Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 36
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Toxicol Appl Pharmacol ; 408: 115280, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33065154

RESUMO

The pulmonary inflammatory response to inhalation exposure to a fracking sand dust (FSD 8) was investigated in a rat model. Adult male Sprague-Dawley rats were exposed by whole-body inhalation to air or an aerosol of a FSD, i.e., FSD 8, at concentrations of 10 or 30 mg/m3, 6 h/d for 4 d. The control and FSD 8-exposed rats were euthanized at post-exposure time intervals of 1, 7 or 27 d and pulmonary inflammatory, cytotoxic and oxidant responses were determined. Deposition of FSD 8 particles was detected in the lungs of all the FSD 8-exposed rats. Analysis of bronchoalveolar lavage parameters of toxicity, oxidant generation, and inflammation did not reveal any significant persistent pulmonary toxicity in the FSD 8-exposed rats. Similarly, the lung histology of the FSD 8-exposed rats showed only minimal changes in influx of macrophages following the exposure. Determination of global gene expression profiles detected statistically significant differential expressions of only six and five genes in the 10 mg/m3, 1-d post-exposure, and the 30 mg/m3, 7-d post-exposure FSD 8 groups, respectively. Taken together, data obtained from the present study demonstrated that FSD 8 inhalation exposure resulted in no statistically significant toxicity or gene expression changes in the lungs of the rats. In the absence of any information about its potential toxicity, a comprehensive rat animal model study (see Fedan, J.S., Toxicol Appl Pharmacol. 000, 000-000, 2020) has been designed to investigate the bioactivities of several FSDs in comparison to MIN-U-SIL® 5, a respirable α-quartz reference dust used in previous animal models of silicosis, in several organ systems.

2.
Toxicol Appl Pharmacol ; 409: 115284, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33068619

RESUMO

Hydraulic fracturing creates fissures in subterranean rock to increase the flow and retrieval of natural gas. Sand ("proppant") in fracking fluid injected into the well bore maintains fissure patency. Fracking sand dust (FSD) is generated during manipulation of sand to prepare the fracking fluid. Containing respirable crystalline silica, FSD could pose hazards similar to those found in work sites where silica inhalation induces lung disease such as silicosis. This study was performed to evaluate the possible toxic effects following inhalation of a FSD (FSD 8) in the lung and airways. Rats were exposed (6 h/d × 4 d) to 10 or 30 mg/m3 of a FSD collected at a gas well, and measurements were performed 1, 7, 27 and, in one series of experiments, 90 d post-exposure. The following ventilatory and non-ventilatory parameters were measured in vivo and/or in vitro: 1) lung mechanics (respiratory system resistance and elastance, tissue damping, tissue elastance, Newtonian resistance and hysteresivity); 2) airway reactivity to inhaled methacholine (MCh); airway epithelium integrity (isolated, perfused trachea); airway efferent motor nerve activity (electric field stimulation in vitro); airway smooth muscle contractility; ion transport in intact and cultured epithelium; airway effector and sensory nerves; tracheal particle deposition; and neurogenic inflammation/vascular permeability. FSD 8 was without large effect on most parameters, and was not pro-inflammatory, as judged histologically and in cultured epithelial cells, but increased reactivity to inhaled MCh at some post-exposure time points and affected Na+ transport in airway epithelial cells.

3.
Toxicol Appl Pharmacol ; 409: 115282, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33068622

RESUMO

Hydraulic fracturing ("fracking") is used in unconventional gas drilling to allow for the free flow of natural gas from rock. Sand in fracking fluid is pumped into the well bore under high pressure to enter and stabilize fissures in the rock. In the process of manipulating the sand on site, respirable dust (fracking sand dust, FSD) is generated. Inhalation of FSD is a potential hazard to workers inasmuch as respirable crystalline silica causes silicosis, and levels of FSD at drilling work sites have exceeded occupational exposure limits set by OSHA. In the absence of any information about its potential toxicity, a comprehensive rat animal model was designed to investigate the bioactivities of several FSDs in comparison to MIN-U-SIL® 5, a respirable α-quartz reference dust used in previous animal models of silicosis, in several organ systems (Fedan, J.S., Toxicol Appl Pharmacol. 00, 000-000, 2020). The present report, part of the larger investigation, describes: 1) a comparison of the physico-chemical properties of nine FSDs, collected at drilling sites, and MIN-U-SIL® 5, a reference silica dust, and 2) a comparison of the pulmonary inflammatory responses to intratracheal instillation of the nine FSDs and MIN-U-SIL® 5. Our findings indicate that, in many respects, the physico-chemical characteristics, and the biological effects of the FSDs and MIN-U-SIL® 5 after intratracheal instillation, have distinct differences.

