RESUMO
We conducted a series of experiments with ultrafine particles (approximately 20 nm) and larger particles (less than 200 nm) of "nuisance" dusts to evaluate the involvement of alveolar macrophages (AM) in particle-induced lung injury and particle translocation in rats. After intratracheal instillation of both ultrafine particles and larger particles of TiO2, we found a highly increased interstitial access of the ultrafine particles combined with a large acute inflammatory reaction as determined by lung lavage parameters. An additional experiment revealed that intratracheal instillation of phagocytized ultrafine TiO2 particles (inside AM) prevented both the pulmonary inflammatory reaction and the interstitial access of the ultrafine particles. Another experiment showed that the influx of polymorphonuclear cells (PMN) into the alveolar space unexpectedly decreased with higher doses of ultrafine particles, whereas alveolar epithelial permeability (protein leakage) increased. The divergence between PMN influx into the alveolar space and changes in alveolar epithelial permeability implies that they are separate events. Pulmonary inflammatory parameters determined by lung lavage analysis correlated best with the surface area of the retained particles rather than with their mass, volume, or numbers. Because higher doses resulted in an increased interstitialized fraction of particles, we suggest that inflammatory events induced by particles in the interstitial space can modify the inflammation in the alveolar space detectable by lung lavage. Our results demonstrate the dual role of AM for modifying particle-induced lung injury, i.e., both preventing such injury and contributing to it. We conclude that the increased pulmonary toxicity of ultrafine particles is related to their larger surface area and to their increased interstitial access.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Pneumoconiose/patologia , Titânio/farmacocinética , Animais , Relação Dose-Resposta a Droga , Espaço Extracelular/química , Espaço Extracelular/efeitos dos fármacos , Instilação de Medicamentos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/patologia , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Tamanho da Partícula , Pneumoconiose/etiologia , Pneumoconiose/metabolismo , Proteínas/análise , Ratos , Ratos Endogâmicos F344 , Titânio/administração & dosagem , Titânio/efeitos adversosRESUMO
Inhaled endotoxin (lipopolysaccharide, LPS) can induce acute lung injury and at high doses may lead to respiratory distress syndrome. Using a mouse model of acute lung inflammation induced by inhalation of low doses of LPS we examined the kinetics of chemokine, proinflammatory cytokine, and metallothionein. Eight-week-old C57BL/6 mice were dosed for 10 min with LPS, resulting in an estimated alveolar dose of < 10 ng LPS/mouse, and euthanized 2,6, or 24 h postexposure. Analysis of bronchoalveolar lavage fluid demonstrated increased polymorphonuclear neutrophils (PMNs) of 6.94, 32.7, and 38.8% after 2, 6, and 24 h, respectively. Examination of proinflammatory cytokine, chemokine, and Mt mRNA in the lung revealed increases for messages encoding IL-1 alpha, IL-1 beta, IL-6, IFN-gamma, TNF alpha, Eotaxin, MIP-1 alpha, MIP-1 beta, MIP-2, Mt, and IP-10, while messages encoding IL-12, IL-10, IFN-beta, Ltn, MCP-1, TGF beta 1 + 2, and RANTES were unchanged from those of sham-exposed mice 2 h postexposure. By 6 h most messages had returned to near control levels. Comparison to 5 mg/kg body weight intraperitoneal injection and 5 micrograms/mouse intratracheal instillation 2 h postexposure demonstrated similar message responses. Our results demonstrate that low levels of LPS exposure by inhalation induce a strong PMN response and a selective cytokine response in the lung, supporting the hypothesis that PMNs may regulate inflammatory processes via cytokine and chemokine response.
