Pulmonary Inflammation After Intraperitoneal Administration of Ultrafine Titanium Dioxide (TiO₂) At Rest or in Lungs Primed with Lipopolysaccharide

Abstract

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 (TiO₂, 40 mg/kg) in mice at rest or in lungs primed with lipopolysaccharide (LPS, ip, 5 mg/kg). Ultrafine TiO₂ 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)-α, interleukin (IL)-1β, and macrophage inflammatory protein (MIP)-2 in BAL fluid and mRNA expression of TNF-α and IL-1β in lung tissue were elevated post ultrafine TiO₂ exposure. Ultrafine TiO₂ 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)-κB pathway in pulmonary tissue. Furthermore, ultrafine TiO₂ 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-α at the level of protein and mRNA expression. These results suggest that ultrafine TiO₂ (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-κB pathway, leading to increased production of proinflammatory mediators.

Acknowledgments

This work was supported by the special grant from Ewha Medical Research Center, School of Medicine, Ewha Woman's University. The Ethics Review Committee for Animal Experimentation of Ewha Woman's University School of Medicine approved the experimental protocol. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health.