Respiratory exposure to nano-TiO₂ induces pulmonary toxicity in mice involving reactive free radical-activated TGF-β/Smad/p38MAPK/Wnt pathways.

Abstract

Numerous studies have shown that lung injury can be caused by respiratory exposure to nanoparticulate titanium dioxide (nano-TiO₂ ), but whether pulmonary inflammation and fibrosis are related to the activation of the TGF-β/Smad/p38MAPK/Wnt pathways remains unclear. In this study, mice were administrated nano-TiO₂ by nasal instillation for nine consecutive months, and the molecular mechanisms of nano-TiO₂ on the pulmonary toxicity of mice were examined. The findings suggested that nano-TiO₂ caused pneumonia and pulmonary fibrosis. Furthermore, the results also showed that an overproduction of reactive free radicals occurred in mouse lungs, and that the expression of TGF-β/p38MAPK/Wnt pathway-related factors, including hypoxia-inducible factor 1α (HIF-1α), transforming growth factor-β1 (TGF-β1), phosphorylated p38 mitogen activated protein kinases (p-p38MAPK), small mothers against decapentaplegic homolog 2 (Smad2), extracellular matrix (ECM), Wingless/Integrated 3 (Wnt3), Wingless/Integrated 4 (Wnt4), integrin-linked kinase (ILK), β-catenin, nuclear factor-κB (NF-κB), α-smooth muscle actin (α-SMA), c-Myc, Type I collage (collagen I), and Type collage III (collagen III) were remarkably elevated, while phosphorylated glycogen synthase kinase-3β (p-GSK-3β) expression was decreased. Those data implied that the pulmonary inflammation and fibrosis caused by nano-TiO₂ exposure may be involved in reactive free radical-mediated activation of the TGF-β/Smad/p38MAPK/Wnt pathways.