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Titanium dioxide (TiO 2 ) nanoparticles are indispensable for daily life but induce acute inflammation, mainly via inhalation exposure. TiO 2 nanoparticles can be phagocytosed by alveolar macrophages (AMs) in vivo and cause necroptosis of exposed cells in vitro . However, the relationship between localization of TiO 2 nanoparticles in the lungs after exposure and their biological responses including cell death and inflammation remains unclear. This study was conducted to investigate the intra/extracellular localization of TiO 2 nanoparticles in murine lungs at 24 h after intratracheal exposure to rutile TiO 2 nanoparticles and subsequent local biological reactions, specifically necroptosis of AMs and lung inflammation. We found that TiO 2 exposure induced leukocyte migration into the alveolar region and increased the secretion of C-C motif ligand (CCL) 3 in the bronchoalveolar lavage (BAL) fluid. A combination of Raman spectroscopy and staining of cell and tissue samples confirmed that AMs phagocytose TiO 2 . AMs that phagocytosed TiO 2 nanoparticles showed necroptosis, characterized by the expression of phosphorylated mixed lineage kinase domain-like protein and translocation of high mobility group box-1 from the cell nucleus to the cytoplasm. In primary cultured AMs, TiO 2 also induced necroptosis and increased the secretion of CCL3. Necroptosis inhibitors suppressed the increase in CCL3 secretion in both the BAL fluid and culture supernatant of AMs and suppressed the increase in leukocytes in the BAL fluid. These data suggest that necroptosis of AMs that phagocytose TiO 2 nanoparticles is involved as part of the mechanism by which TiO 2 induces acute lung inflammation.

Evaluation of the health effects of particulate matter with aerodynamic dias. ≤ 2.5 μm (PM2.5) should reflect realistic condition in ambient atmosphere. However, using conventional filtration methods, only extracts from PM2.5 collected on the filter can be analyzed and not the particle itself. Cyclonic separation is a technique that enables the direct analysis of the effects of the crude "powder form" of PM2.5 on respiratory health. Airway epithelial cells and antigen-presenting cells were exposed to PM2.5 collected during the same period using a conventional filtration method or cyclonic separation. PM2.5 collected using cyclonic separation led to a higher secretion of interleukins 6 and 8 (IL-6, IL-8) from airway epithelial cells, and IL-6, IL-1β, tumor necrosis factor-α (TNF-α) secretion, cluster of differentiation 86 (CD86), and dendritic and epithelial cells 205 (DEC205) expression on antigen-presenting cells, compared with the effects of filter-collected PM2.5. Furthermore, PM2.5 collected using cyclonic separation increased inflammatory cytokine levels and induced lung inflammation in vivo. These results suggest that crude PM2.5 collected using cyclonic separation causes stronger biological responses than filter-collected PM2.5. Hence, PM2.5 collected using cyclonic separation can be utilized for a reliable evaluation of the health effects of ambient PM2.5. [Display omitted] • Cyclonic separation is a technique that enables the direct analysis of particle itself. • PM2.5 collected using cyclonic separation causes stronger biological responses. • Cyclonic separation can be utilized for a reliable evaluation of health effects. [ABSTRACT FROM AUTHOR]