Li Tongxi, Bai Junjie, Du Yichao, Tan Peng, Zheng Tianxiang, Chen Yifan, Cheng Yonglang, Cai Tianying, Huang Meizhou, Fu Wenguang, Wen Jian
Department of General Surgery (Hepatopancreatobiliary surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
Int Immunopharmacol. 2022 Jul;108:108892. doi: 10.1016/j.intimp.2022.108892. Epub 2022 May 28.
As a major metabolic site, the liver is an important target organ of endotoxemia. High serum lipopolysaccharide (LPS) levels can cause hepatocyte necrosis and produce cholestasis, which results in severe liver injury. Contrastingly, thiamine (THA) has shown anti-inflammatory effects against severe infections and may be indicated for systemic endotoxemia treatment. Therefore, the present study was conducted to investigate the effective treatment of endotoxemia-induced liver injury with THA and the possible molecular mechanisms.
METHODOLOGY/PRINCIPAL FINDINGS: in vivo, We established two models of endotoxemia-induced liver injury at the in vivo level using LPS and bile duct ligation (BDL) + LPS, administering prophylactic THA intraperitoneally to mice. In vitro, the effects of THA on RAW264.7 and THP-1 administration of LPS-induced inflammatory macrophage activation were observed. Metabolomic analysis screening and subsequent validation experiments were also performed. THA has different degrees of preventive therapeutic effects on different causes of endotoxemia-induced liver injury, as evidenced by a decreased alanine aminotransferase (ALT) and decreased inflammatory factors. This study aimed to clarify the specific mechanism. We subsequently found that THA reduced the inflammatory macrophages produced by RAW264.7 and THP-1 in response to LPS. Additionally, THA reduced galactose liver accumulation and improved glucose metabolism. Moreover, Galectin-3 (Gal-3), as a point of interaction between macrophage activation and galactose metabolism mechanisms, was observed to inhibit Gal-3 expression by THA at both in vivo and in vitro levels.
This study revealed that THA may be a viable prophylactic treatment option for the prevention of liver injury occurring in endotoxemia, which is associated with its effects on the modulation of Gal-3 to improve the inflammatory response and the inhibition of galactose metabolism. Additional evidence is provided for its clinical application.
肝脏作为主要的代谢器官，是内毒素血症的重要靶器官。高血清脂多糖（LPS）水平可导致肝细胞坏死并产生胆汁淤积，从而导致严重的肝损伤。相反，硫胺素（THA）已显示出对严重感染的抗炎作用，可能适用于全身性内毒素血症的治疗。因此，本研究旨在探讨THA对内毒素血症诱导的肝损伤的有效治疗方法及可能的分子机制。
方法/主要发现：在体内，我们使用LPS和胆管结扎（BDL）+LPS在体内水平建立了两种内毒素血症诱导的肝损伤模型，对小鼠腹腔注射预防性THA。在体外，观察了THA对RAW264.7和THP-1细胞给予LPS诱导的炎性巨噬细胞活化的影响。还进行了代谢组学分析筛选及后续验证实验。THA对不同原因引起的内毒素血症诱导的肝损伤具有不同程度的预防治疗作用，丙氨酸转氨酶（ALT）降低和炎性因子减少证明了这一点。本研究旨在阐明具体机制。随后我们发现，THA减少了RAW264.7和THP-1细胞对LPS产生的炎性巨噬细胞。此外，THA减少了肝脏半乳糖蓄积并改善了葡萄糖代谢。此外，半乳糖凝集素-3（Gal-3）作为巨噬细胞活化与半乳糖代谢机制之间的一个相互作用点，在体内和体外水平均观察到THA抑制Gal-3表达。
本研究表明，THA可能是预防内毒素血症中肝损伤的一种可行的预防性治疗选择，这与其对Gal-3的调节作用以改善炎症反应和抑制半乳糖代谢有关。为其临床应用提供了更多证据。