4.
Nanotoxicology ; 11(8): 1040-1058, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29094619

RESUMO

Boron nitride nanotubes (BNNTs) are an emerging engineered nanomaterial attracting significant attention due to superior electrical, chemical and thermal properties. Currently, the toxicity profile of this material is largely unknown. Commercial grade BNNTs are composed of a mixture (BNNT-M) of ∼50-60% BNNTs, and ∼40-50% impurities of boron and hexagonal boron nitride. We performed acute in vitro and in vivo studies with commercial grade BNNT-M, dispersed by sonication in vehicle, in comparison to the extensively studied multiwalled carbon nanotube-7 (MWCNT-7). THP-1 wild-type and NLRP3-deficient human monocytic cells were exposed to 0-100 µg/ml and C57BL/6 J male mice were treated with 40 µg of BNNT-M for in vitro and in vivo studies, respectively. In vitro, BNNT-M induced a dose-dependent increase in cytotoxicity and oxidative stress. This was confirmed in vivo following acute exposure increase in bronchoalveolar lavage levels of lactate dehydrogenase, pulmonary polymorphonuclear cell influx, loss in mitochondrial membrane potential and augmented levels of 4-hydroxynonenal. Uptake of this material caused lysosomal destabilization, pyroptosis and inflammasome activation, corroborated by an increase in cathepsin B, caspase 1, increased protein levels of IL-1ß and IL-18 both in vitro and in vivo. Attenuation of these effects in NLRP3-deficient THP-1 cells confirmed NLRP3-dependent inflammasome activation by BNNT-M. BNNT-M induced a similar profile of inflammatory pulmonary protein production when compared to MWCNT-7. Functionally, pretreatment with BNNT-M caused suppression in bacterial uptake by THP-1 cells, an effect that was mirrored in challenged alveolar macrophages collected from exposed mice and attenuated with NLRP3 deficiency. Analysis of cytokines secreted by LPS-challenged alveolar macrophages collected after in vivo exposure to dispersions of BNNT-M showed a differential macrophage response. The observed results demonstrated acute inflammation and toxicity in vitro and in vivo following exposure to sonicated BNNT-M was in part due to NLRP3 inflammasome activation.


Assuntos
Compostos de Boro/toxicidade , Pulmão/efeitos dos fármacos , Nanotubos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Inflamação , Pulmão/metabolismo , Pulmão/patologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Tamanho da Partícula , Piroptose/efeitos dos fármacos
5.
Inhal Toxicol ; 29(7): 322-339, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28967277

RESUMO

The effects of acute pulmonary coexposures to silica and diesel particulate matter (DPM), which may occur in various mining operations, were investigated in vivo. Rats were exposed by intratracheal instillation (IT) to silica (50 or 233 µg), DPM (7.89 or 50 µg) or silica and DPM combined in phosphate-buffered saline (PBS) or to PBS alone (control). At one day, one week, one month, two months and three months postexposure bronchoalveolar lavage and histopathology were performed to assess lung injury, inflammation and immune response. While higher doses of silica caused inflammation and injury at all time points, DPM exposure alone did not. DPM (50 µg) combined with silica (233 µg) increased inflammation at one week and one-month postexposure and caused an increase in the incidence of fibrosis at one month compared with exposure to silica alone. To assess susceptibility to lung infection following coexposure, rats were exposed by IT to 233 µg silica, 50 µg DPM, a combination of the two or PBS control one week before intratracheal inoculation with 5 × 105 Listeria monocytogenes. At 1, 3, 5, 7 and 14 days following infection, pulmonary immune response and bacterial clearance from the lung were evaluated. Coexposure to DPM and silica did not alter bacterial clearance from the lung compared to control. Although DPM and silica coexposure did not alter pulmonary susceptibility to infection in this model, the study showed that noninflammatory doses of DPM had the capacity to increase silica-induced lung injury, inflammation and onset/incidence of fibrosis.


Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Pulmão/efeitos dos fármacos , Material Particulado/toxicidade , Quartzo/toxicidade , Emissões de Veículos/toxicidade , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Contagem de Células , Citocinas/imunologia , L-Lactato Desidrogenase/metabolismo , Listeria monocytogenes/patogenicidade , Listeriose , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Masculino , Ratos Sprague-Dawley , Testes de Toxicidade Aguda
6.
Toxicol Appl Pharmacol ; 323: 16-25, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28315692

RESUMO

The emission of cerium oxide nanoparticles (CeO2) from diesel engines, using cerium compounds as a catalyst to lower the diesel exhaust particles, is a health concern. We have previously shown that CeO2 induced pulmonary inflammation and lung fibrosis. The objective of the present study was to investigate the modification of fibroblast function and the role of epithelial-mesenchymal transition (EMT) in CeO2-induced fibrosis. Male Sprague-Dawley rats were exposed to CeO2 (0.15 to 7mg/kg) by a single intratracheal instillation and sacrificed at various times post-exposure. The results show that at 28days after CeO2 (3.5mg/kg) exposure, lung fibrosis was evidenced by increased soluble collagen in bronchoalveolar lavage fluid, elevated hydroxyproline content in lung tissues, and enhanced sirius red staining for collagen in the lung tissue. Lung fibroblasts and alveolar type II (ATII) cells isolated from CeO2-exposed rats at 28days post-exposure demonstrated decreasing proliferation rate when compare to the controls. CeO2 exposure was cytotoxic and altered cell function as demonstrated by fibroblast apoptosis and aggregation, and ATII cell hypertrophy and hyperplasia with increased surfactant. The presence of stress fibers, expressed as α-smooth muscle actin (SMA), in CeO2-exposed fibroblasts and ATII cells was significantly increased compared to the control. Immunohistofluorescence analysis demonstrated co-localization of TGF-ß or α-SMA with prosurfactant protein C (SPC)-stained ATII cells. These results demonstrate that CeO2 exposure affects fibroblast function and induces EMT in ATII cells that play a role in lung fibrosis. These findings suggest potential adverse health effects in response to CeO2 nanoparticle exposure.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Cério/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Fibrose Pulmonar/induzido quimicamente , Actinas/metabolismo , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Líquido da Lavagem Broncoalveolar/química , Forma Celular/efeitos dos fármacos , Células Cultivadas , Colágeno/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Hidroxiprolina/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Peptídeos/metabolismo , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos Sprague-Dawley , Medição de Risco , Fibras de Estresse/efeitos dos fármacos , Fibras de Estresse/metabolismo , Fibras de Estresse/patologia , Fatores de Tempo , Fator de Crescimento Transformador beta/metabolismo
7.
Nanotoxicology ; 10(7): 992-1000, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26898289

