Fulminant hepatitis (FH) is an acute clinical disease with a poor prognosis and high mortality rate. The purpose of this study was to determine the protective effect of the Toll-like receptor 4 (TLR4) inhibitor TAK-242 on lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced explosive hepatitis and explore in vivo and in vitro mechanisms. Mice were pretreated with TAK-242 for 3 h prior to LPS (10 μg/kg)/D-GalN (250 mg/kg) administration. Compared to the LPS/D-GalN group, the TAK-242 pretreatment group showed significantly prolonged survival, reduced serum alanine aminotransferase and aspartate aminotransferase levels, relieved oxidative stress, and reduced inflammatory interleukin (IL)-6, IL-12, and tumor necrosis factor-α levels. In addition, TAK-242 increased the accumulation of myeloid-derived suppressor cells (MDSCs). Next, mice were treated with an anti-Gr-1 antibody to deplete MDSCs, and adoptive transfer experiments were performed. We found that TAK-242 protected against FH by regulating MDSCs. In the in vitro studies, TAK-242 regulated the accumulation of MDSCs and promoted the release of immunosuppressive inflammatory cytokines. In addition, TAK-242 inhibited protein expression of nuclear factor-κB and mitogen-activated protein kinases. In summary, TAK-242 had a hepatoprotective effect against LPS/D-GalN-induced explosive hepatitis in mice. Its protective effect may be involved in suppressing inflammation, reducing oxidative stress, and increasing the proportion of MDSCs.

暴发性肝炎（FH）是一种临床急性疾病，预后差，死亡率高。本研究的目的是确定所述Toll样受体4（TLR4）抑制剂TAK-242对脂多糖（LPS）/ d半乳糖胺（d氨基半乳糖）的保护作用诱导的炸药肝炎和探索在体内和体外机制。在 LPS (10 μg/kg)/D-GalN (250 mg/kg) 给药之前，小鼠用 TAK-242 预处理 3 小时。与 LPS/D-GalN 组相比，TAK-242 预处理组的生存期显着延长，血清丙氨酸转氨酶和天冬氨酸转氨酶水平降低，氧化应激减轻，炎性白细胞介素 (IL)-6、IL-12 和肿瘤减少坏死因子-α 水平。此外，TAK-242 增加了髓源性抑制细胞 (MDSCs) 的积累。接下来，用抗 Gr-1 抗体处理小鼠以消耗 MDSC，并进行过继转移实验。我们发现 TAK-242 通过调节 MDSC 来防止 FH。在体外研究表明，TAK-242 调节 MDSCs 的积累并促进免疫抑制性炎症细胞因子的释放。此外，TAK-242 抑制核因子-κB 和丝裂原活化蛋白激酶的蛋白质表达。总之，TAK-242对LPS/D-GalN诱导的小鼠爆发性肝炎具有保肝作用。其保护作用可能涉及抑制炎症、减少氧化应激和增加 MDSCs 的比例。