Airway Exposure to Silica-Coated TiO2 Nanoparticles Induces Pulmonary Neutrophilia in Mice

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Abstract
The importance of nanotechnologies and engineered nanoparticles has grown rapidly. It is therefore crucial to acquire up-to-date knowledge of the possible harmful health effects of these materials. Since a multitude of different types of nanosized titanium dioxide (TiO2) particles are used in industry, we explored their inflammatory potential using mouse and cell models. BALB/c mice were exposed by inhalation for 2 h, 2 h on 4 consecutive days, or 2 h on 4 consecutive days for 4 weeks to several commercial TiO2 nanoparticles, SiO2 nanoparticles, and to nanosized TiO2 generated in a gas-to-particle conversion process at 10 mg/m3. In addition, effects of in vitro exposure of human macrophages and fibroblasts (MRC-9) to the different particles were assessed. SiO2-coated rutile TiO2 nanoparticles (cnTiO2) was the only sample tested that elicited clear-cut pulmonary neutrophilia. Uncoated rutile and anatase as well as nanosized SiO2 did not induce significant inflammation. Pulmonary neutrophilia was accompanied by increased expression of tumor necrosis factor-alpha (TNF-α) and neutrophil-attracting chemokine CXCL1 in the lung tissue. TiO2 particles accumulated almost exclusively in the alveolar macrophages. In vitro exposure of murine and human macrophages to cnTiO2 elicited significant induction of TNF-α and neutrophil-attracting chemokines. Stimulation of human fibroblasts with cnTiO2-activated macrophage supernatant induced high expression of neutrophil-attracting chemokines, CXCL1 and CXCL8. Interestingly, the level of lung inflammation could not be explained by the surface area of the particles, their primary or agglomerate particle size, or radical formation capacity but is rather explained by the surface coating. Our findings emphasize that it is vitally important to take into account in the risk assessment that alterations of nanoparticles, e.g., by surface coating, may drastically change their toxicological potential.