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Background: Previous studies have demonstrated that exposure to nickel nanoparticles (Nano-Ni) causes oxidative stress and severe, persistent lung inflammation, which are strongly associated with pulmonary toxicity. However, few studies have investigated whether surface modification of Nano-Ni could alter Nano-Ni-induced lung injury, inflammation, and fibrosis in vivo. Here, we propose that alteration of physicochemical properties of Nano-Ni through modification of Nano-Ni surface may change Nano-Ni-induced lung injury, inflammation, and fibrosis., Methods: At first, dose-response and time-response studies were performed to observe lung inflammation and injury caused by Nano-Ni. In the dose-response studies, mice were intratracheally instilled with 0, 10, 20, 50, and 100 μg per mouse of Nano-Ni and sacrificed at day 3 post-exposure. In the time-response studies, mice were intratracheally instilled with 50 µg per mouse of Nano-Ni and sacrificed at days 1, 3, 7, 14, 28, and 42 post-instillation. At the end of the experiment, mice were bronchoalveolar lavaged (BAL) and the neutrophil count, CXCL1/KC level, LDH activity, and concentration of total protein in the BAL fluid (BALF) were determined. In the comparative studies, mice were intratracheally instilled with 50 μg per mouse of Nano-Ni or with the same molar concentration of Ni as Nano-Ni of either partially [O]-passivated Nano-Ni (Nano-Ni-P) or carbon-coated Nano-Ni (Nano-Ni-C). At day 3 post-exposure, BAL was performed and the above cellular and biochemical parameters in the BALF were analyzed. The MMP-2/9 protein levels and activities in the BALF and mouse lung tissues were also determined. Mouse lung tissues were also collected for H&E staining, and measurement of thiobarbituric acid reactive substances (TBARS) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the genomic DNA. At day 42 post-exposure, mouse right lung tissues were collected for H&E and Trichrome stainings, and left lung tissues were collected to determine the hydroxyproline content., Results: Exposure of mice to Nano-Ni resulted in a dose-response increase in acute lung inflammation and injury reflected by increased neutrophil count, CXCL1/KC level, LDH activity, and concentration of total protein in the BALF. The time-response study showed that Nano-Ni-induced acute lung inflammation and injury appeared as early as day 1, peaked at day 3, and attenuated at day 7 post-instillation. Although the neutrophil count, CXCL1/KC level, LDH activity, and concentration of total protein in the BALF dramatically decreased over the time, their levels were still higher than those of the controls even at day 42 post-exposure. Based on the results of the dose- and time-response studies, we chose a dose of 50 µg per mouse of Nano-Ni, and day 3 post-exposure as short-term and day 42 post-exposure as long-term to compare the effects of Nano-Ni, Nano-Ni-P, and Nano-Ni-C on mouse lungs. At day 3 post-exposure, 50 μg per mouse of Nano-Ni caused acute lung inflammation and injury that were reflected by increased neutrophil count, CXCL1/KC level, LDH activity, concentration of total protein, and MMP-2/9 protein levels and activities in the BALF. Nano-Ni exposure also caused increased MMP-2/9 activities in the mouse lung tissues. Histologically, infiltration of large numbers of neutrophils and macrophages in the alveolar space and interstitial tissues was observed in mouse lungs exposed to Nano-Ni. Nano-Ni-P exposure caused similar acute lung inflammation and injury as Nano-Ni. However, exposure to Nano-Ni-C only caused mild acute lung inflammation and injury. At day 42 post-exposure, Nano-Ni caused extensive interstitial fibrosis and proliferation of interstitial cells with inflammatory cells infiltrating the alveolar septa and alveolar space. Lung fibrosis was also observed in Nano-Ni-P-exposed lungs, but to a much lesser degree. Only slight or no lung fibrosis was observed in Nano-Ni-C-exposed lungs. Nano-Ni and Nano-Ni-P, but not Nano-Ni-C, caused significantly elevated levels of TBARS in mouse lung tissues and 8-OHdG in mouse lung tissue genomic DNA, suggesting that Nano-Ni and Nano-Ni-P induce lipid peroxidation and oxidative DNA damage in mouse lung tissues, while Nano-Ni-C does not., Conclusion: Our results demonstrate that short-term Nano-Ni exposure causes acute lung inflammation and injury, while long-term Nano-Ni exposure causes chronic lung inflammation and fibrosis. Surface modification of Nano-Ni alleviates Nano-Ni-induced pulmonary effects; partially passivated Nano-Ni causes similar effects as Nano-Ni, but the chronic inflammation and fibrosis were at a much lesser degree. Carbon coating significantly alleviates Nano-Ni-induced acute and chronic lung inflammation and injury.