RESUMO

Cerium (Ce) is becoming a popular metal for use in electrochemical applications. When in the form of cerium oxide (CeO2), Ce can exist in both 3 + and 4 + valence states, acting as an ideal catalyst. Previous in vitro and in vivo evidence have demonstrated that CeO2 has either anti- or pro-oxidant properties, possibly due to the ability of the nanoparticles to transition between valence states. Therefore, we chose to chemically modify the nanoparticles to shift the valence state toward 3+. During the hydrothermal synthesis process, 10 mol% gadolinium (Gd) and 20 mol% Gd, were substituted into the lattice of the CeO2 nanoparticles forming a perfect solid solution with various A-site valence states. These two Gd-doped CeO2 nanoparticles were compared to pure CeO2 nanoparticles. Preliminary characteristics indicated that doping results in minimal size and zeta potential changes but alters valence state. Following characterization, male Sprague-Dawley rats were exposed to 0.5 or 1.0 mg/kg nanoparticles via a single intratracheal instillation. Animals were sacrificed and bronchoalveolar lavage fluid and various tissues were collected to determine the effect of valence state and oxygen vacancies on toxicity 1-, 7-, or 84-day post-exposure. Results indicate that damage, as measured by elevations in lactate dehydrogenase, occurred within 1-day post-exposure and was sustained 7-day post-exposure, but subsided to control levels 84-day post-exposure. Furthermore, no inflammatory signaling or lipid peroxidation occurred following exposure with any of the nanoparticles. Our results implicate that valence state has a minimal effect on CeO2 nanoparticle toxicity in vivo.


Assuntos
Cério/química , Cério/toxicidade , Pulmão/efeitos dos fármacos , Nanopartículas/química , Nanopartículas/toxicidade , Animais , Líquido da Lavagem Broncoalveolar/química , Relação Dose-Resposta a Droga , Gadolínio/química , Instilação de Medicamentos , Peroxidação de Lipídeos/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Oxigênio/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
8.
J Appl Toxicol ; 36(4): 618-26, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26472246

RESUMO

Indium-tin oxide (ITO) is used to make transparent conductive coatings for touch-screen and liquid crystal display electronics. Occupational exposures to potentially toxic particles generated during ITO production have increased in recent years as the demand for consumer electronics continues to rise. Previous studies have demonstrated cytotoxicity in vitro and animal models have shown pulmonary inflammation and injury in response to various indium-containing particles. In humans, pulmonary alveolar proteinosis (PAP) and fibrotic interstitial lung disease have been observed in ITO facility workers. However, which indium materials or specific processes in the workplace may be the most toxic to workers is unknown. Here we examined the pulmonary toxicity of three different particle samples that represent real-life worker exposures, as they were collected at various production stages throughout an ITO facility. Indium oxide (In2O3), sintered ITO (SITO) and ventilation dust (VD) particles each caused pulmonary inflammation and damage in rats over a time course (1, 7 and 90 days post-intratracheal instillation), but SITO and VD appeared to induce greater toxicity in rat lungs than In2O3 at a dose of 1 mg per rat. Downstream pathological changes such as PAP and fibrosis were observed in response to all three particles 90 days after treatment, with a trend towards greatest severity in animals exposed to VD when comparing animals that received the same dose. These findings may inform workplace exposure reduction efforts and provide a better understanding of the pathogenesis of an emerging occupational health issue.


Assuntos
Poluentes Atmosféricos/toxicidade , Pneumonia/patologia , Compostos de Estanho/toxicidade , Animais , Lavagem Broncoalveolar , Relação Dose-Resposta a Droga , Poeira , Concentração de Íons de Hidrogênio , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Fagocitose , Pneumonia/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
9.
Toxicol Appl Pharmacol ; 288(1): 63-73, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26210349

RESUMO

Recently cerium compounds have been used in a variety of consumer products, including diesel fuel additives, to increase fuel combustion efficiency and decrease diesel soot emissions. However, cerium oxide (CeO2) nanoparticles have been detected in the exhaust, which raises a health concern. Previous studies have shown that exposure of rats to nanoscale CeO2 by intratracheal instillation (IT) induces sustained pulmonary inflammation and fibrosis. In the present study, male Sprague-Dawley rats were exposed to CeO2 or CeO2 coated with a nano layer of amorphous SiO2 (aSiO2/CeO2) by a single IT and sacrificed at various times post-exposure to assess potential protective effects of the aSiO2 coating. The first acellular bronchoalveolar lavage (BAL) fluid and BAL cells were collected and analyzed from all exposed animals. At the low dose (0.15mg/kg), CeO2 but not aSiO2/CeO2 exposure induced inflammation. However, at the higher doses, both particles induced a dose-related inflammation, cytotoxicity, inflammatory cytokines, matrix metalloproteinase (MMP)-9, and tissue inhibitor of MMP at 1day post-exposure. Morphological analysis of lung showed an increased inflammation, surfactant and collagen fibers after CeO2 (high dose at 3.5mg/kg) treatment at 28days post-exposure. aSiO2 coating significantly reduced CeO2-induced inflammatory responses in the airspace and appeared to attenuate phospholipidosis and fibrosis. Energy dispersive X-ray spectroscopy analysis showed Ce and phosphorous (P) in all particle-exposed lungs, whereas Si was only detected in aSiO2/CeO2-exposed lungs up to 3days after exposure, suggesting that aSiO2 dissolved off the CeO2 core, and some of the CeO2 was transformed to CePO4 with time. These results demonstrate that aSiO2 coating reduce CeO2-induced inflammation, phospholipidosis and fibrosis.


