학술논문
Copper Exposure Induces Epithelial-Mesenchymal Transition-Related Fibrotic Change via Autophagy and Increase Risk of Lung Fibrosis in Human
Document Type
Report
Author
Source
Antioxidants. February 2023, Vol. 12 Issue 2
Subject
Language
English
ISSN
2076-3921
Abstract
Author(s): Hsin-Ying Clair Chiou [1,2,3,†]; Chih-Wen Wang [4,5,6,†]; Szu-Chia Chen [5,6,7]; Mei-Lan Tsai [8,9]; Ming-Hong Lin (corresponding author) [10,11,12,*]; Chih-Hsing Hung (corresponding author) [6,13,14,*]; Chao-Hung Kuo (corresponding author) [5,15,*] 1. [...]
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] in lung epithelial cells at 100 μM consistently decreases cell viability in alveolar type (A549) and human bronchial epithelial (HBE) cells. CuSO[sub.4] promotes epithelial-mesenchymal transition (EMT) as shown by increased cell migration and increased EMT marker and fibrotic gene expressions. Besides, CuSO[sub.4] induced cell autophagy, with an increased LC3, PINK, and decreased p62 expression. Inhibition of ROS by N-acetylcysteine reversed the CuSO[sub.4] -induced PINK1, LC3, and Snail expressions. Inhibition of autophagy by chloroquine reverses the CuSO[sub.4] -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, p = 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.
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] in lung epithelial cells at 100 μM consistently decreases cell viability in alveolar type (A549) and human bronchial epithelial (HBE) cells. CuSO[sub.4] promotes epithelial-mesenchymal transition (EMT) as shown by increased cell migration and increased EMT marker and fibrotic gene expressions. Besides, CuSO[sub.4] induced cell autophagy, with an increased LC3, PINK, and decreased p62 expression. Inhibition of ROS by N-acetylcysteine reversed the CuSO[sub.4] -induced PINK1, LC3, and Snail expressions. Inhibition of autophagy by chloroquine reverses the CuSO[sub.4] -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, p = 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.