Assuntos
Quimiocinas/genética , Citocinas/genética , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , RNA Mensageiro/metabolismo , Administração por Inalação , Animais , Líquido da Lavagem Broncoalveolar/química , Hibridização Genética , Injeções Intraperitoneais , Interleucinas/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/metabolismo , Masculino , Metalotioneína/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Ribonucleases/fisiologia , Fatores de TempoRESUMO
Chronic inhalation of crystalline silica can produce lung tumors in rats whereas this has not been shown for amorphous silica. At present the mechanisms underlying this rat lung tumor response are unknown, although a significant role for chronic inflammation and cell proliferation has been postulated. To examine the processes that may contribute to the development of rat lung tumors after silica exposure, we characterized the effects of subchronic inhalation of amorphous and crystalline silica in rats. Rats were exposed for 6 h/day, on 5 days/week, for up to 13 weeks to 3 mg/m(3) crystalline or 50 mg/m(3) amorphous silica. The effects on the lung were characterized after 6.5 and 13 weeks of exposure as well as after 3 and 8 months of recovery. Exposure concentrations were selected to induce high pulmonary inflammatory-cell responses by both compounds. Endpoints characterized after silica exposure included mutation in the HPRT gene of isolated alveolar cells in an ex vivo assay, changes in bronchoalveolar lavage fluid markers of cellular and biochemical lung injury and inflammation, expression of mRNA for the chemokine MIP-2, and detection of oxidative DNA damage. Lung burdens of silica were also determined. After 13 weeks of exposure, lavage neutrophils were increased from 0.26% (controls) to 47 and 55% of total lavaged cells for crystalline and amorphous silica, with significantly greater lavage neutrophil numbers after amorphous silica (9.3 x 10(7) PMNs) compared to crystalline silica (6.5 x 10(7) PMNs). Lung burdens were 819 and 882 microg for crystalline and amorphous silica, respectively. BAL fluid levels of LDH as an indicator of cytotoxicity were twice as high for amorphous silica compared to those of crystalline silica, at the end of exposure. All parameters remained increased for crystalline silica and decreased rapidly for amorphous silica in the 8-month recovery period. Increased MIP-2 expression was observed at the end of the exposure period for both amorphous and crystalline silica. After 8 months of recovery, those markers remained elevated in crystalline silica-exposed rats, whereas amorphous silica-exposed rats were not significantly different from controls. A significant increase in HPRT mutation frequency in alveolar epithelial cells was detected immediately after 13 weeks of exposure to crystalline, but not to amorphous silica. A significant increase in TUNEL staining was detected in macrophages and terminal bronchiolar epithelial cells of amorphous silica-exposed rats at the end of the exposure period; however, crystalline silica produced far less staining. The observation that genotoxic effects in alveolar epithelial cells occurred only after crystalline but not amorphous silica exposure, despite a high degree of inflammatory-cell response after subchronic exposure to both types of silica, suggests that in addition to an inflammatory response, particle biopersistence, solubility, and direct or indirect epithelial cell cytotoxicity may be key factors for the induction of either mutagenic events or target cell death.
Assuntos
Pulmão/efeitos dos fármacos , Monocinas/genética , Mutagênicos/toxicidade , Dióxido de Silício/toxicidade , Administração por Inalação , Animais , Carga Corporal (Radioterapia) , Líquido da Lavagem Broncoalveolar/química , Quimiocina CXCL2 , Hipoxantina Fosforribosiltransferase/genética , Marcação In Situ das Extremidades Cortadas , Pulmão/metabolismo , Pulmão/patologia , Masculino , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos F344RESUMO
There is potential for human exposure to cyclic siloxanes by the respiratory route. To determine the pharmacokinetics of octamethylcyclotetrasiloxane (D4), a material commonly found in personal care products, the respiratory intake and uptake of D4 were measured in 12 healthy volunteers (25-49 years) on two occasions. Subjects inhaled 10 ppm D4 (122 micrograms/liter) or air (control) during a 1-h exposure via a mouthpiece in a double-blind, randomized fashion. Inspiratory and expiratory D4 concentrations were continuously measured. Exhaled air and plasma D4 levels were measured before, during, and after exposures. Individual D4 uptakes were measured under steady-state conditions during three rest periods (10, 20, and 10 min, respectively) alternating with two 10-min exercise periods. Mean D4 intake was 137 +/- 25 mg (SD) and the mean deposition efficiency was equivalent to 0.74/(1 + 0.45 VE), where VE is the minute ventilation. No changes in lung function were induced by the D4 vapor. Plasma measurements of D4 gave a mean peak value of 79 +/- 5 ng/g (SEM) and indicated a rapid nonlinear blood clearance. Using lung volume and respiratory surface area estimates based on functional residual capacity measurements, we developed a model and determined that the effective mass transfer coefficient for D4 was 5.7 x 10(-5) cm/s from lung air to blood. In an additional eight subjects, we compared D4 deposition with mouthpiece and nasal breathing at resting ventilations. For these individuals, mean deposition was similar for the two exposure protocols, averaging 12% after correction for exposure system losses. These are the first data describing the intake and absorption of D4 and they should contribute to a meaningful safety assessment of the compound.
