Short-term use of MyD88 inhibitor TJ-M2010-5 prevents D-galactosamine/lipopolysaccharide-induced acute liver injury in mice
Short-term use of MyD88 inhibitor TJ-M2010-5 prevents D-galactosamine/lipopolysaccharide-induced acute liver injury in mice
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DOI：
10.1016/j.intimp.2018.11.051
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发表时间：
2019-02-01
影响因子：
5.6
通讯作者：
Zhou, Ping
中科院分区：
文献类型：
--
作者：
Ding, Zuochuan;Du, Dunfeng;Zhou, Ping
TLR/MyD 88信号通路的过度激活有助于几种炎症相关疾病。在此之前，我们实验室合成了一种新的噻唑-氨基化MyD 88抑制剂，命名为TJ-M2010-5。在这项研究中，我们探讨了MyD 88的作用，以及TJ-M2010 -5的保护作用，在D-半乳糖/LPS诱导的急性肝损伤小鼠模型。BALB/c小鼠腹腔注射D-gal和LPS，剂量分别为800 mg/kg和80 μ g/kg体重。所有小鼠在注射后48小时内死亡，无需干预。然而，用TJ-M2010-5预处理以及MyD 88基因的敲除（KO）显著提高了小鼠存活率，在48小时分别为73.3%和80%，并且两种处理都保护了肝功能。这些病理结果表明，TJ-M2010-5和MyD 88 KO减少了炎性细胞的浸润，并保护肝细胞免于凋亡。此外，TJ-M2010-5在体内显著抑制NF-κ B和MAPK信号传导。LPS诱导的巨噬细胞活化以及促炎因子也显示在体内和体外TJ-M2010-5处理后降低。综上所述，这些结果表明，TJ-M2010-5阻断TLR/MyD 88信号通路在预防炎症相关急性肝损伤中具有重要作用。
Excessive activation of the TLR/MyD88 signaling pathway contributes to several inflammation-related diseases. Previously, our laboratory synthesized a novel thiazaol-aminoramification MyD88 inhibitor named TJ-M2010-5. In this study, we interrogated the role of MyD88, as well as the protective effect of TJ-M2010-5, in a D-gal/LPS-induced acute liver injury mouse model. In order to induce acute liver injury, BALB/c mice received intraperitoneal injection of D-gal and LPS at a dose of 800 mg/kg and 80 mu g/kg body weight, respectively. All mice died within 48 h of injection without intervention. However, pre-treatment with TJ-M2010-5 as well as knockout (KO) of the MyD88 gene significantly improved mouse survival rate to 73.3% and 80% at 48 h, respectively, and both treatments protected liver function. These pathological results demonstrated that TJ-M2010-5 and MyD88 KO reduced the infiltration of inflammatory cells and protected hepatocytes against apoptosis. Furthermore, TJ-M2010-5 remarkably inhibited NF-kappa B and MAPK signaling in vivo. LPS-induced activation of macrophages as well as pro-inflammatory factors were also shown to be decreased after TJ-M2010-5 treatment in vivo and in vitro. Taken together, these results suggested that blockage of the TLR/MyD88 signaling pathway by TJ-M2010-5 has an important role in the prevention of inflammation-related acute liver injury.