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1.
Nanoscale Adv ; 2(12): 5635-5647, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34381958

RESUMO

Background: The toxicity of inhaled silver nanoparticles on contractile and pro-inflammatory airway smooth muscle cells (ASMCs) that control airway calibre is unknown. We explored the oxidative activities and sulfidation processes of the toxic-inflammatory response. Method: Silver nanospheres (AgNSs) of 20 nm and 50 nm diameter and silver nanowires (AgNWs), short S-AgNWs, 1.5 µm and long L-AgNWs, 10 µm, both 72 nm in diameter were manufactured. We measured their effects on cell proliferation, mitochondrial reactive oxygen species (ROS) release and membrane potential, and also performed electron microscopic studies. Main results and findings: The greatest effects were observed for the smallest particles with the highest specific surface area and greatest solubility that were avidly internalised. ASMCs exposed to 20 nm AgNSs (25 µg mL-1) for 72 hours exhibited a significant decrease in DNA incorporation (-72.4%; p < 0.05), whereas neither the 50 nm AgNSs nor the s-AgNWs altered DNA synthesis or viability. There was a small reduction in ASMC proliferation for the smaller AgNS, although Ag+ at 25 µL mL-1 reduced DNA synthesis by 93.3% (p < 0.001). Mitochondrial potential was reduced by both Ag+ (25 µg mL-1) by 47.1% and 20 nm Ag NSs (25 µg mL-1) by 40.1% (*both at p < 0.05), but was not affected by 50 nm AgNSs and the AgNWs. None of the samples showed a change in ROS toxicity. However, malondialdehyde release, associated with greater total ROS, was observed for all AgNPs, to an extent following the geometric size (20 nm AgNS: 213%, p < 0.01; 50 nm AgNS: 179.5%, p < 0.01 and L-AgNWs by 156.2%, p < 0.05). The antioxidant, N-acetylcysteine, prevented the reduction in mitochondrial potential caused by 20 nm AgNSs. The smaller nanostructures were internalised and dissolved within the ASMCs with the formation of non-reactive silver sulphide (Ag2S) on their surface, but with very little uptake of L-AgNWs. When ASMCs were incubated with H2S-producing enzyme inhibitors, the spatial extent of Ag2S formation was much greater. Conclusion: The intracellular toxicity of AgNPs in ASMCs is determined by the solubility of Ag+ released and the sulfidation process, effects related to particle size and geometry. Passivation through sulfidation driven by biogenic H2S can outcompete dissolution, thus reducing the toxicity of the smaller intracellular Ag nanostructures.

2.
Nanotoxicology ; 12(6): 539-553, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29750584

RESUMO

Experimental modeling to identify specific inhalation hazards for nanomaterials has in the main focused on in vivo approaches. However, these models suffer from uncertainties surrounding species-specific differences and cellular targets for biologic response. In terms of pulmonary exposure, approaches which combine 'inhalation-like' nanoparticulate aerosol deposition with relevant human cell and tissue air-liquid interface cultures are considered an important complement to in vivo work. In this study, we utilized such a model system to build on previous results from in vivo exposures, which highlighted the small airway epithelium as a target for silver nanoparticle (AgNP) deposition. RNA-SEQ was used to characterize alterations in mRNA and miRNA within the lung. Organotypic-reconstituted 3D human primary small airway epithelial cell cultures (SmallAir) were exposed to the same spark-generated AgNP and at the same dose used in vivo, in an aerosol-exposure air-liquid interface (AE-ALI) system. Adverse effects were characterized using lactate, LDH release and alterations in mRNA and miRNA. Modest toxicological effects were paralleled by significant regulation in gene expression, reflective mainly of specific inflammatory events. Importantly, there was a level of concordance between gene expression changes observed in vitro and in vivo. We also observed a significant correlation between AgNP and mass equivalent silver ion (Ag+) induced transcriptional changes in SmallAir cultures. In addition to key mechanistic information relevant for our understanding of the potential health risks associated with AgNP inhalation exposure, this work further highlights the small airway epithelium as an important target for adverse effects.