Assuntos
Anti-Inflamatórios/farmacologia , Cério/toxicidade , Pulmão/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Pneumonia/induzido quimicamente , Fibrose Pulmonar/induzido quimicamente , Dióxido de Silício/farmacologia , Animais , Anti-Inflamatórios/química , Líquido da Lavagem Broncoalveolar/química , Cério/química , Colágeno/metabolismo , Citocinas/metabolismo , Citoproteção , Relação Dose-Resposta a Droga , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Nanopartículas Metálicas/química , Fosfolipídeos/metabolismo , Pneumonia/metabolismo , Pneumonia/patologia , Pneumonia/prevenção & controle , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fibrose Pulmonar/prevenção & controle , Proteínas Associadas a Surfactantes Pulmonares/metabolismo , Ratos Sprague-Dawley , Dióxido de Silício/química , Espectrometria por Raios X , Propriedades de Superfície , Fatores de Tempo , Inibidores Teciduais de Metaloproteinases/metabolismo
10.
Toxicol Appl Pharmacol ; 278(2): 135-47, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24793434

RESUMO

Cerium compounds have been used as a fuel-borne catalyst to lower the generation of diesel exhaust particles (DEPs), but are emitted as cerium oxide nanoparticles (CeO2) along with DEP in the diesel exhaust. The present study investigates the effects of the combined exposure to DEP and CeO2 on the pulmonary system in a rat model. Specific pathogen-free male Sprague-Dawley rats were exposed to CeO2 and/or DEP via a single intratracheal instillation and were sacrificed at various time points post-exposure. This investigation demonstrated that CeO2 induces a sustained inflammatory response, whereas DEP elicits a switch of the pulmonary immune response from Th1 to Th2. Both CeO2 and DEP activated AM and lymphocyte secretion of the proinflammatory cytokines IL-12 and IFN-γ, respectively. However, only DEP enhanced the anti-inflammatory cytokine IL-10 production in response to ex vivo LPS or Concanavalin A challenge that was not affected by the presence of CeO2, suggesting that DEP suppresses host defense capability by inducing the Th2 immunity. The micrographs of lymph nodes show that the particle clumps in DEP+CeO2 were significantly larger than CeO2 or DEP, exhibiting dense clumps continuous throughout the lymph nodes. Morphometric analysis demonstrates that the localization of collagen in the lung tissue after DEP+CeO2 reflects the combination of DEP-exposure plus CeO2-exposure. At 4 weeks post-exposure, the histological features demonstrated that CeO2 induced lung phospholipidosis and fibrosis. DEP induced lung granulomas that were not significantly affected by the presence of CeO2 in the combined exposure. Using CeO2 as diesel fuel catalyst may cause health concerns.


Assuntos
Cério/toxicidade , Exposição por Inalação/efeitos adversos , Nanopartículas/toxicidade , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Emissões de Veículos/toxicidade , Animais , Cério/análise , Interações Medicamentosas , Masculino , Nanopartículas/análise , Material Particulado/análise , Material Particulado/toxicidade , Ratos , Ratos Sprague-Dawley , Emissões de Veículos/análise
11.
Cardiovasc Toxicol ; 13(4): 323-37, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23645470

RESUMO

Cerium dioxide nanoparticles (CeO2 NPs) are an engineered nanomaterial (ENM) that possesses unique catalytic, oxidative, and reductive properties. Currently, CeO2 NPs are being used as a fuel catalyst but these properties are also utilized in the development of potential drug treatments for radiation and stroke protection. These uses of CeO2 NPs present a risk for human exposure; however, to date, no studies have investigated the effects of CeO2 NPs on the microcirculation following pulmonary exposure. Previous studies in our laboratory with other nanomaterials have shown impairments in normal microvascular function after pulmonary exposures. Therefore, we predicted that CeO2 NP exposure would cause microvascular dysfunction that is dependent on the tissue bed and dose. Twenty-four-hour post-exposure to CeO2 NPs (0-400 µg), mesenteric, and coronary arterioles was isolated and microvascular function was assessed. Our results provided evidence that pulmonary CeO2 NP exposure impairs endothelium-dependent and endothelium-independent arteriolar dilation in a dose-dependent manner. The CeO2 NP exposure dose which causes a 50 % impairment in arteriolar function (EC50) was calculated and ranged from 15 to 100 µg depending on the chemical agonist and microvascular bed. Microvascular assessments with acetylcholine revealed a 33-75 % reduction in function following exposure. Additionally, there was a greater sensitivity to CeO2 NP exposure in the mesenteric microvasculature due to the 40 % decrease in the calculated EC50 compared to the coronary microvasculature EC50. CeO2 NP exposure increased mean arterial pressure in some groups. Taken together, these observed microvascular changes may likely have detrimental effects on local blood flow regulation and contribute to cardiovascular dysfunction associated with particle exposure.


