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首页> 外文期刊>American Journal of Physiology >Increased death receptor pathway of apoptotic signaling in septic mouse aorta: effect of systemic delivery of FADD siRNA.
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Increased death receptor pathway of apoptotic signaling in septic mouse aorta: effect of systemic delivery of FADD siRNA.

机译：化脓性小鼠主动脉中凋亡信号的死亡受体途径增加：FADD siRNA全身递送的作用。

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Recent evidence suggests that apoptotic cell death plays an important role in the pathophysiology of sepsis. Because there is extensive apoptosis of vascular endothelial cells in sepsis, we examined whether the death receptor pathway of apoptotic signaling is altered in thoracic aortas from mice with polymicrobial sepsis, as produced by cecal ligation and puncture (CLP). In septic aorta, total and surface expression levels of the two death receptors tumor necrosis factor receptor 1 and Fas were highly upregulated. Furthermore, marked increases in the mRNA and protein levels of Fas-associated death domain (FADD), an adaptor molecule to recruit procaspase-8 into the death-inducing signal complex, were observed in septic aorta, which were strongly suppressed by systemic delivery of small interfering RNA (siRNA) against FADD. No increase in expression of death receptors and FADD was observed in endothelium-denuded aortic tissues from septic animals. Systemic administration of FADD siRNA also resulted in great attenuation of sepsis-induced increases in expression and activation of caspase-3, an effector protease in the apoptosis cascade. Terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (TUNEL) revealed that the significant appearance of cell apoptosis in aortic endothelium after CLP-induced sepsis was eliminated when FADD siRNA was systemically applied. Light and electron microscopic examinations of septic aorta showed cell swelling, nuclear fragmentation, and partial detachment of endothelial cells from the basal membrane, which were prevented by systemic treatment with FADD siRNA. Finally, FADD siRNA administration dramatically improved survival of CLP mice, supporting the feasibility of this gene-based approach for treating septic shock.
机译：最近的证据表明凋亡性细胞死亡在败血症的病理生理中起重要作用。由于败血症中血管内皮细胞的广泛凋亡，我们检查了盲肠结扎和穿刺（CLP）产生的多菌血症小鼠的胸主动脉中凋亡信号的死亡受体途径是否发生了改变。在败血性主动脉中，两个死亡受体肿瘤坏死因子受体1和Fas的总表达和表面表达水平都被上调。此外，在化脓性主动脉中观察到Fas相关死亡结构域（FADD）（将procaspase-8募集到死亡诱导信号复合体中的衔接分子）的mRNA和蛋白质水平显着增加，这些被全身性递送抑制了抗FADD的小干扰RNA（siRNA）。在败血症动物的内皮剥除的主动脉组织中未观察到死亡受体和FADD表达的增加。 FADD siRNA的全身给药还导致败血症诱导的caspase-3的表达和激活的增加大大降低，败血症诱导的表达和激活是凋亡级联反应中的一种效应蛋白酶。末端脱氧核苷酸转移酶dUTP介导的切口末端标记（TUNEL）显示，当系统应用FADD siRNA时，消除了CLP引起的败血症后主动脉内皮细胞凋亡的显着现象。光和电子显微镜检查化脓性主动脉显示细胞肿胀，核碎裂和内皮细胞从基底膜部分脱​​落，这可以通过用FADD siRNA进行全身治疗来预防。最后，FADD siRNA的给药大大提高了CLP小鼠的存活率，支持了这种基于基因的方法治疗败血性休克的可行性。

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