Intravenous administration of silver nanoparticles causes organ toxicity through intracellular ROS-related loss of inter-endothelial junction.
Intravenous administration of silver nanoparticles causes organ toxicity through intracellular ROS-related loss of inter-endothelial junction.
复制标题
银纳米颗粒的静脉内给药可通过细胞内ROS相关的内皮间结的损失引起器官毒性。
DOI：
10.1186/s12989-016-0133-9
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发表时间：
2016-04-29
影响因子：
10
通讯作者：
Xu H
中科院分区：
文献类型：
--
作者：
Guo H;Zhang J;Boudreau M;Meng J;Yin JJ;Liu J;Xu H
给小鼠注射银纳米粒(AgNPs)可导致其在多个器官中的分布和蓄积，其中以肝、肺和肾的分布最为显著。然而，AgNPs如何通过血泡系统到达靶器官还不清楚，AgNPs和银离子之间的确切毒性机制也仍然不清楚。本研究通过比较AgNPs和AgNO3的作用机制，对这些靶器官的病理变化进行了研究，以期对AgNPs的毒性有一个新的认识。我们研究了柠檬酸银纳米粒(10、75和110 nm)和硝酸银(AgNO3)在原代培养的人脐静脉内皮细胞(HUVEC)中孵育24小时(1-40μg/mL)后的体外细胞毒性。采用VE-钙粘素染色和2‘，7’-二氯二氢荧光素-二乙酸酯(DCFH-DA)法检测AgNPs对细胞间连接和细胞内ROS的影响。为了评估体内毒性，我们对小鼠进行了单次或多次静脉注射(AgNPs为25gμg Ag，AgNO3为2.5gμg Ag)。在体外实验中，透射电子显微镜观察显示，AgNPs被内皮细胞摄取，而AgNO3摄取很少。同时，AgNPs孵育诱导内皮细胞内ROS升高，VE-钙粘附素表达下调，并影响细胞骨架肌动蛋白的重组，这一作用可被抗氧化剂N-乙酰半胱氨酸所挽救。而AgNO_3在浓度高于20μg/mL时直接导致细胞死亡，在较低浓度时不诱导ROS。AgNPs从泄漏的血管中释放，导致肝、肺和肾脏的外周炎症，其严重程度与使用的AgNPs的直径成比例增加。是AgNPs而不是AgNO3被血管内皮细胞摄取并诱导细胞内ROS升高，这与内皮层完整性的破坏密切相关。AgNPs诱导的内皮细胞渗漏可通过静脉暴露介导肝、肾、肺常见的外周炎症。本文的在线版本(doi：10.1186/s12989-0160133-9)包含补充材料，授权用户可以使用。
Administration of silver nanoparticles (AgNPs) to mice could result in their distribution and accumulation in multiple organs, with notable prominence in liver, lungs, and kidneys. However, how AgNPs transport through blood vesicular system to reach the target organs is unclear, and the precise differences in the mechanisms of toxicity between AgNPs and silver ions still remain elusive. In the present research, the pathological changes on these target organs with a focus on inter-endothelial junction was investigated to gain a new insight of AgNPs toxicity by comparing the mechanisms of action of AgNPs and AgNO3. We investigated the in vitro cytotoxicity of either citrated-coated AgNPs (10, 75, and 110 nm) or silver nitrate (AgNO3) following 24 h incubations (1–40 μg/mL) in the presence of primary human umbilical vein endothelial cells (HUVEC). Meanwhile, we detected the effects of AgNPs on intercellular conjunction and intracellular ROS by VE-cadherin staining and 2′, 7′-dichlorodihydrofluorescein diacetate (DCFH-DA) assay, respectively. To assess in vivo toxicity, we administered single or multiple intravenous injections (25 μg Ag for AgNPs and 2.5 μg Ag for AgNO3 per dose) to mice. In the in vitro study, the TEM observation showed that AgNPs were taken up by endothelial cells while AgNO3 was taken up little. Meanwhile AgNPs incubation induced the elevation of intracellular ROS and down-regulation of VE-cadherin between the endothelial cells and affected the cytoskeleton actin reorganization, which could be rescued by antioxidant N-acetylcysteine. In contrast, AgNO3 caused direct cell death when the concentration was higher than 20 μg/mL and without ROS induction at lower concentration. The release of AgNPs from leaking vessels induced peripheral inflammation in the liver, lungs, and kidneys, and the severity increased in proportion to the diameter of the AgNPs used. It is AgNPs but not AgNO3 that were taken up by vascular endothelial cells and induced intracellular ROS elevated, which was closely related to disruption of the integrity of endothelial layer. The AgNPs-induced leakiness of endothelial cells could mediate the common peripheral inflammation in liver, kidney and lung through intravenous exposure. The online version of this article (doi:10.1186/s12989-016-0133-9) contains supplementary material, which is available to authorized users.