Assuntos
Cério/toxicidade , Vasos Coronários/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Nanopartículas/toxicidade , Vasodilatação/efeitos dos fármacos , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/fisiologia , Vasos Coronários/fisiologia , Relação Dose-Resposta a Droga , Humanos , Pulmão/irrigação sanguínea , Pulmão/patologia , Masculino , Artérias Mesentéricas/fisiologia , Técnicas de Cultura de Órgãos , Ratos Sprague-Dawley , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia , Vasodilatação/fisiologia
12.
Toxicol Appl Pharmacol ; 262(3): 255-64, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22613087

RESUMO

Cerium compounds have been used as a diesel engine catalyst to lower the mass of diesel exhaust particles, but are emitted as cerium oxide (CeO(2)) nanoparticles in the diesel exhaust. In a previous study, we have demonstrated a wide range of CeO(2)-induced lung responses including sustained pulmonary inflammation and cellular signaling that could lead to pulmonary fibrosis. In this study, we investigated the fibrogenic responses induced by CeO(2) in a rat model at various time points up to 84 days post-exposure. Male Sprague Dawley rats were exposed to CeO(2) by a single intratracheal instillation. Alveolar macrophages (AM) were isolated by bronchial alveolar lavage (BAL). AM-mediated cellular responses, osteopontin (OPN) and transform growth factor (TGF)-ß1 in the fibrotic process were investigated. The results showed that CeO(2) exposure significantly increased fibrotic cytokine TGF-ß1 and OPN production by AM above controls. The collagen degradation enzymes, matrix metalloproteinase (MMP)-2 and -9 and the tissue inhibitor of MMP were markedly increased in the BAL fluid at 1 day- and subsequently declined at 28 days after exposure, but remained much higher than the controls. CeO(2) induced elevated phospholipids in BAL fluid and increased hydroxyproline content in lung tissue in a dose- and time-dependent manner. Immunohistochemical analysis showed MMP-2, MMP-9 and MMP-10 expressions in fibrotic regions. Morphological analysis noted increased collagen fibers in the lungs exposed to a single dose of 3.5mg/kg CeO(2) and euthanized at 28 days post-exposure. Collectively, our studies show that CeO(2) induced fibrotic lung injury in rats, suggesting it may cause potential health effects.


Assuntos
Cério/toxicidade , Nanopartículas/toxicidade , Fibrose Pulmonar/induzido quimicamente , Animais , Líquido da Lavagem Broncoalveolar/citologia , Relação Dose-Resposta a Droga , Hidroxiprolina/análise , Pulmão/química , Pulmão/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/ultraestrutura , Masculino , Metaloproteinase 10 da Matriz/análise , Metaloproteinase 2 da Matriz/análise , Metaloproteinase 9 da Matriz/análise , Microscopia Eletrônica de Transmissão , Osteopontina/análise , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/análise
13.
Nanotoxicology ; 5(3): 312-25, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20925443

RESUMO

The use of cerium compounds as diesel fuel catalyst results in the emission of cerium oxide nanoparticles (CeO2) in the exhaust. This study characterized the potential effects of CeO2 exposure on lung toxicity. Male Sprague Dawley rats were exposed to CeO2 by a single intratracheal instillation at 0.15, 0.5, 1, 3.5 or 7 mg/kg body weight. At 1 day after exposure, CeO2 significantly reduced NO production, but increased IL-12 production, by alveolar macrophages (AM) in response to ex vivo lipopolysacchride (LPS) challenge, and caused AM apoptosis, through activation of caspases 9 and 3. CeO2 exposure markedly increased suppressor of cytokine signaling-1 at 1-day and elevated arginase-1 at 28-day post exposure in lung cells, while osteopontin was significantly elevated in lung tissue at both time points. CeO2 induced inflammation, cytotoxicity, air/blood barrier damage, and phospholipidosis with enlarged AM. Thus, CeO2 induced lung inflammation and injury in lungs which may lead to fibrosis.


Assuntos
Cério/toxicidade , Inflamação/induzido quimicamente , Pneumopatias/induzido quimicamente , Macrófagos Alveolares/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Animais , Apoptose/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar/citologia , Cério/química , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Macrófagos Alveolares/fisiologia , Masculino , Nanopartículas Metálicas/química , Ratos , Organismos Livres de Patógenos Específicos
14.
J Toxicol Environ Health A ; 72(8): 560-70, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19267316

RESUMO

Pulmonary responses to diesel exhaust particles (DEP) exposure are mediated through enhanced production of reactive oxygen species (ROS) and nitric oxide (NO) by alveolar macrophages (AM). The current study examined the differential roles of ROS and NO in DEP-induced lung injury using C57B/6J wild-type (WT) and inducible NO synthase knockout (iNOS KO) mice. Mice exposed by pharyngeal aspiration to DEP or carbon black particles (CB) (35 mg/kg) showed an inflammatory profile that included neutrophil infiltration, increased lactate dehydrogenase (LDH) activity, and elevated albumin content in bronchoalveolar lavage fluid (BALF) at 1, 3, and 7 d postexposure. The organic extract of DEP (DEPE) did not induce an inflammatory response. Comparing WT to iNOS KO mice, the results show that NO enhanced DEP-induced neutrophils infiltration and plasma albumin content in BALF and upregulated the production of the pro-inflammatory cytokine interleukin 12 (IL-12) by AM. DEP-exposed AM from iNOS KO mice displayed diminished production of IL-12 and, in response to ex vivo lipopolysaccharide (LPS) challenge, decreased production of IL-12 but increased production of IL-10 when compared to cells from WT mice. DEP, CB, but not DEPE, induced DNA damage and mitochondria dysfunction in AM, however, that is independent of cellular production of NO. These results demonstrate that DEP-induced immune/inflammatory responses in mice are regulated by both ROS- and NO-mediated pathways. NO did not affect ROS-mediated mitochondrial dysfunction and DNA damage but upregulated IL-12 and provided a counterbalance to the ROS-mediated adaptive stress response that downregulates IL-12 and upregulates IL-10.


