Hyperphosphorylation of EGFR/ERK signaling facilitates long-term arsenite-induced hepatocytes epithelial-mesenchymal transition and liver fibrosis in sprague-dawley rats
Hyperphosphorylation of EGFR/ERK signaling facilitates long-term arsenite-induced hepatocytes epithelial-mesenchymal transition and liver fibrosis in sprague-dawley rats
复制标题
EGFR/ERK信号的过度磷酸化促进长期亚砷酸盐诱导的sprague-dawley大鼠肝细胞上皮-间质转化和肝纤维化
DOI：
10.1016/j.ecoenv.2022.114386
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发表时间：
2022
影响因子：
6.8
通讯作者：
Ying Jin
中科院分区：
文献类型：
--
作者：
Dapeng Wang;Huifen Xu;Lili Fan;Wenli Ruan;Qian Song;Heng Diao;Rui He;Ying Jin
砷是一种众所周知的环境危害物质，慢性砷暴露会导致不同类型的肝脏损害。其中，肝纤维化因其可逆性成为研究热点，但其潜在机制仍不清楚。先前的研究表明 EGFR/ERK 信号传导似乎在纤维化疾病中发挥重要作用。在这项研究中，sprague-dawley 大鼠暴露于不同剂量的亚砷酸盐 36 周，以研究 EGFR/ERK 信号在亚砷酸盐诱导的肝纤维形成中的作用。我们的研究结果表明，长期暴露于亚砷酸盐会导致肝纤维化，并伴有肝星状细胞（HSC）活化、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，亚砷酸盐暴露引起大鼠肝组织中EGFR/ERK信号过度磷酸化，表明EGFR/ERK信号可能参与亚砷酸盐诱导的肝纤维化。事实上，厄洛替尼（EGFR 的特异性磷酸化抑制剂）干预显着降低亚砷酸盐诱导的 EGFR/ERK 信号过度磷酸化，从而抑制肝细胞 EMT 过程并减轻亚砷酸盐暴露大鼠的肝纤维化。总之，本研究提供的证据表明，EGFR/ERK信号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的发病机制带来了新的见解。
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.