Assuntos
Siloxanas/farmacocinética , Adulto , Método Duplo-Cego , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Masculino , Pessoa de Meia-Idade , Siloxanas/administração & dosagem , Siloxanas/toxicidade , VolatilizaçãoRESUMO
Ultrafine particles (UFP) may contribute to the morbidity and mortality associated with exposure to ambient particles, but few data are available on ultrafine particle numbers in indoor air, where susceptible subjects spend most of their time. We measured particle number, UFP size distribution, and total suspended particulate (JSP) mass in three locations: (I) a medical floor in a large tertiary care hospital, (2) outdoor air above a construction site outside the hospital, and (3) an environmental exposure chamber with purification of intake air. Mass and number concentrations were recorded continuously in each location over 70-110 h. Mean ± SD particle (p) numbers were 3.63 ± 1.l5 } 10(3) p/cm(3) in the hospital, 3.05 ± 6.65 } 10(4) p/cm(3) outside, and 5.86 ± 2.11 } 10(2) p/cm(3) in the environmental chamber. In the hospital, particle number and mass declined during the evening hours when the unit was less active, with the particle number as low as 1.15 } 10(3) p/cm(3). Particle numbers peaked (2.78 } 10(4) p/cm(3)) in the morning hours when activity on the unit was the most intense. "Spikes" in fine particle number were often not accompanied by increases in TSP mass. In the hospital, a distinct population of ultrafine particles (median diameter approximately 23 nm) was observed during the lunch hour, suggesting a change in particle source during this time. Outdoor fine particle numbers above the construction site were highly variable, reaching peaks of greater than 1.7 } 10(6) p/cm(3). These data suggest that, in the indoor environment, particle numbers and size distribution vary with intensity and type of local activity, and significant peaks in particle number are not detected with daily averages. Monitoring of particle mass may be an inaccurate measure of exposure to ultrafine particles indoors.
RESUMO
Ambient fine particles consist of ultrafine particles (< 100 nm) and accumulation-mode particles (approximately 100 to 1,000 nm). Our hypothesis that ultrafine particles can have adverse effects in humans is based on results of our earlier studies with particles of both sizes and on the finding that urban ultrafine particles can reach mass concentrations of 40 to 50 micrograms/m3, equivalent to number concentrations of 3 to 4 x 10(5) particles/cm3. The objectives of the exploratory studies reported here were to (1) evaluate pulmonary effects induced in rats and mice by ultrafine particles of known high toxicity (although not occurring in the ambient atmosphere) in order to obtain information on principles of ultrafine particle toxicology; (2) characterize the generation and coagulation behavior of ultrafine particles that are relevant for urban air; (3) study the influence of animals' age and disease status; and (4) evaluate copollutants as modifying factors. We used ultrafine Teflon (polytetrafluoroethylene [PTFE]*) fumes (count median diameter [CMD] approximately 18 nm) generated by heating Teflon in a tube furnace to 486 degrees C to evaluate principles of ultrafine particle toxicity that might be helpful in understanding potential effects of ambient ultrafine particles. Teflon fumes at ultrafine particle concentrations of approximately 50 micrograms/m3 are extremely toxic to rats when inhaled for only 15 minutes. We found that neither the ultrafine Teflon particles alone when generated in argon nor the Teflon fume gas-phase constituents when generated in air were toxic after 25 minutes of exposure. Only the combination of both phases when generated in air caused high toxicity, suggesting the existence of either radicals on the particle surface or a carrier mechanism of the ultrafine particles for adsorbed gas-phase compounds. We also found rapid translocation of the ultrafine Teflon particles across the epithelium after their deposition, which appears to be an important difference from the behavior of larger particles. Furthermore, the pulmonary toxicity of the ultrafine Teflon fumes could be prevented by adapting the animals with short 5-minute exposures on 3 days prior to a 15-minute exposure. This shows the importance of preexposure history in susceptibility to acute effects of ultrafine particles. Aging of the fresh Teflon fumes for 3.5 minutes led to a predicted coagulation resulting in particles greater than 100 nm that no longer caused toxicity in exposed animals. This result is consistent with greater toxicity of ultrafine particles compared with accumulation-mode particles. When establishing dose-response relationships for intratracheally instilled titanium dioxide (TiO2) particles of the size of the urban ultrafine particles (20 nm) and of the urban accumulation-mode particles (250 nm), we observed significantly greater pulmonary inflammatory response to ultrafine TiO2 in rats and mice. The greater toxicity of the ultrafine TiO2 particles correlated well with their greater surface area per mass. Ultrafine particles of carbon, platinum, iron, iron oxide, vanadium, and vanadium oxide were generated by electric spark discharge and characterized to obtain particles of environmental relevance for study. The CMD of the ultrafine carbon particles was approximately 26 nm, and that of the metal particles was 15 to 20 nm, with geometric standard deviations (GSDs) of 1.4 to 1.7. For ultrafine carbon particles, approximately 100 micrograms/m3 is equivalent to 12 x 10(6) particles/cm3. Homogeneous coagulation of these ultrafine particles in an animal exposure chamber occurred rapidly at 1 x 10(7) particles/cm3, so that particles quickly grew to sizes greater than 100 nm. Thus, controlled aging of ultrafine carbon particles allowed the