Department of Physiology, School of Medicine, Ewha Woman's University, Seoul, South Korea.
J Toxicol Environ Health A. 2010;73(5):396-409. doi: 10.1080/15287390903486543.
Nanoparticles are widely used in nanomedicines, including for targeted delivery of pharmacological, therapeutic, and diagnostic agents. Since nanoparticles might translocate across cellular barriers from the circulation into targeted organs, it is important to obtain information concerning the pathophysiologic effects of these particles through systemic migration. In the present study, acute pulmonary responses were examined after intraperitoneal (ip) administration of ultrafine titanium dioxide (TiO(2), 40 mg/kg) in mice at rest or in lungs primed with lipopolysaccharide (LPS, ip, 5 mg/kg). Ultrafine TiO(2) exposure increased neutrophil influx, protein levels in bronchoalveolar lavage (BAL) fluid, and reactive oxygen species (ROS) activity of BAL cells 4 h after exposure. Concomitantly, the levels of proinflammatory mediators, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and macrophage inflammatory protein (MIP)-2 in BAL fluid and mRNA expression of TNF-alpha and IL-1beta in lung tissue were elevated post ultrafine TiO(2) exposure. Ultrafine TiO(2) exposure resulted in significant activation of inflammatory signaling molecules, such as c-Src and p38 MAP kinase, in lung tissue and alveolar macrophages, and the nuclear factor (NF)-kappaB pathway in pulmonary tissue. Furthermore, ultrafine TiO(2) additively enhanced these inflammatory parameters and this signaling pathway in lungs primed with lipopolysaccharide (LPS). Contrary to this trend, a synergistic effect was found for TNF-alpha at the level of protein and mRNA expression. These results suggest that ultrafine TiO(2) (P25) induces acute lung inflammation after ip administration, and exhibits additive or synergistic effects with LPS, at least partly, via activation of oxidant-dependent inflammatory signaling and the NF-kappaB pathway, leading to increased production of proinflammatory mediators.
纳米粒子广泛应用于纳米医学，包括靶向递药的药理学、治疗学和诊断剂。由于纳米粒子可能从循环系统穿过细胞屏障转移到靶向器官，因此通过全身迁移获得有关这些粒子的病理生理效应的信息是很重要的。在本研究中，在休息或用脂多糖（ip，5mg/kg）预先处理肺部的小鼠中，研究了腹膜内（ip）给予超细微二氧化钛（TiO2，40mg/kg）后的急性肺反应。超细微 TiO2 暴露增加了中性粒细胞的浸润、支气管肺泡灌洗液（BAL）中的蛋白水平以及 BAL 细胞中的活性氧（ROS）活性，在暴露后 4 小时。同时，BAL 液中的促炎介质如肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β和巨噬细胞炎症蛋白（MIP）-2的水平以及肺组织中 TNF-α和 IL-1β的 mRNA 表达在超细微 TiO2 暴露后升高。超细微 TiO2 暴露导致肺部组织和肺泡巨噬细胞中的炎症信号分子如 c-Src 和 p38MAP 激酶，以及肺部组织中的核因子（NF）-κB 途径显著激活。此外，超细微 TiO2 在脂多糖（LPS）预先处理的肺部中，这些炎症参数和信号通路的活性增加。与这一趋势相反，在蛋白质和 mRNA 表达水平上，TNF-α 表现出协同作用。这些结果表明，超细微 TiO2（P25）经腹膜内给予后会引起急性肺炎症，并且至少部分通过激活氧化应激依赖性炎症信号和 NF-κB 途径，与 LPS 表现出相加或协同作用，导致促炎介质的产生增加。