Assuntos
Doenças Mitocondriais/induzido quimicamente , Óxido Nítrico Sintase Tipo II/fisiologia , Óxido Nítrico/toxicidade , Material Particulado/toxicidade , Pneumonia/induzido quimicamente , Espécies Reativas de Oxigênio/toxicidade , Emissões de Veículos/toxicidade , Animais , Disponibilidade Biológica , Líquido da Lavagem Broncoalveolar/citologia , Células Cultivadas , Ensaio Cometa , Citocinas/metabolismo , Dano ao DNA , L-Lactato Desidrogenase/metabolismo , Camundongos , Camundongos Knockout , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Doenças Mitocondriais/patologia , Óxido Nítrico Sintase Tipo II/genética , Material Particulado/farmacocinética , Pneumonia/patologia , Alvéolos Pulmonares/patologia
15.
J Toxicol Environ Health A ; 71(8): 521-32, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18338287

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) are products of incomplete combustion that are commonly inhaled by workers in the dusty trades. Many PAHs are metabolized by cytochrome P-4501A1 (CYP1A1), which may facilitate excretion but may activate pulmonary carcinogens. PAHs also stimulate their own metabolism by inducing CYP1A1. Recent studies suggest that respirable coal dust exposure inhibits induction of pulmonary CYP1A1 using the model PAH beta-naphthoflavone. The effect of the occupational particulate respirable crystalline silica was investigated on PAH-dependent pulmonary CYP1A1 induction. Male Sprague-Dawley rats were exposed to intratracheal silica or vehicle and then intraperitoneal beta-naphthoflavone, a CYP1A1 inducer, and/or phenobarbital, an inducer of hepatic CYP2B1, or vehicle. Beta-naphthoflavone induced pulmonary CYP1A1, but silica attenuated this beta-naphthoflavone-induced CYP1A1 activity and also suppressed the activity of CYP2B1, the major constitutive CYP in rat lung. The magnitude of CYP activity suppression was similar regardless of silica exposure dose within a range of 5 to 20 mg/rat. Phenobarbital and beta-naphthoflavone had no effect on pulmonary CYP2B1 activity. Both enzymatic immunohistochemistry and immunofluorescent staining for CYP1A1 indicated that sites of CYP1A1 induction were nonciliated airway epithelial cells, endothelial cells, and the alveolar septum. Using immunofluorescent colocalization of CYP1A1 with cytokeratin 8, a marker of alveolar type II cells, the proximal alveolar region was the site of both increased alveolar type II cells and decreased proportional CYP1A1 expression in alveolar type II cells. Our findings suggest that in PAH-exposed rat lung, silica is a negative modifier of CYP1A1 induction and CYP2B1 activity.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Citocromo P-450 CYP1A1/metabolismo , Poeira , Material Particulado/efeitos adversos , Alvéolos Pulmonares/metabolismo , Dióxido de Silício/efeitos adversos , Silicose/fisiopatologia , Animais , Citocromo P-450 CYP1A1/efeitos dos fármacos , Citocromo P-450 CYP2B1/efeitos dos fármacos , Citocromo P-450 CYP2B1/metabolismo , Modelos Animais de Doenças , Indução Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Exposição por Inalação/efeitos adversos , Masculino , Exposição Ocupacional/efeitos adversos , Alvéolos Pulmonares/patologia , Ratos , Ratos Sprague-Dawley , beta-Naftoflavona/administração & dosagem
16.
J Toxicol Environ Health A ; 70(23): 1967-76, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17966068

RESUMO

Studies suggested that 15-deoxy-delta-(12,14)-prostaglandin J2 (PGJ2) may exert anti-inflammatory effects, including in the lung. Thus, in vitro studies were conducted to (1) investigate whether PGJ2 inhibited the production of inflammatory mediators from lipopolysaccharide (LPS)-exposed primary rat alveolar macrophages (AM), and (2) investigate possible mechanisms underlying PGJ2-mediated inhibition of inflammatory mediator production. These studies determined that PGJ2 inhibited LPS-induced nitric oxide (NO) production in a concentration- and time-dependent manner. PGJ2-mediated inhibition of NO, as well as of tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-2 (MIP-2), was also determined to be dependent on the time of addition of PGJ2 relative to LPS, and suggested the PGJ2 inhibitory mechanism is an early event. PGJ2 was shown not to interfere with binding or internalization of LPS by AM, indicating this was not responsible for PGJ2 inhibitory effects. Another possible mechanism underlying PGJ2-mediated inhibition was via peroxisome proliferator-activated receptor-gamma (PPAR-gamma). However, biochemical studies suggested that PGJ2-mediated inhibition was not occurring through PPAR-gamma dependent mechanism, and molecular studies further established that both LPS and PGJ2 decrease PPAR-gamma mRNA expression. A third possible mechanism underlying PGJ2-mediated inhibition was by alteration of nuclear factor (NF)-kappaB. Molecular studies confirmed that LPS stimulated NF-kappaB mRNA expression, and PGJ2 reduced this stimulation, which is consistent with PGJ2 effect on LPS-induced production of NO, TNF-alpha and MIP-2. Thus, data in this study established that PGJ2 inhibited LPS-induced inflammatory mediator production in rat AM, and this inhibition is mediated, at least in part, by reducing the expression of NF-kappaB mRNA.