generation of accumulation-mode carbon particles (due to coagulation growth) for use in comparative toxicity studies. We also developed a technique to generate ultrafine particles consisting of the stable isotope 13C by using 13C-graphite electrodes made in our laboratory from amorphous 13C powder. These particles are particularly useful tools for determining deposition efficiencies of ultrafine carbon particles in the respiratory tracts of laboratory animals and the translocation of particles to extrapulmonary sites. For compromised animals, we used acute and chronic pulmonary emphysema; a low-dose endotoxin inhalation aimed at priming target cells in the lung was also developed. Other modifying factors were age and copollutant (ozone) exposure. Exposure concentrations of the generated ultrafine particles for acute rodent inhalation studies were selected on the basis of lung doses predicted to occur in people inhaling approximately 50 micrograms/m3 urban ultrafine particles. Concentrations that achieved the same predicted lung burden per unit alveolar surface were used in rodents. (ABSTRACT TRUNCATED)
Assuntos
Carbono/toxicidade , Pneumopatias/induzido quimicamente , Politetrafluoretileno/toxicidade , Titânio/toxicidade , Administração por Inalação , Fatores Etários , Análise de Variância , Animais , Lavagem Broncoalveolar , Carbono/farmacocinética , Relação Dose-Resposta a Droga , Medições Luminescentes , Pneumopatias/metabolismo , Pneumopatias/patologia , Metais/farmacocinética , Metais/toxicidade , Camundongos , Microscopia Eletrônica de Varredura , Neutrófilos/metabolismo , Estresse Oxidativo , Tamanho da Partícula , Politetrafluoretileno/farmacocinética , Enfisema Pulmonar/metabolismo , Ratos , Titânio/farmacocinéticaRESUMO
The possibility of widespread methanol exposure via inhalation stemming from its adoption as an automotive fuel or fuel component arouses concerns about the potential vulnerability of the fetal brain. This project was designed to help address such concerns by studying the behavior of neonate and adult rats following perinatal exposure to methanol vapor. Four cohorts of pregnant Long-Evans hooded rats, each cohort consisting of an exposure and a control group, were exposed to 0 parts per million (ppm) (control) or 4,500 ppm methanol vapor for six hours daily beginning on gestation day (GD) 6 with dams and pups then being exposed postnatal day (PND) 21. Exposures took place in 2-m3 Rochester-type inhalation chambers while the animals remained in their plastic breeder cages. Prenatal and postnatal blood methanol concentrations were determined by gas chromatography. Blood methanol concentrations of the dams, measured immediately following a six-hour exposure, were approximately 500 to 800 micrograms/mL throughout gestation and lactation. Average blood methanol concentrations of the pups were about twice those of the dams. Because such results appeared consistently across the other cohorts, we decided to obtain additional data with Cohort 4. Once it had undergone the standard exposure protocol, we selected sets of extra pups from those that had not been assigned previously to the adult phase of behavioral testing. Each set was exposed once, at ages that extended out to PND 52, for one additional six-hour session of exposure to 4,500 ppm methanol. The blood methanol concentrations of these pups declined until about PND 48, at which time they approximated those of the dams. These findings might be accounted for by a process of metabolic maturation in the pups that remains to be identified.
Assuntos
Deficiências do Desenvolvimento/induzido quimicamente , Modelos Animais de Doenças , Exposição por Inalação/efeitos adversos , Exposição Materna/efeitos adversos , Metanol/toxicidade , Emissões de Veículos/toxicidade , Animais , Animais Recém-Nascidos , Criança , Deficiências do Desenvolvimento/diagnóstico , Avaliação Pré-Clínica de Medicamentos , Feminino , Feto/efeitos dos fármacos , Idade Gestacional , Humanos , Masculino , Gravidez , Ratos , Ratos Long-Evans , Fatores de TempoRESUMO
Nineteen UF6/UO2F2 inhalation studies were undertaken in purebred, female beagle dogs (N = 16) to examine inter alia, (a) the possible relations of exposure, whole body, lung and renal uranium levels to excretion rates; (b) the threshold U6+ dose and renal concentration for renal injury; (c) the distribution and retention functions for U6+ in major tissues; (d) biochemical indicators of renal injury; and (e) aspects of U-induced tolerance. Each of these issues was investigated in the context of the chemical toxicity of U6+ following brief exposures to 235UO2F2 in the presence or absence of HF (the decomposition products of 235UF6). Both gamma-(235U) and alpha-(234U) counting methods were applied. In nine studies on 5 dogs, UO2F2 was administered intravenously. The major findings from both types of studies include: (1) UO2F2 retention time in the lungs is shorter than for UO3 or uranyl nitrate, viz. greater than 80% translocated with T 1/2 of less than 20 min; (2) the urinary elimination of U6+ follows closely to the ICRP excretion equation; (c) an absorbed dose of approximately 10 micrograms U6+ kg-1 body weight appears to be effective in producing renal injury; (d) a renal concentration of 0.3 micrograms g-1 kidney is close to a threshold concentration for renal injury; and (e) urinary and blood biochemical changes and histopathologic data were acquired and evaluated in both novice and tolerant animals. This report, considers all of these objectives and findings: Those involving biochemical indices and uranium-induced tolerance will be more fully reported elsewhere. In general, the dog studies attest to the usefulness of the intravenous human studies for certain U6+ dose-response data and interface well with new retention data on intravenous uranyl citrate in dogs by Stevens et al.
