Abstract

Recently, some researchers have demonstrated that inhaled zinc oxide nanoparticles (ZnONPs) induce an acute systemic inflammatory response in workers. Considering nonhuman primates are preferably considered an animal model for translational research due to their proven similarity with humans in terms of genetics and physiology, we intratracheally instilled ZnONPs to cynomolgus monkey for 14 days and identified the toxic mechanism and bioaccumulation. ZnONPs were rapidly ionized or aggregated in a simulated pulmonary fluid, and they attracted neutrophils to the lungs and increased the pulmonary level of inflammatory mediators. Additionally, thickened alveolar walls, fibrin clots, and hemorrhages were observed in the lungs of the monkeys instilled with the higher dose accompanied by cell debris in the alveolar ducts and alveoli. Dark-field microscopy images revealed translocation of ZnONPs into other tissues accompanied by an increase in the relative weight of livers to body weight. In addition, when instilled at the higher dose, the albumin/globulin ratio notably decreased compared to the control, whereas the C-reactive protein (CRP) level was significantly elevated. ZnONPs also clearly induced apoptotic cell death in a 24 h exposure to alveolar macrophages. Taken together, part of inhaled ZnONPs may be ionized in the lung, resulting in acute toxic effects, including cell death and tissue damage, and the rest may move to other tissues in the form of particles, causing a systemic inflammatory response. Based on the proven evidence among workers, we also suggest that the CRP level can be recommended as a biomarker for ZnONPs-induced adverse health effects.

摘要

最近，一些研究人员已经证明，吸入氧化锌纳米颗粒 (ZnONPs) 会引起工人的急性全身炎症反应。考虑到非人类灵长类动物因其在遗传学和生理学方面与人类的相似性而被优先考虑作为转化研究的动物模型，我们将 ZnONPs 气管内滴注给食蟹猴 14 天，并确定了毒性机制和生物积累。ZnONPs 在模拟肺液中迅速电离或聚集，它们将中性粒细胞吸引到肺部并增加肺部炎症介质的水平。此外，在灌注较高剂量的猴子的肺中观察到肺泡壁增厚、纤维蛋白凝块和出血，并伴有肺泡管和肺泡中的细胞碎片。暗视野显微镜图像显示 ZnONPs 易位到其他组织中，伴随着肝脏相对于体重的相对重量的增加。此外，当以较高剂量滴注时，与对照相比，白蛋白/球蛋白比率显着降低，而 C 反应蛋白 (CRP) 水平显着升高。在暴露于肺泡巨噬细胞 24 小时内，ZnONPs 也明显诱导细胞凋亡。总之，部分吸入的ZnONPs可能在肺中电离，导致急性毒性作用，包括细胞死亡和组织损伤，其余可能以颗粒形式转移到其他组织，引起全身炎症反应。根据工人中已证实的证据，我们还建议将 CRP 水平推荐为 ZnONPs 引起的不良健康影响的生物标志物。