Assuntos
Lipopolissacarídeos/imunologia , Macrófagos Alveolares/imunologia , NF-kappa B/imunologia , Prostaglandina D2/análogos & derivados , Animais , Líquido da Lavagem Broncoalveolar/citologia , Células Cultivadas , Quimiocina CXCL2/imunologia , Macrófagos Alveolares/efeitos dos fármacos , Masculino , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Óxido Nítrico/imunologia , Óxido Nítrico/metabolismo , PPAR gama/efeitos dos fármacos , PPAR gama/metabolismo , Prostaglandina D2/imunologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/imunologia
17.
Environ Health Perspect ; 114(8): 1253-8, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16882535

RESUMO

Diesel exhaust particles (DEPs) have been shown to activate oxidant generation by alveolar macrophages (AMs), alter xenobiotic metabolic pathways, and modify the balance of pro-antiinflammatory cytokines. In this study we investigated the role of nitric oxide (NO) in DEP-mediated and DEP organic extract (DEPE) -mediated inflammatory responses and evaluated the interaction of inducible NO synthase (iNOS) and cytochrome P450 1A1 (CYP1A1). Male Sprague-Dawley rats were intratracheally (IT) instilled with saline, DEPs (35 mg/kg), or DEPEs (equivalent to 35 mg DEP/kg), with or without further treatment with an iNOS inhibitor, aminoguanidine (AG; 100 mg/kg), by intraperitoneal injection 30 min before and 3, 6, and 9 hr after IT exposure. At 1 day postexposure, both DEPs and DEPEs induced iNOS expression and NO production by AMs. AG significantly lowered DEP- and DEPE-induced iNOS activity but not the protein level while attenuating DEPE- but not DEP-mediated pulmonary inflammation, airway damage, and oxidant generation by AMs. DEP or DEPE exposure resulted in elevated secretion of both interleukin (IL) -12 and IL-10 by AMs. AG significantly reduced DEP- and DEPE-activated AMs in IL-12 production. In comparison, AG inhibited IL-10 production by DEPE-exposed AMs but markedly increased its production by DEP-exposed AMs, suggesting that NO differentially regulates the pro- and antiinflammatory cytokine balance in the lung. Both DEPs and DEPEs induced CYP1A1 expression. AG strongly inhibited CYP1A1 activity and lung S9 activity-dependent 2-aminoanthracene mutagenicity. These studies show that NO plays a major role in DEPE-induced lung inflammation and CYP-dependent mutagen activation but a lesser role in particulate-induced inflammatory damage.


Assuntos
Poluentes Atmosféricos/toxicidade , Citocromo P-450 CYP1A1/fisiologia , Gasolina/toxicidade , Mutagênicos , Óxido Nítrico Sintase Tipo II/fisiologia , Pneumonia/enzimologia , Pneumonia/etiologia , Emissões de Veículos/toxicidade , Animais , Células Cultivadas , Citocromo P-450 CYP1A1/biossíntese , Citocromo P-450 CYP1A1/metabolismo , Citocinas/análise , Técnicas In Vitro , L-Lactato Desidrogenase/metabolismo , Luminescência , Masculino , Microssomos/enzimologia , Microssomos/metabolismo , Testes de Mutagenicidade , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Nitritos/metabolismo , Ácido Peroxinitroso/metabolismo , Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Salmonella typhimurium/genética , Frações Subcelulares/enzimologia , Frações Subcelulares/metabolismo
18.
Environ Health Perspect ; 114(3): 412-9, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16507465

RESUMO

The epidemiologic association between pulmonary exposure to ambient particulate matter (PM) and cardiovascular dysfunction is well known, but the systemic mechanisms that drive this effect remain unclear. We have previously shown that acute pulmonary exposure to PM impairs or abolishes endothelium-dependent arteriolar dilation in the rat spinotrapezius muscle. The purpose of this study was to further characterize the effect of pulmonary PM exposure on systemic microvascular function and to identify local inflammatory events that may contribute to these effects. Rats were intratracheally instilled with residual oil fly ash (ROFA) or titanium dioxide at 0.1 or 0.25 mg/rat 24 hr before measurement of pulmonary and systemic microvascular responses. In vivo microscopy of the spinotrapezius muscle was used to study systemic arteriolar responses to intraluminal infusion of the Ca2+ ionophore A23187 or iontophoretic abluminal application of the adrenergic agonist phenylephrine (PHE). Leukocyte rolling and adhesion were quantified in venules paired with the studied arterioles. Histologic techniques were used to assess pulmonary inflammation, characterize the adherence of leukocytes to systemic venules, verify the presence of myeloperoxidase (MPO) in the systemic microvascular wall, and quantify systemic microvascular oxidative stress. In the lungs of rats exposed to ROFA or TiO2, changes in some bronchoalveolar lavage markers of inflammation were noted, but an indication of cellular damage was not found. In rats exposed to 0.1 mg ROFA, focal alveolitis was evident, particularly at sites of particle deposition. Exposure to either ROFA or TiO2 caused a dose-dependent impairment of endothelium-dependent arteriolar dilation. However, exposure to these particles did not affect microvascular constriction in response to PHE. ROFA and TiO2 exposure significantly increased leukocyte rolling and adhesion in paired venules, and these cells were positively identified as polymorphonuclear leukocytes (PMNLs). In ROFA- and TiO2-exposed rats, MPO was found in PMNLs adhering to the systemic microvascular wall. Evidence suggests that some of this MPO had been deposited in the microvascular wall. There was also evidence for oxidative stress in the microvascular wall. These results indicate that after PM exposure, the impairment of endothelium-dependent dilation in the systemic microcirculation coincides with PMNL adhesion, MPO deposition, and local oxidative stress. Collectively, these microvascular observations are consistent with events that contribute to the disruption of the control of peripheral resistance and/or cardiac dysfunction associated with PM exposure.