Assuntos
Fluoretos , Compostos de Urânio , Urânio/administração & dosagem , Aerossóis , Animais , Carga Corporal (Radioterapia) , Cães , Fezes/análise , Feminino , Injeções Intravenosas , Rim/efeitos da radiação , Pulmão/efeitos da radiação , Distribuição Tecidual , Urânio/metabolismoRESUMO
PURPOSE: The purpose of this research was to examine the effects of inhalation of toluene on respiratory function and neuropsychological performance of humans. METHODS: We exposed six healthy adults to 100 ppm toluene or air (control) for 6 h, in a double-blind, randomized fashion, with exposures separated by at least 14 d and including 30 min of exercise at a level that quadrupled minute ventilation. Blood and exhaled air toluene levels were measured before, during, immediately, and 1 and 2 h post-exposure. Lung function was measured before and immediately after exposure. Three repetitions of two computerized neuropsychological tests were performed, including a brief standard neuropsychological battery (ANAM) and a 1-h complex performance test (SYNWORK). Statistical analysis of the psychological data was conducted as a repeated measures ANOVA. FINDINGS: Following exercise, the mean blood and exhaled air toluene levels averaged 1.5 micrograms and 28 ppm, respectively. Lung function was unchanged post-exposure. On the SYNWORK test, the Composite score obtained over time during toluene exposure was lower than that during room air (F = 29.20, p = 0.005), with the score from the final hour reduced by 10%. On standard neuropsychological tests, latency but not accuracy proved the sensitive measure for five of the seven subtests presented. CONCLUSIONS: Performance of complex tests and response time to simple brief tests can be disrupted by toluene inhalation at 100 ppm. Differences in performance between air and toluene conditions were greatest after exercise, indicating that physical activity may enhance the response to volatile organic solvents.
Assuntos
Poluição do Ar em Ambientes Fechados/efeitos adversos , Processos Mentais/efeitos dos fármacos , Exposição Ocupacional/efeitos adversos , Tolueno/efeitos adversos , Adulto , Medicina Aeroespacial , Análise de Variância , Estudos Cross-Over , Feminino , Humanos , Masculino , Memória/efeitos dos fármacos , Exposição Ocupacional/análise , Tempo de Reação , Tolueno/metabolismoRESUMO
Clodronate liposomes were given to rats via intratracheal inhalation to investigate the importance of alveolar macrophages (AMs) in inhaled endotoxin-induced lung injury. When AM depletion was maximal (87% to 90%), rats were exposed to lipopolysaccharide (LPS) or saline. Neither clodronate nor saline liposomes induced an influx of neutrophils (PMNs) into the lungs. However, depleted LPS-exposed rats had 5- to 8-fold higher numbers of lavage PMNs and greater lavage cell reactive oxygen species release compared to undepleted rats. Although AM depletion by itself did not significantly increase inflammatory cytokine expression in lung tissue, LPS-induced message levels for interleukin (IL)-1alpha, IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha were approximately 2-fold higher in AM-depleted rats compared to undepleted rats. These results indicate that cells other than AMs can recruit inflammatory cells into the lungs during acute LPS-induced injury and that AMs play an important suppressive role in the innate pulmonary inflammatory response.
