Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, PR China.
Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, PR China; Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed By the Province and Ministry, Guizhou Medical University, Guiyang 550025, Guizhou, PR China.
Int Immunopharmacol. 2024 Oct 25;140:112823. doi: 10.1016/j.intimp.2024.112823. Epub 2024 Jul 30.
Arsenic, a poisonous metalloid element, is linked to liver diseases, but the exactmechanisms for this process are not yet to be completely elucidated. Toll like receptor 4 (TLR4), acting as a pathogenic pattern recognition receptor, plays a pivotal role in various inflammatory diseases via the myeloid differentiation factor 88 (MyD88) pathway. This study aims to investigate the involvement of the TLR4-MyD88 signaling pathway in liver injury induced by prolonged exposure to sodium arsenite (NaAsO) in Sprague-Dawley rats. Our research findings demonstratethe activation of TLR4-MyD88 signaling pathway in long-term NaAsO-exposed rat liver tissues, leading to a significant release of inflammatory factors, which suggests its potential involvement in the pathogenesis of NaAsO-induced liver injury. We further administered lipopolysaccharide (LPS), a natural ligand of TLR4, and TAK-242, a specific inhibitor of TLR4, to rats in order to validate the specific involvement of the TLR4-MyD88 signaling pathway in NaAsO-induced liver injury. The results showed that, 1 mg/kg.bw LPS treatment significantly activated TLR4-MyD88 signalling pathway and its mediated pro-inflammatory factors, leading to up-regulation of activation indicators in hepatic stellate cells (HSCs) as well as increased secretion levels of extracellular matrix (ECM) in the liver, and ultimately induced liver fibrosis and dysfunction in rats. Relevantly, subsequent administration of 0.5 mg/kg.bw TAK-242 significantly attenuated the expression levels of TLR4 and its associated proteins, mitigated collagen deposition, and partially improved liver fibrosis and dysfunction caused by NaAsO in rats. Our study fully confirms the pivotal role of the TLR4-MyD88 signaling in promoting liver injury induced by NaAsO, thereby providing a novel molecular target for preventing and treating patients with arsenic poisoning-related liver injury.
砷是一种有毒的类金属元素，与肝脏疾病有关，但这一过程的确切机制尚未完全阐明。Toll 样受体 4（TLR4）作为一种致病模式识别受体，通过髓样分化因子 88（MyD88）途径在各种炎症性疾病中发挥关键作用。本研究旨在探讨 TLR4-MyD88 信号通路在长期暴露于亚砷酸钠（NaAsO）诱导的大鼠肝损伤中的作用。我们的研究结果表明，TLR4-MyD88 信号通路在长期 NaAsO 暴露的大鼠肝组织中被激活，导致炎症因子的大量释放，这表明其可能参与了 NaAsO 诱导的肝损伤的发病机制。我们进一步给予脂多糖（LPS），TLR4 的天然配体，和 TAK-242，TLR4 的特异性抑制剂，以验证 TLR4-MyD88 信号通路在 NaAsO 诱导的肝损伤中的特异性作用。结果表明，1mg/kg.bw LPS 处理显著激活 TLR4-MyD88 信号通路及其介导的促炎因子，导致肝星状细胞（HSCs）的激活标志物上调，以及肝脏细胞外基质（ECM）分泌水平增加，最终导致大鼠肝纤维化和肝功能障碍。相关地，随后给予 0.5mg/kg.bw TAK-242 可显著降低 TLR4 及其相关蛋白的表达水平，减轻胶原沉积，并部分改善 NaAsO 引起的大鼠肝纤维化和肝功能障碍。本研究充分证实了 TLR4-MyD88 信号通路在促进 NaAsO 诱导的肝损伤中的关键作用，为预防和治疗砷中毒相关肝损伤提供了新的分子靶点。
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