation, MAPKs activation, and MMP-3 expression. Nano-CuO-induced ROS generation was not observed in mitochondrial DNA-depleted BEAS-2B ρ0 cells, indicating that mitochondria may be the main source of Nano-CuO-induced ROS generation. Pre-treatment of cells with ROS scavengers or inhibitors or depleting mitochondrial DNA significantly attenuated Nano-CuO-induced MAPKs activation and MMP-3 upregulation, and pre-treatment of cells with MAPKs inhibitors abolished Nano-CuO-induced MMP-3 upregulation, suggesting Nano-CuO-induced MMP-3 upregulation is through Nano-CuO-induced ROS generation and MAPKs activation. In addition, exposure of cells to Nano-CuO for 48 h resulted in decreased E-cadherin expression and increased expression of vimentin, α-SMA, and fibronectin, which was ameliorated by MMP-3 siRNA transfection, suggesting an important role of MMP-3 in Nano-CuO-induced EMT. Taken together, our study demonstrated that Nano-CuO exposure caused mitochondrial ROS generation, MAPKs activation, and MMP-3 upregulation. Nano-CuO exposure also caused cells to undergo EMT, which was through Nano-CuO-induced dysregulation of ROS/MAPKs/MMP-3 pathway. Our findings will provide further understanding of the potential mechanisms involved in metal nanoparticle-induced various toxic effects including EMT and pulmonary fibrosis.
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影响因子：
3.4
作者：
Bałkowiec M;Maksym RB;Włodarski PK
通讯作者：
Włodarski PK
DOI：
10.1097/00043764-198312000-00011
发表时间：
1983-01-01
影响因子：
3.2
作者：
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3.3
作者：
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影响因子：
3.3
作者：
Costa, Pedro M.;Gosens, Ilse;Fadeel, Bengt
通讯作者：
Fadeel, Bengt