The increased development and use of nanoparticles in various fields may lead to increased exposure, directly affecting human health. Our current knowledge of the health effects of metal nanoparticles such as cobalt and titanium dioxide (Nano-Co and Nano-TiO2 ) is limited but suggests that some metal nanoparticles may cause genotoxic effects including cell cycle arrest, DNA damage, and apoptosis. The growth arrest and DNA damage-inducible 45α protein (Gadd45α) has been characterized as one of the key players in the cellular responses to a variety of DNA damaging agents. The aim of this study was to investigate the alteration of Gadd45α expression in mouse embryo fibroblasts (PW) exposed to metal nanoparticles and the possible mechanisms. Non-toxic doses of Nano-Co and Nano-TiO2 were selected to treat cells. Our results showed that Nano-Co caused a dose- and time-dependent increase in Gadd45α expression, but Nano-TiO2 did not. To investigate the potential pathways involved in Nano-Co-induced Gadd45α up-regulation, we measured the expression of hypoxia inducible factor 1α (HIF-1α) in PW cells exposed to Nano-Co and Nano-TiO2 . Our results showed that exposure to Nano-Co caused HIF-1α accumulation in the nucleus. In addition, hypoxia inducible factor 1α knock-out cells [HIF-1α (-/-)] and its wild-type cells [HIF-1α (+/+)] were used. Our results demonstrated that Nano-Co caused a dose- and time-dependent increase in Gadd45α expression in wild-type HIF-1α (+/+) cells, but only a slight increase in HIF-1α (-/-) cells. Pre-treatment of PW cells with heat shock protein 90 inhibitor, 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG), prior to exposure to Nano-Co significantly abolished Nano-Co-induced Gadd45α expression. These results suggest that HIF-1α accumulation may be partially involved in the increased Gadd45α expression in cells exposed to Nano-Co. These findings may have important implications for understanding the potential health effects of metal nanoparticle exposure., (Copyright © 2013 Wiley Periodicals, Inc.)

Exposure to metal nanoparticles causes both pulmonary and systemic effects. Nanoparticles can enter the circulation and act directly or indirectly on blood cells, such as monocytes. Monocytes/macrophages are among the first cells to home to inflammatory sites and play a key role in the immune response. Here we investigated the effects of nickel nanoparticles (Nano-Ni), partially [O]-passivated Nano-Ni (Nano-Ni-P), and carbon-coated Nano-Ni (Nano-Ni-C) on MMP-2 and MMP-9 production in mouse primary monocytes both in vitro and in vivo and explored the potential mechanisms involved. The dose- and time-response studies showed that exposure of primary monocytes from wild-type (WT) mice to 30 μg/mL of Nano-Ni for 24 h caused significant MMP-2 and MMP-9 production; therefore, these dose and time point were chosen for the following in vitro studies. Nano-Ni and Nano-Ni-P caused miR-21 upregulation, as well as MMP-2, MMP-9, TIMP-1 and TIMP-2 upregulation in monocytes from WT, but not miR-21 knock-out (KO), mice, indicating the important role of miR-21 in Nano-Ni-induced MMPs and TIMPs upregulation. However, Nano-Ni-C did not cause these effects, suggesting surface modification of Nano-Ni, such as carbon coating, alleviates Nano-Ni-induced miR-21 and MMPs upregulation. These results were further confirmed by in vivo studies by intratracheal instillation of nickel nanoparticles into WT and miR-21 KO mice. Finally, our results demonstrated that exposure of primary monocytes from WT mice to Nano-Ni and Nano-Ni-P caused downregulation of RECK, a direct miR-21 target, suggesting the involvement of miR-21/RECK pathway in Nano-Ni-induced MMP-2 and MMP-9 production. Image 1 • Primary monocytes were isolated from mouse peripheral blood. • Nano-Ni upregulated miR-21, MMP-2 and MMP-9, and downregulated RECK in WT monocytes. • Nano-Ni did not cause the above effects in monocytes from miR-21 knock-out mice. • Carbon-coating (Nano-Ni-C) ameliorated Nano-Ni-induced MMP-2/9 upregulation. • miR-21/RECK pathway is involved in Nano-Ni-induced MMP-2/9 production. [ABSTRACT FROM AUTHOR]