Necroptosis as a potential therapeutic target in multiple organ dysfunction syndrome.
Necroptosis as a potential therapeutic target in multiple organ dysfunction syndrome.
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DOI：
10.18632/oncotarget.18252
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发表时间：
2017-08-22
期刊：
影响因子：
--
通讯作者：
Wang YQ
中科院分区：
文献类型：
--
作者：
Cui YL;Qiu LH;Zhou SY;Li LF;Qian ZZ;Liu XM;Zhang HL;Ren XB;Wang YQ
研究坏死性凋亡（即程序性坏死）如何参与MODS，并检查特异性坏死性凋亡抑制剂Nec-1是否改善MODS中的多器官损伤。采用6周龄SD大鼠骨折创伤后出血建立MODS模型。对照动物接受假手术。通过荧光激活细胞分选和蛋白质印迹法测定细胞死亡形式和坏死体形成。MODS大鼠随机分为Nec-1组和生理盐水组，分别给予预处理和每日1次。第一个终点是72小时生存期。还记录了器官损伤和功能障碍、炎性细胞因子水平和坏死性执行蛋白表达。MODS组的器官损伤和功能障碍明显比假手术组严重（均P<0.01）。此外，MODS诱导的肝、肺和肾组织损伤的特征是坏死性凋亡而不是凋亡，并伴有坏死体形成。与MODS组相比，给予Nec-1显著提高了72小时存活率（p<0.01）。在MODS大鼠中，给予NEC-1显著减少坏死性凋亡诱导的肝、肺和肾损伤和功能障碍，抑制炎性细胞因子的产生，抑制坏死性凋亡执行蛋白如高迁移率族蛋白1和混合谱系激酶结构域样蛋白假激酶的释放（所有p<0.01）。提示坏死性凋亡参与了MODS的病理过程。此外，坏死性凋亡抑制剂Nec-1可被认为是MODS的辅助治疗。
To investigate how necroptosisis, i.e. programmed necrosis, is involved in MODS, and to examine whether Nec-1, a specific necroptosis inhibitor, ameliorates multiorgan injury in MODS. A model of MODS was established in six-week old SD rats using fracture trauma followed by hemorrhage. Control animals received sham surgery. Cell death form and necrosome formation were measured by fluorescence-activated cell sorting and western blotting. MODS rats were randomly assigned to receive Nec-1 or saline with pretreatment and once daily. The first end-point was 72 hours survival. Organ injury and dysfunction, inflammatory cytokine levels, and necroptotic execution protein expression were also recorded. Organ injury and dysfunction were significantly more severe in the MODS group than the sham group (all p<0.01). Furthermore, MODS-induced liver, lung and kidney tissue injury was characterized by necroptosis rather than apoptosis, and accompanied by necrosome formation. Compared to MODS group, Nec-1 administration significantly improved 72 hours survival (p<0.01). Nec-1 administration significantly reduced necroptosis-induced liver, lung and kidney injury and dysfunction, inhibited inflammatory cytokines production, inhibited release of necroptotic execution proteins such as high-mobility group box 1 and mixed-lineage kinase domain-like protein pseudokinase in MODS rats (all p<0.01). These results suggest that necroptosis is involved the pathology of MODS. Further, a necroptotic inhibitor Nec-1 may be considered as an adjunct treatment for MODS.
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影响因子：
19.6
作者：
Linkermann, Andreas;Braesen, Jan H.;Krautwald, Stefan
通讯作者：
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影响因子：
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作者：
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影响因子：
8.8
作者：
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通讯作者：
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