Assuntos
Pulmão/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Prata/toxicidade , Aerossóis , Animais , Células Cultivadas , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Humanos , Exposição por Inalação , Pulmão/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
3.
ACS Nano ; 11(3): 2652-2664, 2017 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-28221763

RESUMO

There is a potential for silver nanowires (AgNWs) to be inhaled, but there is little information on their health effects and their chemical transformation inside the lungs in vivo. We studied the effects of short (S-AgNWs; 1.5 µm) and long (L-AgNWs; 10 µm) nanowires instilled into the lungs of Sprague-Dawley rats. S- and L-AgNWs were phagocytosed and degraded by macrophages; there was no frustrated phagocytosis. Interestingly, both AgNWs were internalized in alveolar epithelial cells, with precipitation of Ag2S on their surface as secondary Ag2S nanoparticles. Quantitative serial block face three-dimensional scanning electron microscopy showed a small, but significant, reduction of NW lengths inside alveolar epithelial cells. AgNWs were also present in the lung subpleural space where L-AgNWs exposure resulted in more Ag+ve macrophages situated within the pleura and subpleural alveoli, compared with the S-AgNWs exposure. For both AgNWs, there was lung inflammation at day 1, disappearing by day 21, but in bronchoalveolar lavage fluid (BALF), L-AgNWs caused a delayed neutrophilic and macrophagic inflammation, while S-AgNWs caused only acute transient neutrophilia. Surfactant protein D (SP-D) levels in BALF increased after S- and L-AgNWs exposure at day 7. L-AgNWs induced MIP-1α and S-AgNWs induced IL-18 at day 1. Large airway bronchial responsiveness to acetylcholine increased following L-AgNWs, but not S-AgNWs, exposure. The attenuated response to AgNW instillation may be due to silver inactivation after precipitation of Ag2S with limited dissolution. Our findings have important consequences for the safety of silver-based technologies to human health.


Assuntos
Pulmão/efeitos dos fármacos , Nanofios/química , Prata/química , Animais , Instilação de Medicamentos , Pulmão/metabolismo , Pulmão/patologia , Nanofios/administração & dosagem , Ratos , Ratos Sprague-Dawley , Prata/administração & dosagem
4.
Environ Sci Process Impacts ; 18(10): 1333-1342, 2016 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-27711787

RESUMO

Nanoceria (i.e., CeO2 nanoparticles) fuel additives have been used in Europe and elsewhere to improve fuel efficiency. Previously we have shown that the use of a commercial fuel additive Envirox™ in a diesel-powered electricity generator reduced emissions of diesel exhaust particle (DEP) mass and other pollutants. However, such additives are currently not permitted for use in on-road vehicles in North America, largely due to limited data on the potential health impact. In this study, we characterized a variety of physicochemical properties of DEPs emitted from the same engine. Our methods include novel techniques such as Raman spectrometry for analyzing particle surface structure and an assay for DEP oxidative potential. Results show that with increasing Envirox™ concentrations in the fuel (0×, 0.1×, 1×, and 10× of manufacturer recommended 0.5 mL Envirox™ per liter fuel), DEP sizes decreased from 194.6 ± 20.1 to 116.3 ± 14.8 nm; the zeta potential changed from -28.4 mV to -22.65 mV; DEP carbon content decreased from 91.8% to 79.4%; cerium and nitrogen contents increased from 0.3% to 6.5% and 0.2% to 0.6%, respectively; the ratio of organic carbon (OC) to elemental carbon (EC) increased from 22.9% to 38.7%; and the ratio of the disordered carbon structure to the ordered carbon structure (graphitized carbon) in DEPs decreased. Compared to DEPs emitted from 0×, 0.1×, and 1× fuels, DEPs from the 10× fuel had a lower oxidative potential likely due to the increased ceria content because pure ceria nanoparticles exhibited the lowest oxidative potential compared to all the DEPs. Since the physicochemical parameters tested here are among the determinants of particle toxicity, our findings imply that adding ceria nanoparticles into diesel may alter the toxicity of DEPs. The findings from the present study, hence, can help future studies that will examine the impact of nanoceria additives on DEP toxicities.


Assuntos
Poluentes Atmosféricos/análise , Cério/química , Nanopartículas Metálicas/química , Material Particulado/análise , Emissões de Veículos/análise , Carbono/análise , Gasolina , Tamanho da Partícula
5.
Respir Res ; 17(1): 85, 2016 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-27435725

