Department of Occupational and Environmental Health, Dalian Medical University, Dalian, China.
Experimental Teaching Center of Public Health, Dalian Medical University, Dalian, China.
J Cell Physiol. 2021 Feb;236(2):1469-1480. doi: 10.1002/jcp.29952. Epub 2020 Aug 10.
Liver fibrosis is a severe health problem worldwide, and it is characterized by the activation of hepatic stellate cells (HSCs) and excessive deposition of collagen. Prolonged arsenic exposure can induce HSCs activation and liver fibrosis. In the present study, the results showed that chronic NaAsO ingestion could result in liver fibrosis and oxidative stress in Sprague-Dawley rats, along with representative collagen deposition and HSCs activation. In addition, the inositol-requiring enzyme 1α (IRE1α)-endoplasmic reticulum (ER)-stress pathway was activated, and the activity of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) was upregulated in rat livers. Simultaneously, the excessive production of reactive oxygen species (ROS) could induce HSCs activation, and NOX4 played an important role in generating ROS in vitro. Moreover, ER stress occurred with HSCs activation at the same time under NaAsO exposure, and during ER stress, the IRE1α pathway was responsible for NOX4 activation. Therefore, inhibition of IRE1α activation could attenuate the HSCs activation induced by NaAsO . In conclusion, the present study manifested that inorganic arsenic exposure could activate HSCs through IRE1α/NOX4-mediated ROS generation.
肝纤维化是全球范围内的严重健康问题，其特征是肝星状细胞（HSCs）的激活和胶原的过度沉积。长期砷暴露可诱导 HSCs 激活和肝纤维化。在本研究中，结果表明，慢性 NaAsO 摄入可导致 Sprague-Dawley 大鼠肝纤维化和氧化应激，同时伴有代表性的胶原沉积和 HSCs 激活。此外，肌醇需求酶 1α（IRE1α）-内质网（ER）应激途径被激活，烟酰胺腺嘌呤二核苷酸磷酸氧化酶 4（NOX4）的活性在大鼠肝脏中上调。同时，过量的活性氧（ROS）可诱导 HSCs 激活，而 NOX4 在体外产生 ROS 中发挥重要作用。此外，在 NaAsO 暴露下，HSCs 激活与 ER 应激同时发生，在 ER 应激过程中，IRE1α 途径负责 NOX4 的激活。因此，抑制 IRE1α 的激活可以减轻 NaAsO 诱导的 HSCs 激活。总之，本研究表明，无机砷暴露可通过 IRE1α/NOX4 介导的 ROS 生成激活 HSCs。