Assuntos
Antimetabólitos/farmacologia , Ácido Clodrônico/farmacologia , Macrófagos Alveolares/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Administração por Inalação , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/genética , Lipopolissacarídeos , Macrófagos Alveolares/enzimologia , Macrófagos Alveolares/imunologia , Masculino , Peroxidase/metabolismo , Pneumonia/induzido quimicamente , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos F344 , Espécies Reativas de Oxigênio/metabolismo , Cloreto de Sódio/farmacologia , Organismos Livres de Patógenos EspecíficosRESUMO
Effective elimination of particles deposited in the respiratory tract is an important defense function to protect the organism from potentially adverse effects of inhaled particles. Delivery of radioactively labeled tracer particles and subsequent measurement in vivo of their retention in different regions of the respiratory tract provides an adequate method for characterizing this defensive function. However, the delivery of such tracer particles by inhalation may result in some external contamination of the animals and requires specific protective measures while working with radioactive aerosols. In this study, 85Sr-labeled tracer particles (3 microns) were administered to the lower respiratory tract of rats by intratracheal inhalation to avoid external contamination, and also by intratracheal instillation in order to compare the 2 technique with respect to their suitability for measuring normal and impaired particle clearance rates. It was postulated that particle clearance function in the alveolar region can be determined equally well with intratracheally instilled particles despite their uneven distribution in the lung. For both techniques, rats were anesthesized with halothane and the particles were administered via oral intubation. Retention in the lower respiratory tract of about 30 micrograms (inhalation) and 6 micrograms (instillation) of the administered particles was followed over a period of 180 days by external counting of lung 85Sr-activity in a collimated detection system. To impair alveolar particle clearance rates, groups of rats were subjected to 12 weeks of inhalation exposure prior to delivery of the tracer particles as follows: (1) sham-exposed control; (2) pigment-grade TiO2 particles to induce lung overload: (3) ultrafine TiO2 particles: (4) crystalline SiO2 particles (cristobalite). The following results were obtained: The long-term retention half-times (T1/2) of the tracer particles reflecting alveolar clearance consistently showed the same ranking of the treatment groups whether measured after intratracheal inhalation or instillation. Control values were 66 and 72 days, respectively, and significantly prolonged long-term clearance was measured by both methods for pigment-grade TiO2 (117 and 99 days), ultrafine TiO2 (541 and 600 days) and SiO2 (1901 and 1368 days). Comparison of these values between the two modes of administration of tracer particles showed no significant differences. In contrast, the short-term T1/2 (mucociliary clearance) of the intratracheally instilled tracer particles in the different treatment groups were variable and did not accurately reflect particle clearance from the conducting airways. However, short-term T1/2 after intratracheal inhalation of tracer particles were consistent with fast conducting airway clearance, and mucociliary clearance appears to be stimulated when alveolar clearance is significantly impaired due to particle overload or to effects of cytotoxic particles. The results suggest that intratracheal instillation of a low dose (< or = 10 micrograms) of tracer particles in the rat provides an adequate method for reliably determining effects of inhaled toxicants on alveolar particle clearance function. Further, intratracheal inhalation of tracer particles is useful for measuring both short-term (mucociliary) and long-term (alveolar) particle clearance rates in the lower respiratory tract of the rat.
Assuntos
Pulmão/metabolismo , Radioisótopos de Estrôncio , Administração por Inalação , Animais , Instilação de Medicamentos , Pulmão/efeitos dos fármacos , Masculino , Tamanho da Partícula , Ratos , Ratos Endogâmicos F344 , Dióxido de Silício/farmacocinética , Titânio/farmacocinética , TraqueiaRESUMO
The effectiveness of 2,3-dimercaptopropane-1-sulfonate (DMPS) as a rescue agent for the acute nephropathy induced by HgCl2 was studied in uninephrectomized (NPX) and sham-operated (SO) rats. NPX and SO rats that were given a toxic 2.5-mumol/kg dose of HgCl2 developed severe renal damage within 24 hr after the HgCl2 was administered. Renal injury was assessed by measuring plasma creatinine, creatinine clearance, fractional excretion of several biological markers, the rate of excretion of cellular enzymes and plasma solutes and severity of morphologically demonstrable necrosis in the pars recta of proximal tubules. When a 10-mg/kg dose of DMPS was given to the NPX and SO rats 1 hr after treatment with the 2.5-mumol/kg dose of HgCl2, the nephropathy induced by the dose of HgCl2 was less severe. Moreover, the NPX rats had significantly less severe renal damage than did the SO rats. Renal damage was completely absent from both NPX and SO rats that were given a 100-mg/kg dose of DMPS 1 hr after treatment with the 2.5-mumol/kg dose of HgCl2. These data indicate that at the 10-mg/kg dose of DMPS, NPX rats are protected against the nephrotoxic effects of a 2.5-mumol/kg dose of HgCl2 to a greater extent than are SO rats. Moreover, the data show that complete rescue from the 2.5-mumol/kg dose of HgCl2 is afforded to NPX and SO rats given 100 mg/kg of DMPS within 1 hr after treatment with HgCl2. This complete rescue is afforded for at least 24 hr. Based on the present findings DMPS may prove to be a useful rescue agent against the acute nephropathy induced by HgCl2.