RESUMO

BACKGROUND: The increasing use of silver nanoparticles (AgNPs) in consumer products is concerning. We examined the potential toxic effects when inhaled in Brown-Norway (BN) rats with a pre-inflammatory state compared to Sprague-Dawley (SD) rats. METHODS: We determined the effect of AgNPs generated from a spark generator (mass concentration: 600-800 µg/mm(3); mean diameter: 13-16 nm; total lung doses: 8 [Low] and 26-28 [High] µg) inhaled by the nasal route in both rat strains. Rats were sacrificed at day 1 and day 7 after exposure and measurement of lung function. RESULTS: In both strains, there was an increase in neutrophils in bronchoalveolar lavage (BAL) fluid at 24 h at the high dose, with concomitant eosinophilia in BN rats. While BAL inflammatory cells were mostly normalised by Day 7, lung inflammation scores remained increased although not the tissue eosinophil scores. Total protein levels were elevated at both lung doses in both strains. There was an increase in BAL IL-1ß, KC, IL-17, CCL2 and CCL3 levels in both strains at Day 1, mostly at high dose. Phospholipid levels were increased at the high dose in SD rats at Day 1 and 7, while in BN rats, this was only seen at Day 1; surfactant protein D levels decreased at day 7 at the high dose in SD rats, but was increased at Day 1 at the low dose in BN rats. There was a transient increase in central airway resistance and in tissue elastance in BN rats at Day 1 but not in SD rats. Positive silver-staining was seen particularly in lung tissue macrophages in a dose and time-dependent response in both strains, maximal by day 7. Lung silver levels were relatively higher in BN rat and present at day 7 in both strains. CONCLUSIONS: Presence of cellular inflammation and increasing silver-positive macrophages in lungs at day 7, associated with significant levels of lung silver indicate that lung toxicity is persistent even with the absence of airway luminal inflammation at that time-point. The higher levels and persistence of lung silver in BN rats may be due to the pre-existing inflammatory state of the lungs.


Assuntos
Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Pneumonia/induzido quimicamente , Prata/toxicidade , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Mediadores da Inflamação/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/fisiopatologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Masculino , Fosfolipídeos/metabolismo , Pneumonia/imunologia , Pneumonia/metabolismo , Pneumonia/fisiopatologia , Eosinofilia Pulmonar/induzido quimicamente , Eosinofilia Pulmonar/imunologia , Eosinofilia Pulmonar/metabolismo , Proteína D Associada a Surfactante Pulmonar/metabolismo , Ratos Endogâmicos BN , Ratos Sprague-Dawley , Mecânica Respiratória/efeitos dos fármacos , Fatores de Tempo
6.
Biomaterials ; 55: 24-32, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25934449

RESUMO

Multiwalled carbon nanotubes (MWCNTs) are now synthesized on a large scale, increasing the risk of occupational inhalation. However, little is known of the MWCNT-pulmonary surfactant (PS) interface and its effect on PS functionality. The Langmuir-Blodgett trough was used to evaluate the impact of MWCNTs on fundamental properties of PS lipids which influence PS function, i.e. compression resistance and maximum obtainable pressure. Changes were found to be MWCNT length-dependent. 'Short' MWCNTs (1.1 µm, SD = 0.61) penetrated the lipid film, reducing the maximum interfacial film pressure by 10 mN/m (14%) in dipalmitoylphosphatidylcholine (DPPC) and PS, at an interfacial MWCNT-PS lipid mass ratio range of 50:1 to 1:1. 'Long' commercial MWCNTs (2.1 µm, SD = 1.2) caused compression resistance at the same mass loadings. 'Very long' MWCNTs (35 µm, SD = 19) sequestered DPPC and were squeezed out of the DPPC film. High resolution transmission electron microscopy revealed that all MWCNT morphologies formed DPPC coronas with ordered arrangements. These results provide insight into how nanoparticle aspect ratio affects the interaction mechanisms with PS, in its near-native state at the air-water interface.


Assuntos
1,2-Dipalmitoilfosfatidilcolina/química , Lipídeos/química , Pulmão/efeitos dos fármacos , Nanotubos de Carbono/química , Surfactantes Pulmonares/química , Animais , Força Compressiva , Microscopia de Força Atômica , Microscopia Eletrônica , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Propriedades de Superfície , Tensoativos , Temperatura
7.
PLoS One ; 10(3): e0119726, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25747867

RESUMO

Particle size and surface chemistry are potential determinants of silver nanoparticle (AgNP) respiratory toxicity that may also depend on the lung inflammatory state. We compared the effects of intratracheally-administered AgNPs (20 nm and 110 nm; polyvinylpyrrolidone (PVP) and citrate-capped; 0.1 mg/Kg) in Brown-Norway (BN) and Sprague-Dawley (SD) rats. In BN rats, there was both a neutrophilic and eosinophilic response, while in SD rats, there was a neutrophilic response at day 1, greatest for the 20 nm citrate-capped AgNPs. Eosinophilic cationic protein was increased in bronchoalveolar lavage (BAL) in BN and SD rats on day 1. BAL protein and malondialdehyde levels were increased in BN rats at 1 and 7 days, and BAL KC, CCL11 and IL-13 levels at day 1, with increased expression of CCL11 in lung tissue. Pulmonary resistance increased and compliance decreased at day 1, with persistence at day 7. The 20 nm, but not the 110 nm, AgNPs increased bronchial hyperresponsiveness on day 1, which continued at day 7 for the citrate-capped AgNPs only. The 20 nm versus the 110 nm size were more proinflammatory in terms of neutrophil influx, but there was little difference between the citrate-capped versus the PVP-capped AgNPs. AgNPs can induce pulmonary eosinophilic and neutrophilic inflammation with bronchial hyperresponsiveness, features characteristic of asthma.


