Abstract

Nickel nanoparticles (NiNPs) are increasingly used in nanotechnology applications, yet information on sex differences in NiNP-induced lung disease is lacking. The goal of this study was to explore mechanisms of susceptibility between male and female mice after acute or subchronic pulmonary exposure to NiNPs. For acute exposure, male and female mice received a single dose of NiNPs with or without LPS by oropharyngeal aspiration and were necropsied 24 h later. For subchronic exposure, mice received NiNPs with or without LPS six times over 3 weeks prior to necropsy. After acute exposure to NiNPs and LPS, male mice had elevated cytokines (CXCL1 and IL-6) and more neutrophils in bronchoalveolar lavage fluid (BALF), along with greater STAT3 phosphorylation in lung tissue. After subchronic exposure to NiNPs and LPS, male mice exhibited increased monocytes in BALF. Moreover, subchronic exposure of male mice to NiNP only induced higher CXCL1 and CCL2 in BALF along with increased alveolar infiltrates and CCL2 in lung tissue. STAT1 in lung tissue was induced by subchronic exposure to NiNPs in females but not males. Males had a greater induction of IL-6 mRNA in liver after acute exposure to NiNPs and LPS, and greater CCL2 mRNA in liver after subchronic NiNP exposure. These data indicate that susceptibility of males to acute lung inflammation involves enhanced neutrophilia with increased CXCL1 and IL-6/STAT3 signaling, whereas susceptibility to subchronic lung inflammation involves enhanced monocytic infiltration with increased CXCL1 and CCL2. STAT transcription factors appear to play a role in these sex differences. This study demonstrates sex differences in the lung inflammatory response of mice to NiNPs that has implications for human disease.

摘要

镍纳米粒子 (NiNPs) 越来越多地用于纳米技术应用，但缺乏关于 NiNP 诱导的肺病性别差异的信息。本研究的目的是探索急性或亚慢性肺部暴露于 NiNPs 后雄性和雌性小鼠之间的易感性机制。对于急性暴露，雄性和雌性小鼠通过口咽抽吸接受单剂量含或不含 LPS 的 NiNPs，并在 24 小时后进行尸检。对于亚慢性暴露，小鼠在尸检前 3 周内接受了含或不含 LPS 的 NiNPs 六次。急性暴露于 NiNPs 和 LPS 后，雄性小鼠的细胞因子（CXCL1 和 IL-6）升高，支气管肺泡灌洗液 (BALF) 中的中性粒细胞增多，肺组织中 STAT3 磷酸化程度更高。在亚慢性暴露于 NiNPs 和 LPS 后，雄性小鼠在 BALF 中表现出增加的单核细胞。此外，雄性小鼠亚慢性暴露于 NiNP 仅诱导 BALF 中更高的 CXCL1 和 CCL2，以及肺组织中肺泡浸润和 CCL2 的增加。肺组织中的 STAT1 是由女性而非男性亚慢性暴露于 NiNPs 诱导的。男性在急性暴露于 NiNPs 和 LPS 后肝脏中 IL-6 mRNA 的诱导更大，亚慢性 NiNP 暴露后肝脏中的 CCL2 mRNA 更大。这些数据表明，男性对急性肺部炎症的易感性涉及中性粒细胞增多，CXCL1 和 IL-6/STAT3 信号传导增加，而对亚慢性肺部炎症的易感性涉及单核细胞浸润增强，CXCL1 和 CCL2 增加。STAT 转录因子似乎在这些性别差异中起作用。