Blockade of the receptor for advanced glycation end products attenuates acetaminophen-induced hepatotoxicity in mice
Blockade of the receptor for advanced glycation end products attenuates acetaminophen-induced hepatotoxicity in mice
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DOI：
10.1111/j.1440-1746.2006.04225.x
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发表时间：
2006-04-01
影响因子：
4.1
通讯作者：
Emond, JC
中科院分区：
文献类型：
--
作者：
Ekong, U;Zeng, S;Emond, JC
背景和目的：对肝脏的严重损伤，例如由毒性剂量的对乙酰氨基酚引起的损伤，触发导致肝细胞死亡的级联事件。据推测，晚期糖基化终产物受体（ADCP）的激活可能有助于对乙酰氨基酚诱导的肝毒性，这是由于其至少部分地通过烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶产生活性氧的能力，从而激活导致细胞损伤的下游信号传导途径。采用一种模型，其中向C57 BL/6小鼠施用毒性剂量的对乙酰氨基酚（1125 mg/kg）。为了阻断slipidase，小鼠接受小鼠可溶性（S）slipidase，受体的细胞外配体结合结构域，作为诱饵中断配体-slipidase signaling.Results：与车辆治疗相比，slipidase治疗的动物显示增加的生存，并显着减少肝坏死。与RAGE触发的氧化应激在对乙酰氨基酚诱导的损伤中的重要作用一致，在接受对乙酰氨基酚的sRAGE治疗小鼠与溶媒治疗小鼠的肝组织中观察到硝基酪氨酸蛋白加合物显著减少，同时谷胱甘肽水平显著增加。此外，促再生细胞因子肿瘤坏死因子-α和白细胞介素-6增加sRAGE治疗与车辆-treated mice.Conclusion：这些研究结果牵连RAGE依赖机制对乙酰氨基酚诱导的肝损伤，并表明，封锁这一途径可能会带来有益的影响，毒素诱导的肝损伤。
Background and Aim: Severe injury to the liver, such as that induced by toxic doses of acetaminophen, triggers a cascade of events leading to hepatocyte death. It is hypothesized that activation of the receptor for advanced glycation end products (RAGE) might contribute to acetaminophen-induced liver toxicity by virtue of its ability to generate reactive oxygen species, at least in part via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and thereby activate downstream signaling pathways leading to cellular injury.Methods: A model was employed in which toxic doses of acetaminophen (1125 mg/kg) were administered to C57BL/6 mice. To block RAGE, mice received murine soluble (s) RAGE, the extracellular ligand binding domain of the receptor that acts as a decoy to interrupt ligand-RAGE signaling.Results: Animals treated with sRAGE displayed increased survival compared with vehicle treatment, and markedly decreased hepatic necrosis. Consistent with an important role for RAGE-triggered oxidant stress in acetaminophen-induced injury, a significant reduction of nitrotyrosine protein adducts was observed in hepatic tissue in sRAGE-treated versus vehicle-treated mice receiving acetaminophen, in parallel with significantly increased levels of glutathione. In addition, pro-regenerative cytokines tumor necrosis factor-alpha and interleukin-6 were increased in sRAGE-treated versus vehicle-treated mice.Conclusion: These findings implicate RAGE-dependent mechanisms in acetaminophen-induced liver damage and suggest that blockade of this pathway may impart beneficial effects in toxin-induced liver injury.