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)-, interleukin (IL)-1▀, and macrophage inflammatory protein (MIP)-2 in BAL fluid and mRNA expression of TNF- and IL-1▀ 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)-kappa▀ 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-alpha 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-kappa▀ pathway, leading to increased production of proinflammatory mediators.
Biodynamics; Biological-effects; Cell-biology; Cellular-reactions; Cytology; Exposure-assessment; Exposure-levels; Exposure-methods; Inhalation-studies; Laboratory-animals; Laboratory-testing; Particle-aerodynamics; Particulates; Pathogenicity; Physiological-effects; Physiological-factors; Toxic-effects; Nanotechnology
Dr. Jihee Lee Kang, Department of Physiology, School of Medicine, Ewha Woman's University, 911-1 Mok-6-dong, Yangcheon-ku, Seoul 158-056, Korea