Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China.
International School of Public Health and One Health, Hainan Medical University, Haikou, China.
Environ Pollut. 2024 Jan 15;341:122950. doi: 10.1016/j.envpol.2023.122950. Epub 2023 Nov 16.
The widespread application of zinc oxide nanoparticles (ZnO-NPs) brings convenience to our lives while also renders threats to public health and ecological environment. The lung has been recognized as a primary target of ZnO-NPs, however, the detrimental effects and mechanism of ZnO-NPs on the respiratory system have not been thoroughly characterized so far. To investigate the effect of ZnO-NPs on acute lung injury (ALI), Sprague Dawley rats were intratracheally instilled with ZnO-NPs suspension at doses of 1, 2, and 4 mg/kg/day for 3 consecutive days. Our study revealed that ZnO-NPs induced ALI in rats characterized by increased airway resistance, excessive inflammatory response and lung histological damage. In addition, we identified several molecular biomarkers related to the potential mechanism of ZnO-NP-induced ALI, including oxidative stress, mitochondrial damage, and NLRP3 inflammasome activation. The results of in vitro experiments showed that the viability of A549 cells decreased with the increase in ZnO-NPs concentration. Meanwhile, it was also found that ZnO-NP treatment induced the production of ROS, the decrease in mitochondrial membrane potential and activation of NLRP3 inflammasome in A549 cells. Furthermore, to explore the underlying molecular mechanisms of ZnO-NP-induced ALI, N-acetyl-L-cysteine (a ROS scavenger), Cyclosporin A (an inhibitor for mitochondrial depolarization) and Glibenclamide (an inhibitor for NLRP3 inflammasome activity) were used to pre-treat A549 cells before ZnO-NPs stimulation in the in vitro experiments, respectively. The results from this study suggested that ZnO-NP-induced ROS production triggered the accumulation of damaged mitochondria and assembly of NLRP3 inflammatory complex, leading to maturation and release of IL-1β. Moreover, ZnO-NP-induced NLRP3 inflammasome activation was partly mediated by mitochondrial damage. Taken together, our study suggested that ZnO-NPs induced ALI through oxidative stress-mediated mitochondrial damage and NLRP3 inflammasome activation and provided insight into the mechanisms of ZnO-NPs-induced ALI.
氧化锌纳米粒子（ZnO-NPs）的广泛应用给我们的生活带来了便利，同时也对公众健康和生态环境构成了威胁。肺已被认为是 ZnO-NPs 的主要靶器官，但 ZnO-NPs 对呼吸系统的有害影响及其机制尚未得到充分描述。为了研究 ZnO-NPs 对急性肺损伤（ALI）的影响，我们将 ZnO-NPs 混悬液以 1、2 和 4mg/kg/天的剂量连续 3 天经气管内滴注到 Sprague Dawley 大鼠体内。我们的研究表明，ZnO-NPs 诱导大鼠发生 ALI，其特征为气道阻力增加、过度炎症反应和肺组织学损伤。此外，我们鉴定了几个与 ZnO-NP 诱导的 ALI 潜在机制相关的分子生物标志物，包括氧化应激、线粒体损伤和 NLRP3 炎性小体激活。体外实验结果表明，A549 细胞的活力随着 ZnO-NPs 浓度的增加而降低。同时，还发现 ZnO-NP 处理诱导 A549 细胞产生 ROS、降低线粒体膜电位并激活 NLRP3 炎性小体。此外，为了探索 ZnO-NP 诱导的 ALI 的潜在分子机制，我们在体外实验中分别使用 N-乙酰-L-半胱氨酸（ROS 清除剂）、环孢菌素 A（线粒体去极化抑制剂）和格列本脲（NLRP3 炎性小体活性抑制剂）对 A549 细胞进行预处理，然后再用 ZnO-NPs 刺激。本研究结果表明，ZnO-NP 诱导的 ROS 产生触发了受损线粒体的积累和 NLRP3 炎性复合物的组装，导致 IL-1β的成熟和释放。此外，ZnO-NP 诱导的 NLRP3 炎性小体激活部分由线粒体损伤介导。总之，我们的研究表明，ZnO-NPs 通过氧化应激介导的线粒体损伤和 NLRP3 炎性小体激活诱导 ALI，并深入了解了 ZnO-NPs 诱导的 ALI 机制。
