Arsenic is a well-known environmental toxicant and carcinogen, which has been epidemiologically proved related to the increased hepatic disorders. Researches have shown that aseptic inflammation and abnormal immune response are associated with arsenic-induced liver injury. However, the immunotoxic effects of liver have not been extensively characterized. Ginkgo biloba extract (GBE), a natural products of G. biloba leaves with proven anti-inflammatory and potential immunoregulatory activities, was used as intervention agent to explore its protective effects on arsenic-induced hepatotoxicity. Thus, the underlying mechanism of the immunotoxic effects on arsenic-induced liver injury were investigated in 2.5, 5.0, and 10.0 mg/kg NaAsO₂ of Wistar rats for 16 weeks. Subsequently, GBE was used as intervention agent in 50 mg/kg for 6 weeks after cessation of arsenic exposure. The ratio of Th17 to Treg cells in peripheral blood as well as the secretion of inflammatory cytokines IL-17A, IL-6, TGF-β1, and IL-10 in serum and liver were detected. Meanwhile, the notable activation of aseptic inflammation-related molecule TLR4 and its downstream targets MyD88 and NF-κB in the liver were observed. In this work, we confirmed that subchronic exposed to arsenic triggered the infiltration of inflammatory cells in rat liver, coupled with obvious histopathological changes and aberrant hepatic serum biochemical parameters. Meanwhile, imbalanced immune response was verified by the notable abnormal ratio of Th17 to Treg cells in peripheral blood as well as the secretion of inflammatory cytokines IL-17A, IL-6, TGF-β1, and IL-10 in serum and liver of arsenic exposed rats. Further, the level of TLR4, MyD88, and NF-κB in liver both transcription and translation activity were raised. Subsequently, GBE markedly mitigated arsenic-induced liver injury, most impressively, post treatment with GBE prominently suppressed the overactivated inflammatory-related TLR4-MyD88-NF-κB pathway and evidently decreased the secretion of inflammation cytokines. Meanwhile, the disturbance of pro- and anti-inflammatory response was reversed. We concluded that the disruption of pro- and anti-inflammatory T-cells balance caused by cytokines mediated cell–cell interactions may be one of the mechanisms underlying arsenic-induced liver injury and that GBE intervention exerts an evidence protective effects, which might be closely associated with the suppression of inflammatory-related TLR4 pathway.

中文翻译：

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亚慢性砷诱导肝损伤的不平衡炎症反应和银杏叶提取物对大鼠的保护作用：细胞因子介导的细胞-细胞相互作用的潜在作用

砷是一种众所周知的环境毒物和致癌物，流行病学证明它与增加的肝脏疾病有关。研究表明，无菌性炎症和异常免疫反应与砷致肝损伤有关。然而，肝脏的免疫毒性作用尚未得到广泛表征。银杏叶提取物 (GBE) 是G. biloba叶的天然产物，具有经证实的抗炎和潜在的免疫调节活性，被用作干预剂，探索其对砷诱导的肝毒性的保护作用。因此，研究了 2.5、5.0 和 10.0 mg/kg NaAsO ₂对砷诱导的肝损伤的免疫毒性作用的潜在机制Wistar 大鼠 16 周。随后，在停止接触砷后，GBE被用作干预剂，剂量为 50 mg/kg，持续 6 周。检测外周血中Th17与Treg细胞的比例以及血清和肝脏中炎性细胞因子IL-17A、IL-6、TGF-β1、IL-10的分泌情况。同时，无菌炎症相关分子TLR4及其下游靶标MyD88和NF-κB的显着激活在肝脏中观察到。在这项工作中，我们证实亚慢性砷暴露引发了大鼠肝脏炎症细胞的浸润，并伴有明显的组织病理学变化和肝脏血清生化参数异常。同时，外周血中Th17与Treg细胞的显着异常以及砷的血清和肝脏中炎性细胞因子IL-17A、IL-6、TGF-β1和IL-10的分泌也证实了免疫反应失衡。暴露的老鼠。此外，肝脏中TLR4、MyD88和NF-κB 的水平提高了转录和翻译活性。随后，GBE显着减轻了砷引起的肝损伤，最令人印象深刻的是，用GBE治疗后显着抑制过度激活的炎症相关 TLR4-MyD88-NF-κB 通路，并明显减少炎症细胞因子的分泌。同时，促炎和抗炎反应的紊乱得到逆转。我们得出结论，由细胞因子介导的细胞间相互作用引起的促炎性和抗炎性 T 细胞平衡的破坏可能是砷诱导肝损伤的潜在机制之一，并且GBE干预发挥了证据保护作用，这可能与与抑制炎症相关的 TLR4 通路有关。