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 (r2 = 0.987, p <0.001), while the number of neutrophils showed good correlation with the surface area dose of the biopersistent NPs (r2 = 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.

中文翻译：

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钴基纳米颗粒对急性肺部炎症反应的响应度量。

尽管已经提出了表面积度量作为用于纳米颗粒（NP）的可能的剂量度量，但是它仅限于低溶解度NP，并且对高溶解度NP的剂量度量知之甚少。在这项研究中，我们旨在使用两种基于钴（Co）的NP，一氧化钴（CoO）和氧化钴（Co3O4）来评估NP的适当剂量度量或响应度量，二者均显示出独特的溶解度，并确定可溶性Co离子在炎症中的作用。我们评估了NP的理化性质，包括在人工溶酶体液（ALF，pH 5.5）中的溶解度。使用大鼠气管内滴注模型，通过支气管肺泡灌洗液分析评估急性肺炎性。然后通过针对肺部炎症的参数绘制几种剂量指标来确定适当的反应指标。为了研究CoO NPs的可溶性部分的影响，从CoCl2中滴入了等剂量的Co离子。Co3O4和CoO NP在ALF中的溶解度分别约为11.46％和92.65％。滴注Co3O4 NP会产生嗜中性炎症，但CoO NP会诱发嗜酸性炎症。嗜酸性粒细胞的数量与NPs的可溶性Co离子剂量具有良好的相关性（r2 = 0.987，p <0.001），而嗜中性粒细胞的数量与生物持久性NPs的表面积剂量具有良好的相关性（r2 = 0.876，p <0.001） ）。滴注CoCl2显示出与CoO NP类似的炎症类型和严重程度。在基于Co的NP中，Co离子根据离子度量产生嗜酸性炎症，