Response-metrics for acute lung inflammation pattern by cobalt-based nanoparticles

Jiyoung Jeong, Youngju Han, Craig A. Poland, Wan-Seob Cho

Although the surface area metric has been proposed as a possible dose-metric for nanoparticles (NPs), it is limited to low-solubility NPs and the dose-metric for high-solubility NPs is poorly understood. In this study, we aimed to assess the appropriate dose-metric or response-metric for NPs using two cobalt (Co)-based NPs, cobalt monoxide (CoO) and cobalt oxide (Co3O4), which both show distinctive solubility, and determine the role of their soluble Co ions in inflammation. We evaluated the physicochemical properties of NPs, including solubility in artificial lysosomal fluid (ALF, pH 5.5). Acute lung inflammogenicity was evaluated by bronchoalveolar lavage fluid analysis using the rat intratracheal instillation model. The appropriate response-metric was then determined by plotting several dose-metrics against parameters for lung inflammation. To investigate the effect of the soluble fraction of CoO NPs, the equivalent doses of Co ions from CoCl2 were instilled. The Co3O4 and CoO NPs showed about 11.46 % and 92.65 % solubility in ALF, respectively. Instillation of Co3O4 NPs produced neutrophilic inflammation, but CoO NPs induced eosinophilic inflammation. The number of eosinophils showed good correlation with the soluble Co ions dose from NPs (r(2) = 0.987, p <0.001), while the number of neutrophils showed good correlation with the surface area dose of the biopersistent NPs (r(2) = 0.876, p <0.001). Instillation of CoCl2 showed a similar type and magnitude of inflammation as CoO NPs. In the Co-based NPs, the eosinophilic inflammation was produced by Co ions based on the ion metric, while the neutrophilic inflammation was developed based on the surface area metric of the biopersistent NPs.