Chiou Hsin-Ying Clair, Wang Chih-Wen, Chen Szu-Chia, Tsai Mei-Lan, Lin Ming-Hong, Hung Chih-Hsing, Kuo Chao-Hung
Teaching and Research Center, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Antioxidants (Basel). 2023 Feb 20;12(2):532. doi: 10.3390/antiox12020532.
Copper is an essential trace element involved in several vital biological processes of the human body. However, excess exposure to copper caused by occupational hazards and environmental contamination, such as food, water, and air, damages human health. In this study, in vitro cell culture model and epidemiologic studies were conducted to evaluate the effect of copper on lung fibrosis. In vitro, treatment of CuSO in lung epithelial cells at 100 μM consistently decreases cell viability in alveolar type (A549) and human bronchial epithelial (HBE) cells. CuSO promotes epithelial-mesenchymal transition (EMT) as shown by increased cell migration and increased EMT marker and fibrotic gene expressions. Besides, CuSO induced cell autophagy, with an increased LC3, PINK, and decreased p62 expression. Inhibition of ROS by N-acetylcysteine reversed the CuSO-induced PINK1, LC3, and Snail expressions. Inhibition of autophagy by chloroquine reverses the CuSO-induced EMT changes. Nature flavonoids, especially kaempferol, and fustin, were shown to inhibit Copper-induced EMT. In humans, a unit increase in urinary copper concentration was significantly associated with an increased risk of lung fibrotic changes (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.01-1.36, = 0.038). These results indicated that Copper is a risk factor for lung fibrosis through activation of the ROS-autophagy-EMT pathway, which can be reversed by flavonoids.
铜是人体多种重要生物过程中必需的微量元素。然而，职业危害和环境污染（如食物、水和空气）导致的过量铜暴露会损害人体健康。在本研究中，进行了体外细胞培养模型和流行病学研究，以评估铜对肺纤维化的影响。在体外，100μM的硫酸铜处理肺上皮细胞会持续降低肺泡型（A549）和人支气管上皮（HBE）细胞的活力。硫酸铜促进上皮-间质转化（EMT），表现为细胞迁移增加以及EMT标志物和纤维化基因表达增加。此外，硫酸铜诱导细胞自噬，表现为LC3、PINK增加，p62表达降低。N-乙酰半胱氨酸抑制ROS可逆转硫酸铜诱导的PINK1、LC3和Snail表达。氯喹抑制自噬可逆转硫酸铜诱导的EMT变化。天然黄酮类化合物，尤其是山奈酚和黄颜木素，被证明可抑制铜诱导的EMT。在人类中，尿铜浓度每增加一个单位与肺纤维化改变风险增加显著相关（比值比[OR]=1.17，95%置信区间[CI]=1.01-1.36，P=0.038）。这些结果表明，铜通过激活ROS-自噬-EMT途径成为肺纤维化的一个风险因素，而黄酮类化合物可逆转这一过程。