Assuntos
Poluentes Atmosféricos/toxicidade , Albuminas/análise , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/fisiopatologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Calcimicina/farmacologia , Carbono/toxicidade , Cinza de Carvão , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , L-Lactato Desidrogenase/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/enzimologia , Material Particulado , Peroxidase/metabolismo , Fenilefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Titânio/toxicidade , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
19.
Toxicol Sci ; 88(1): 150-60, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16120749

RESUMO

Exposure to diesel exhaust particles (DEP) during the sensitization process has been shown to increase antigen-specific IgE production and aggravate allergic airway inflammation in human and animal models. In this study, we evaluated the effect of short-term DEP exposure on ovalbumin (OVA)-mediated responses using a post-sensitization model. Brown Norway rats were first exposed to filtered air or DEP (20.6 +/- 2.7 mg/m3) for 4 h/day for five consecutive days. One day after the final air or DEP exposure (day 1), rats were sensitized with aerosolized OVA (40.5 +/- 6.3 mg/m3), and then again on days 8 and 15, challenged with OVA on day 29, and sacrificed on days 9 or 30, 24 h after the second OVA exposure or the final OVA challenge, respectively. Control animals received aerosolized saline instead of OVA. DEP were shown to elicit an adjuvant effect on the production of antigen-specific IgE and IgG on day 30. At both time points, no significant airway inflammatory responses and lung injury were found for DEP exposure alone. However, the OVA-induced inflammatory cell infiltration, acellular lactate dehydrogenase activity and albumin content in bronchoalveolar lavage (BAL) fluid, and numbers of T cells and their CD4+ and CD8+ subsets in lung-draining lymph nodes were markedly reduced by DEP on day 30 compared with the air-plus-OVA exposure group. The OVA-induced nitric oxide (NO) in the BAL fluid and production of NO, interleukin (IL)-10, and IL-12 by alveolar macrophages (AM) were also significantly lowered by DEP on day 30 as well as day 9. DEP or OVA alone decreased intracellular glutathione (GSH) in AM and lymphocytes on days 9 and 30. The combined DEP and OVA exposure resulted in further depletion of GSH in both cell types. These results show that short-term DEP exposure prior to sensitization had a delayed effect on enhancement of the sensitization in terms of allergen-specific IgE and IgG production, but caused an attenuation of the allergen-induced airway inflammatory responses.


Assuntos
Poluentes Atmosféricos/toxicidade , Hiper-Reatividade Brônquica/induzido quimicamente , Bronquite/induzido quimicamente , Exposição por Inalação , Ovalbumina/administração & dosagem , Emissões de Veículos/toxicidade , Adjuvantes Imunológicos/administração & dosagem , Poluentes Atmosféricos/imunologia , Alérgenos/efeitos adversos , Alérgenos/imunologia , Animais , Hiper-Reatividade Brônquica/imunologia , Bronquite/imunologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/metabolismo , Modelos Animais de Doenças , Glutationa/metabolismo , Imunoglobulina E/sangue , L-Lactato Desidrogenase/análise , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Masculino , Óxido Nítrico/análise , Ovalbumina/imunologia , Ratos , Ratos Endogâmicos BN , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia
20.
Toxicol Sci ; 88(1): 202-12, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16107553

RESUMO

We have previously demonstrated that exposure to diesel exhaust particles (DEP) prior to ovalbumin (OVA) sensitization in rats reduced OVA-induced airway inflammation. In the present study, Brown Norway rats were first sensitized to OVA (42.3 +/- 5.7 mg/m3) for 30 min on days 1, 8, and 15, then exposed to filtered air or DEP (22.7 +/- 2.5 mg/m3) for 4 h/day on days 24-28, and challenged with OVA on day 29. Airway responsiveness was examined on day 30, and animals were sacrificed on day 31. Ovalbumin sensitization and challenge resulted in a significant infiltration of neutrophils, lymphocytes, and eosinophils into the lung, elevated presence of CD4+ and CD8+ T lymphocytes in lung draining lymph nodes, and increased production of serum OVA-specific immunoglobulin (Ig)E and IgG. Diesel exhaust particles pre-exposure augmented OVA-induced production of allergen-specific IgE and IgG and pulmonary inflammation characterized by marked increases in T lymphocytes and infiltration of eosinophils after OVA challenge, whereas DEP alone did not have these effects. Although OVA-sensitized rats showed modest response to methacholine challenge, it was the combined DEP and OVA exposure that produced significant airway hyperresponsiveness in this animal model. The effect of DEP pre-exposure on OVA-induced immune responses correlated with an interactive effect of DEP with OVA on increased production of reactive oxygen species (ROS) and nitric oxide (NO) by alveolar macrophages (AM) and alveolar type II (ATII) cells, NO levels in bronchoalveolar lavage fluid, the induction of inducible NO synthase expression in AM and ATII cells, and a depletion of total intracellular glutathione (GSH) in AM and lymphocytes. These results show that DEP pre-exposure exacerbates the allergic responses to the subsequent challenge with OVA in OVA-sensitized rats. This DEP effect may be, at least partially, attributed to the elevated generation of ROS in AM and ATII cells, a depletion of GSH in AM and lymphocytes, and an increase in AM and ATII cell production of NO.


Assuntos
Poluentes Atmosféricos/toxicidade , Alérgenos/administração & dosagem , Hiper-Reatividade Brônquica/induzido quimicamente , Exposição por Inalação , Ovalbumina/administração & dosagem , Emissões de Veículos/toxicidade , Alérgenos/imunologia , Animais , Hiper-Reatividade Brônquica/imunologia , Testes de Provocação Brônquica , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucócitos/patologia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Masculino , Óxido Nítrico/metabolismo , Ovalbumina/imunologia , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Ratos , Ratos Endogâmicos BN , Espécies Reativas de Oxigênio/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA