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 (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.

A mixture of anatase and rutile TiO2 nanoparticles induces histamine secretion in mast cells

“…In addition, the associated underlying cellular mechanisms leading to the final degranulation are not clear. TiO 2 NPs have previously been shown to trigger mucin secretion, pulmonary inflammatory responses and emphysema-like pathology [17,18,29,30]. In this study, we demonstrate that TiO 2 NPs can directly stimulate histamine release from RBL-2H3 mast cells via a Ca 2+ - dependent pathway.…”

Anemia and genotoxicity induced by sub-chronic intragastric treatment of rats with titanium dioxide nanoparticles

“…In this study, the TiO 2 NPs treated animals also exhibited significantly higher WBC than the control animals. Increase of leucocytes might indicate the activation of the defense and immune systems of the body [28,29]. In addition, there was inflammation in the tissues of various animal organs, including lungs, kidneys, liver, and brain, previously described [27,28,[30][31][32][33].…”

Immunotoxicological impact of occupational and environmental nanoparticles exposure: The influence of physical, chemical, and combined characteristics of the particles

“…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)-kappa B pathway in pulmonary tissue. 64 Regarding the impact on innate immunity, recently, several studies have demonstrated the effects of NPs on innate immunity via toll-like receptors (TLRs) signaling pathways. Several nanoparticles (e.g.…”

“…TiO 2 exposure increased neutrophil influx, protein levels in bronchoalveolar lavage fluid, ROS activity of BAL cells 4 h after exposure. 64 Manna et al found an increased oxidative stress and inhibition of cell proliferation in response to treatment of keratinocytes with single-walled carbon nanotubes (SWCNTs) and suggest that nanotubes can activate NF-kB in a dose-dependent manner. 87 De Marzi et al investigated the effects of short-term and long-term ceria NPs (CeO 2 -NPs) exposure to A549, CaCo 2 , and HepG 2 cell lines showing that after 24-h exposure NPs can induce ROS damages.…”