Wang Dapeng, Xu Huifen, Fan Lili, Ruan Wenli, Song Qian, Diao Heng, He Rui, Jin Ying
Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, China.
Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, China.
Ecotoxicol Environ Saf. 2023 Jan 1;249:114386. doi: 10.1016/j.ecoenv.2022.114386. Epub 2022 Dec 9.
Arsenic is a well known environmental hazardous material, chronic arsenic exposure results in different types of liver damage. Among them, liver fibrosis has become a research hotspot because of its reversibility, while the underlying mechanism is still unclear. Previous studies revealed that EGFR/ERK signaling appears to play an important role in fibrosis diseases. In this study, sprague-dawley rats were exposed to different doses of arsenite for 36 weeks to investigate the roles of EGFR/ERK signaling on arsenite-induced liver fibrogenesis. Our results showed that long-term arsenite exposure induced liver fibrosis, accompanied by hepatic stellate cells (HSCs) activation, excessive serum secretion of extracellular matrix (ECM), and hepatocytes epithelial-mesenchymal transformation (EMT). In addition, arsenite exposure caused hyperphosphorylation of EGFR/ERK signaling in liver tissue of rats, indicating that EGFR/ERK signaling may be involved in arsenite-induced liver fibrosis. Indeed, erlotinib (a specific phosphorylation inhibitor of EGFR) intervention significantly decreased arsenite induced hyperphosphorylation of EGFR/ERK signaling, thereby suppressed hepatocytes EMT process and alleviated liver fibrogenesis in arsenite exposed rats. In summary, the present study provides evidences showing that hyperphosphorylation of EGFR/ERK signaling facilitates long-term arsenite-induced hepatocytes EMT and liver fibrosis in rats, which brings new insights into the pathogenesis of arsenic-induced liver injury.
砷是一种众所周知的环境有害物质，长期接触砷会导致不同类型的肝损伤。其中，肝纤维化因其可逆性已成为研究热点，但其潜在机制仍不清楚。先前的研究表明，表皮生长因子受体/细胞外信号调节激酶（EGFR/ERK）信号通路似乎在纤维化疾病中起重要作用。在本研究中，将斯普拉格-道利大鼠暴露于不同剂量的亚砷酸盐中36周，以研究EGFR/ERK信号通路在亚砷酸盐诱导的肝纤维化中的作用。我们的结果表明，长期暴露于亚砷酸盐会导致肝纤维化，伴有肝星状细胞（HSCs）激活、细胞外基质（ECM）血清分泌过多以及肝细胞上皮-间质转化（EMT）。此外，亚砷酸盐暴露导致大鼠肝组织中EGFR/ERK信号通路的过度磷酸化，表明EGFR/ERK信号通路可能参与亚砷酸盐诱导的肝纤维化。事实上，厄洛替尼（一种EGFR的特异性磷酸化抑制剂）干预显著降低了亚砷酸盐诱导的EGFR/ERK信号通路的过度磷酸化，从而抑制了亚砷酸盐暴露大鼠的肝细胞EMT过程并减轻了肝纤维化。总之，本研究提供的证据表明，EGFR/ERK信号通路的过度磷酸化促进了长期亚砷酸盐诱导的大鼠肝细胞EMT和肝纤维化，这为砷诱导的肝损伤发病机制带来了新的见解。