Assuntos
Rim/efeitos dos fármacos , Cloreto de Mercúrio/toxicidade , Unitiol/uso terapêutico , Acetilglucosaminidase/urina , Animais , Aspartato Aminotransferases/urina , Peso Corporal/efeitos dos fármacos , Creatinina/sangue , Creatinina/urina , Glicosúria/metabolismo , Rim/metabolismo , Rim/patologia , Nefropatias/prevenção & controle , L-Lactato Desidrogenase/urina , Masculino , Nefrectomia , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Unitiol/farmacologia , gama-Glutamiltransferase/urinaRESUMO
The aim of the present study was to determine if a reduction of renal mass altered the dose-effect relationship for the nephropathy induced by cadmium-metallothionein. Uninephrectomized (NPX) and sham-operated (SO) rats were given a single i.v. injection of cadmium-metallothionein at a dose of 0.1, 0.2 or 0.3 mg of cadmium per kg, and were sacrificed 24 hr after the injection. Quantitative computerized morphometric analysis of sections of kidney, plasma creatinine and the urinary excretion of some cellular enzymes and plasma solutes were used to evaluate the severity of renal injury at each dose of cadmium-metallothionein. No renal injury was detected in either the NPX or SO rats given the lowest dose of cadmium-metallothionein. At the middle dose of cadmium-metallothionein, renal injury occurred in both the NPX and SO rats, but the severity of injury was substantially greater in the NPX rats. This increased renal injury in the NPX rats correlated with increased renal content of cadmium and increased urinary excretion of cadmium. At the highest dose of cadmium-metallothionein, renal injury was quite severe. Some of the data show that renal injury was more severe in the NPX rats than in the SO rats. In summary, our findings indicate that there is a shift to the left in the dose effect relationship in the nephropathy induced by cadmium-metallothionein. The mechanism for this shift is not known at present, although it appears to be related, in part, to increased renal accumulation and/or retention of cadmium.
Assuntos
Rim/efeitos dos fármacos , Metalotioneína/farmacologia , Acetilglucosaminidase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Cádmio/metabolismo , Cádmio/urina , Creatinina/sangue , Relação Dose-Resposta a Droga , Rim/metabolismo , Rim/patologia , L-Lactato Desidrogenase/metabolismo , Fígado/efeitos dos fármacos , Masculino , Metalotioneína/metabolismo , Nefrectomia , Ratos , Ratos EndogâmicosRESUMO
Recent epidemiological studies show an association between particulate air pollution and acute mortality and morbidity down to ambient particle concentrations below 100 micrograms/m3. Whether this association also implies a causality between acute health effects and particle exposure at these low levels is unclear at this time; no mechanism is known that would explain such dramatic effects of low ambient particle concentrations. Based on results of our past and most recent inhalation studies with ultrafine particles in rats, we propose that such particles, that is, particles below approximately 50 nm in diameter, may contribute to the observed increased mortality and morbidity In the past we demonstrated that inhalation of highly insoluble particles of low intrinsic toxicity, such as TiO2, results in significantly increased pulmonary inflammatory responses when their size is in the ultrafine particle range, approximately 20 nm in diameter. However, these effects were not of an acute nature and occurred only after prolonged inhalation exposure of the aggregated ultrafine particles at concentrations in the milligrams per cubic meter range. In contrast, in the course of our most recent studies with thermodegradation products of polytetrafluoroethylene (PTFE) we found that freshly generated PTFE fumes containing singlet ultrafine particles (median diameter 26 nm) were highly toxic to rats at inhaled concentrations of 0.7-1.0 x 10(6) particles/cm3, resulting in acute hemorrhagic pulmonary inflammation and death after 10-30 min of exposure. We also found that work performance of the rats in a running wheel was severely affected by PTFE fume exposure. These results confirm reports from other laboratories of the highly toxic nature of PTFE fumes, which cannot be attributed to gas-phase components of these fumes such as HF, carbonylfluoride, or perfluoroisobutylene, or to reactive radicals. The calculated mass concentration of the inhaled ultrafine PTFE particles in our studies was less than 60 micrograms/m3, a very low value to cause mortality in healthy rats. Aging of the fumes with concomitant aggregation of the ultrafine particles significantly decreases their toxicity. Since ultrafine particles are always present in the urban atmosphere, we suggest that they play a role in causing acute lung injury in sensitive parts of the population.
