Role of toll-like receptor 4 in mediating multiorgan dysfunction in mice with acetaminophen induced acute liver failure.

Naina Shah, Montserrat Montes de Oca, Maria Jover-Cobos, Ken-Ichi Tanamoto, Masashi Muroi, Kei-Ichi Sugiyama, Nathan A Davies, Rajeshwar P Mookerjee, Dipok Kumar Dhar, Rajiv Jalan
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引用次数: 55

Abstract

Strategies for the prevention of multiorgan dysfunction (MOD) in acetaminophen (APAP)-induced acute liver failure (ALF) are an unmet need. Our study tested the hypothesis that sterile inflammation induced by APAP in a mouse model would activate toll-like receptor 4 (TLR4) in the liver and extrahepatic organs and lead to the progression of ALF and MOD and that the administration of the novel TLR4 antagonist STM28 (a peptide formed of 17 amino-acids) would prevent liver injury and associated MOD. ALF and, subsequently, MOD were induced in TLR4-knockout (KO) mice (B6.B10ScN-Tlr4 (lpsdel) /JthJ) and wild-type (WT) mice (C57BL/6) with APAP (500 mg/kg). A second set of experiments was conducted to evaluate the effects of a pretreatment with a novel TLR4 antagonist, STM28, on APAP-induced MOD in CD1 mice. Animals were sacrificed at the coma stage, and plasma, peripheral blood cells, liver, kidneys, and brain were collected. Biochemistry values and cytokines were measured. Liver and kidneys were studied histologically and were stained for TLR4 and activated Kupffer cells, and the expression of nuclear factor kappa B-p65 was quantified with western blotting. Brain water was measured in the frontal cortex. After APAP administration, TLR4-KO (NFkBp65) mice were relatively protected from liver necrosis and end-organ dysfunction and had significantly better survival than WT controls (P < 0.01). STM28 attenuated liver injury and necrosis, reduced creatinine levels, and delayed the time to a coma significantly. The increases in cytokines in the plasma and liver, including TLR4 expression and the activation of Kupffer cells, after APAP administration were reduced significantly in the STM28-treated animals. The increased number of circulating myeloid cells was reduced significantly after STM28 treatment. In conclusion, these data provide evidence for an important role of the TLR4 antagonist in the prevention of the progression of APAP-induced ALF and MOD.

toll样受体4在对乙酰氨基酚诱导的急性肝衰竭小鼠多器官功能障碍中的作用
对乙酰氨基酚(APAP)诱导的急性肝衰竭(ALF)的多器官功能障碍(MOD)预防策略是一个未满足的需求。我们的研究验证了APAP在小鼠模型中诱导的无菌炎症会激活肝脏和肝外器官中的toll样受体4 (TLR4),导致ALF和MOD的进展,并且给药新型TLR4拮抗剂STM28(一种由17个氨基酸组成的肽)可以预防肝损伤和相关的MOD。在TLR4敲除(KO)小鼠(B6)中诱导ALF和MOD。APAP (500 mg/kg)给药B10ScN-Tlr4 (lpsdel) /JthJ)和野生型(WT)小鼠(C57BL/6)。第二组实验评估了新型TLR4拮抗剂STM28预处理对apap诱导的CD1小鼠MOD的影响。动物在昏迷期处死,收集血浆、外周血、肝、肾、脑。测定生化指标和细胞因子。对肝脏和肾脏进行组织学研究,并对TLR4和活化的Kupffer细胞进行染色,用western blotting定量检测核因子κ B-p65的表达。在额叶皮层测量脑水。APAP给药后,TLR4-KO (NFkBp65)小鼠的肝坏死和终末器官功能障碍得到相对保护,生存率明显高于WT对照组(P
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