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Exposure to titanium dioxide nanoparticles (TiO(2) NPs) elicits an adverse response such as oxidative damage. The molecular targets of TiO(2) NPs remain largely unidentified. In the present study, the function and signal pathway of nuclear factor erythroid 2 related factor 2 (Nrf2) in protection against TiO(2) NPs-induced oxidative stress in the mouse lung were investigated. Mice were exposed to 10 mg/kg body weight by an intratracheal administration for 15-90 days. With increasing exposed terms, TiO(2) NPs were significantly accumulated and increased the reactive oxygen species (ROS) production in lung, which resulted in severe pulmonary edema, inflammatory response and pneumonocyte apoptosis for 90 days. Furthermore, TiO(2) NPs exposure could greatly induce expression of Nrf2, heme oxygenase 1 (HO-1), and glutamate-cysteine ligase catalytic subunit (GCLC) from 15-day to 75-day exposure, whereas 90-day exposure caused significant decreases of three factors expression levels in lung. Our findings imply that the induction of Nrf2 expression is an adaptive intracellular response to TiO(2) NPs-induced oxidative stress in the mouse lung, and that Nrf2 is protective against TiO(2) NPs-induced pulmonary damages during certain exposure terms., (Copyright © 2012 Wiley Periodicals, Inc.)

Abstract: Exposure to titanium dioxide nanoparticles (TiO2 NPs) has been demonstrated to result in pulmonary inflammation in animals; however, very little is known about the molecular mechanisms of pulmonary injury due to TiO2 NPs exposure. The aim of this study was to evaluate the oxidative stress and molecular mechanism associated with pulmonary inflammation in chronic lung toxicity caused by the intratracheal instillation of TiO2 NPs for 90 consecutive days in mice. Our findings suggest that TiO2 NPs are significantly accumulated in the lung, leading to an obvious increase in lung indices, inflammation and bleeding in the lung. Exposure to TiO2 NPs significantly increased the accumulation of reactive oxygen species and the level of lipid peroxidation, and decreased antioxidant capacity in the lung. Furthermore, TiO2 NPs exposure activated nuclear factor-κB, increased the levels of tumor necrosis factor-α, cyclooxygenase-2, heme oxygenase-1, interleukin-2, interleukin-4, interleukin-6, interleukin-8, interleukin-10, interleukin-18, interleukin-1β, and CYP1A1 expression. However, TiO2 NPs exposure decreased NF-κB-inhibiting factor and heat shock protein 70 expression. Our results suggest that the generation of pulmonary inflammation caused by TiO2 NPs in mice is closely related to oxidative stress and the expression of inflammatory cytokines. [Copyright &y& Elsevier]