Inhaled zinc oxide nanoparticles (ZnO-NPs) induce lung inflammation associated with oxidative stress. The NLRP3 inflammasome plays a pivotal role in the development of lung inflammation. However, the underlying effects of the NLRP3 inflammasome on ZnO-NPs-induced inflammation remain obscure. In the present study, reactive oxygen species (ROS) generation, expression of NLRP3, caspase-1 p10, and cytokines release of interleukin (IL)-1β and IL-18 were determined after A549 cells were exposed to ZnO-NPs. The ROS scavenger N-acetyl-L-cysteine (NAC), nuclear factor kappa B (NF-κB inhibitor BAY11-7082, and NLRP3 inhibitor glibenclamide (GEL) were used to explore the mechanism of NLRP3 inflammasome activation-induced by ZnO-NPs. ZnO-NPs stimulation induced ROS generation and NF-κB p65 phosphorylation. Similarly, the expression of NLRP3 and caspase-1 p10 and the release of IL-1β and IL-18 were significantly increased after ZnO-NPs treatment, which indicated that the NLRP3 inflammasome was activated by ZnO-NPs. Meanwhile, NAC pretreatment inhibited ZnO-NPs-induced activation of NF-κB and NLRP3 inflammasome. The NF-κB inhibitor BAY11-7082 did not affect ROS production but significantly reduced the NLRP3 inflammasome activation induced by ZnO-NPs. Furthermore, the ability of ZnO-NPs to increase the production of IL-1β and IL-18 was significantly inhibited by GEL. The ZnO-NPs induced the activation of the NLRP3 inflammasome in A549 cells, which might be via a ROS-NF-κB-NLRP3 signaling pathway.

It has been previously shown that inhaled zinc oxide nanoparticles (ZnO-NPs) can modulate inflammation. MicroRNAs (miRNAs) enclosed in exosomes have been identified as an important signature for inflammatory responses. However, the role of exosomal miRNAs during pathogenic inflammation has not been investigated. Healthy rats were exposed to ZnO-NPs (41.7 nm; 2, 4, and 8 mg/kg) or saline (control) via oropharyngeal aspiration. ZnO-NPs induced significant increases in the serum levels of interleukin 8 (IL-8), interleukin-1 beta (IL-1β), and tumor necrosis factor α (TNF-α), and elevated the number of cells and the percentage of neutrophils in the blood. Moreover, exposure to ZnO-NPs increased the levels of lactate dehydrogenase (LDH) activity and total protein in bronchoalveolar lavage fluid (BALF). Differential profiling of miRNAs in isolated serum exosomes revealed that 16 miRNAs were up-regulated and 7 down-regulated in ZnO-NP-treated rats compared with the controls. Functional and pathway analysis indicated that miRNAs may participate in inflammation directly and indirectly through protein and vesicle-mediated transport or regulation of IL-1, oxidative stress, apoptosis, and autophagy. These results suggest that miRNAs in serum exosomes are involved in pulmonary neutrophilic inflammation induced by ZnO-NPs.

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