Copper Exposure Induces Epithelial-Mesenchymal Transition-Related Fibrotic Change via Autophagy and Increase Risk of Lung Fibrosis in Human
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...
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| Format: | Article |
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MDPI AG
2023-02-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/12/2/532 |
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| author | Hsin-Ying Clair Chiou Chih-Wen Wang Szu-Chia Chen Mei-Lan Tsai Ming-Hong Lin Chih-Hsing Hung Chao-Hung Kuo |
| author_facet | Hsin-Ying Clair Chiou Chih-Wen Wang Szu-Chia Chen Mei-Lan Tsai Ming-Hong Lin Chih-Hsing Hung Chao-Hung Kuo |
| author_sort | Hsin-Ying Clair Chiou |
| collection | DOAJ |
| description | 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<sub>4</sub> in lung epithelial cells at 100 μM consistently decreases cell viability in alveolar type (A549) and human bronchial epithelial (HBE) cells. CuSO<sub>4</sub> promotes epithelial-mesenchymal transition (EMT) as shown by increased cell migration and increased EMT marker and fibrotic gene expressions. Besides, CuSO<sub>4</sub> induced cell autophagy, with an increased LC3, PINK, and decreased p62 expression. Inhibition of ROS by N-acetylcysteine reversed the CuSO<sub>4</sub>-induced PINK1, LC3, and Snail expressions. Inhibition of autophagy by chloroquine reverses the CuSO<sub>4</sub>-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, <i>p</i> = 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. |
| first_indexed | 2024-03-11T09:13:58Z |
| format | Article |
| id | doaj.art-5921b776edcb41089a3efdfa90e4cec6 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-11T09:13:58Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-5921b776edcb41089a3efdfa90e4cec62023-11-16T18:49:36ZengMDPI AGAntioxidants2076-39212023-02-0112253210.3390/antiox12020532Copper Exposure Induces Epithelial-Mesenchymal Transition-Related Fibrotic Change via Autophagy and Increase Risk of Lung Fibrosis in HumanHsin-Ying Clair Chiou0Chih-Wen Wang1Szu-Chia Chen2Mei-Lan Tsai3Ming-Hong Lin4Chih-Hsing Hung5Chao-Hung Kuo6Teaching and Research Center, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung 807, TaiwanDivision of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, TaiwanDepartment of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung 807, TaiwanGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanDepartment of Microbiology and Immunology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanResearch Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanDepartment of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung 807, TaiwanCopper 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<sub>4</sub> in lung epithelial cells at 100 μM consistently decreases cell viability in alveolar type (A549) and human bronchial epithelial (HBE) cells. CuSO<sub>4</sub> promotes epithelial-mesenchymal transition (EMT) as shown by increased cell migration and increased EMT marker and fibrotic gene expressions. Besides, CuSO<sub>4</sub> induced cell autophagy, with an increased LC3, PINK, and decreased p62 expression. Inhibition of ROS by N-acetylcysteine reversed the CuSO<sub>4</sub>-induced PINK1, LC3, and Snail expressions. Inhibition of autophagy by chloroquine reverses the CuSO<sub>4</sub>-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, <i>p</i> = 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.https://www.mdpi.com/2076-3921/12/2/532copperpulmonary fibrosisepithelial-mesenchymal transitionflavonoidautophagy |
| spellingShingle | Hsin-Ying Clair Chiou Chih-Wen Wang Szu-Chia Chen Mei-Lan Tsai Ming-Hong Lin Chih-Hsing Hung Chao-Hung Kuo Copper Exposure Induces Epithelial-Mesenchymal Transition-Related Fibrotic Change via Autophagy and Increase Risk of Lung Fibrosis in Human Antioxidants copper pulmonary fibrosis epithelial-mesenchymal transition flavonoid autophagy |
| title | Copper Exposure Induces Epithelial-Mesenchymal Transition-Related Fibrotic Change via Autophagy and Increase Risk of Lung Fibrosis in Human |
| title_full | Copper Exposure Induces Epithelial-Mesenchymal Transition-Related Fibrotic Change via Autophagy and Increase Risk of Lung Fibrosis in Human |
| title_fullStr | Copper Exposure Induces Epithelial-Mesenchymal Transition-Related Fibrotic Change via Autophagy and Increase Risk of Lung Fibrosis in Human |
| title_full_unstemmed | Copper Exposure Induces Epithelial-Mesenchymal Transition-Related Fibrotic Change via Autophagy and Increase Risk of Lung Fibrosis in Human |
| title_short | Copper Exposure Induces Epithelial-Mesenchymal Transition-Related Fibrotic Change via Autophagy and Increase Risk of Lung Fibrosis in Human |
| title_sort | copper exposure induces epithelial mesenchymal transition related fibrotic change via autophagy and increase risk of lung fibrosis in human |
| topic | copper pulmonary fibrosis epithelial-mesenchymal transition flavonoid autophagy |
| url | https://www.mdpi.com/2076-3921/12/2/532 |
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