Assuntos
Ácido Cítrico/toxicidade , Materiais Revestidos Biocompatíveis/toxicidade , Pulmão/metabolismo , Nanopartículas Metálicas/efeitos adversos , Povidona/análogos & derivados , Prata/toxicidade , Animais , Pulmão/patologia , Masculino , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/patologia , Tamanho da Partícula , Povidona/toxicidade , Ratos , Ratos Sprague-Dawley
8.
PLoS One ; 8(11): e80782, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24260479

RESUMO

INTRODUCTION: Chronic exposure to high levels of ozone induces emphysema and chronic inflammation in mice. We determined the recovery from ozone-induced injury and whether an antioxidant, N-acetylcysteine (NAC), could prevent or reverse the lung damage. METHODS: Mice were exposed to ozone (2.5 ppm, 3 hours/12 exposures, over 6 weeks) and studied 24 hours (24h) or 6 weeks (6W) later. Nac (100 mg/kg, intraperitoneally) was administered either before each exposure (preventive) or after completion of exposure (therapeutic) for 6 weeks. RESULTS: After ozone exposure, there was an increase in functional residual capacity, total lung volume, and lung compliance, and a reduction in the ratio of forced expiratory volume at 25 and 50 milliseconds to forced vital capacity (FEV25/FVC, FEV50/FVC). Mean linear intercept (Lm) and airway hyperresponsiveness (AHR) to acetylcholine increased, and remained unchanged at 6W after cessation of exposure. Preventive NAC reduced the number of BAL macrophages and airway smooth muscle (ASM) mass. Therapeutic NAC reversed AHR, and reduced ASM mass and apoptotic cells. CONCLUSION: Emphysema and lung function changes were irreversible up to 6W after cessation of ozone exposure, and were not reversed by NAC. The beneficial effects of therapeutic NAC may be restricted to the ASM.


Assuntos
Acetilcisteína/farmacologia , Expectorantes/farmacologia , Ozônio/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , 8-Hidroxi-2'-Desoxiguanosina , Acetilcisteína/administração & dosagem , Animais , Apoptose , Hiper-Reatividade Brônquica/induzido quimicamente , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Desoxiguanosina/análogos & derivados , Desoxiguanosina/sangue , Modelos Animais de Doenças , Enfisema/patologia , Expectorantes/administração & dosagem , Expressão Gênica , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Malondialdeído/metabolismo , Camundongos , Doença Pulmonar Obstrutiva Crônica/patologia , Testes de Função Respiratória
9.
Chem Res Toxicol ; 25(1): 140-52, 2012 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-22054034

RESUMO

The increased use of nanoparticles in industrial and medical products is driving the need for accurate, high throughput in vitro testing procedures to screen new particles for potential toxicity. While approaches using standard viability assays have been widely used, there have been increased reports of the interactions of nanoparticles with their soluble labels or optical readouts which raise concerns over the potential generation of false positive results. Here, we describe the use of an impedance spectroscopy approach to provide real-time reagent free detection of toxicity for a panel of metal oxide nanoparticles (ZnO, CuO, and TiO(2)). Using this approach, we show how impedance measurements can be used to track nanoparticle toxicity over time with comparable IC(50) values to those of standard assays (ZnO-55 µg/mL, CuO-28 µg/mL) as well as being used to identify a critical 6 h period following exposure during which the nanoparticles trigger rapid cellular responses. Through targeted analysis during this response period and the use of a novel image analysis approach, we show how the ZnO and CuO nanoparticles trigger the active export of intracellular glutathione via an increase in the activity of the ATP dependent MRP/1 efflux pumps. The loss of glutathione leads to increased production of reactive oxygen species which after 2.5 h triggers the cells to enter apoptosis resulting in a dose dependent cytotoxic response. This targeted testing strategy provides comprehensive information beyond that achieved with standard toxicity assays and indicates the potential for cell-nanoparticle interactions that could occur following in vivo exposure.


Assuntos
Cobre/toxicidade , Nanopartículas Metálicas/toxicidade , Titânio/toxicidade , Óxido de Zinco/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Impedância Elétrica , Glutationa/metabolismo , Humanos , Espécies Reativas de Oxigênio/metabolismo
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