Assuntos
Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Pneumopatias/induzido quimicamente , Mortalidade , Politetrafluoretileno/toxicidade , Aerossóis , Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/análise , Poluição do Ar/estatística & dados numéricos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Temperatura Alta , Humanos , Exposição por Inalação/efeitos adversos , Pneumopatias/epidemiologia , Pneumopatias/mortalidade , Masculino , Atividade Motora , Tamanho da Partícula , Politetrafluoretileno/administração & dosagem , Politetrafluoretileno/efeitos adversos , Ratos , Ratos Endogâmicos F344RESUMO
The aim of the present study was to determine whether the nephrotoxicity of the uranium-containing compound uranyl fluoride (UO2F2) is enhanced after unilateral nephrectomy. Unilaterally nephrectomized (NPX) and sham-operated (SO) rats were given single intravenous injections of UO2F2 at doses delivering 100 or 250 micrograms U/kg 16 days after surgery. Between the second and third day after the administration of either dose of UO2F2, the urinary excretion of the cellular enzymes lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) and the plasma solute albumin began to increase significantly in both the NPX and SO rats. The urinary excretion of the plasma solute glucose did not begin to increase significantly in the NPX and SO rats until 4 days after the administration of either dose of UO2F2. During the fifth day following the administration of either dose of UO2F2 (which was also the last day that urinary data were collected) the urinary excretion of LDH, AST, and glucose in the NPX and SO rats was greater than that during any previous day. The urinary excretion of these three compounds during this fifth day was greater in the SO rats than in the NPX rats. Also during the fifth day following the injection of either dose of UO2F2, the fractional excretion of glucose was higher in the SO rats than in the NPX rats. By the end of the fifth day, the level of histologically demonstrable cellular necrosis in the pars recta of proximal tubules in the renal cortex and outer medulla of the NPX and SO rats was statistically similar. Therefore, the nephropathy in rats induced by UO2F2 is not made more severe as a result of unilateral nephrectomy.
Assuntos
Fluoretos , Rim/efeitos dos fármacos , Nefrectomia , Compostos de Urânio , Urânio/toxicidade , Alanina Transaminase/urina , Albuminúria , Animais , Creatinina/farmacocinética , Glucose/metabolismo , Rim/patologia , L-Lactato Desidrogenase/urina , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Urânio/metabolismoRESUMO
Rat alveolar macrophages (AMs) were depleted via intratracheal inhalation (ITIH) of clodronate-containing liposomes. AM depletion following ITIH delivery of clodronate liposomes was 33.2 +/- 14.2 on day 1, 88.1 +/- 6.2 on day 3, and 91.4 +/- 1.8 on day 4 relative to control rats given saline-containing liposomes. Almost all (approximately 99%) of the AMs remaining at the 3-day time point were peroxidase negative, suggesting that immature macrophages were not recruited from the circulation to replace those undergoing cell death on that day. Only 0.5% +/- 0.5% of bronchoalveolar lavage (BAL) cells were neutrophils at this time (normalized to controls). Whole-body inhalation did not induce as much AM depletion at 3 days (37.6% +/- 10.1%) and required larger amounts of liposome-encapsulated clodronate compared to ITIH. Intratracheal instillation (as opposed to inhalation) of clodronate liposomes produced a significant inflammatory response characterized by the influx of both polymorphonuclear neutrophils (PMNs) and macrophages. In subsequent pilot studies, the response to intratracheally instilled crystalline silica (75 microg) was found to be markedly reduced in rats depleted of AMs by the ITIH method. We conclude that ITIH of clodronate liposomes in rats is both efficient and useful for examining the role of AMs in pulmonary toxicology.
Assuntos
Ácido Clodrônico/administração & dosagem , Macrófagos Alveolares/efeitos dos fármacos , Administração por Inalação , Aerossóis , Animais , Lipossomos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Macrófagos Alveolares/patologia , Masculino , Ratos , Ratos Endogâmicos F344 , Dióxido de Silício/administração & dosagem , Dióxido de Silício/toxicidade , Fatores de TempoRESUMO
Ultrafine particles (UFP, particles <100 nm) are ubiquitous in ambient urban and indoor air from multiple sources and may contribute to adverse respiratory and cardiovascular effects of particulate matter (PM). Depending on their particle size, inhaled UFP are efficiently deposited in nasal, tracheobronchial, and alveolar regions due to diffusion. Our previous rat studies have shown that UFP can translocate to interstitial sites in the respiratory tract as well as to extrapulmonary organs such as liver within 4 to 24 h postexposure. There were also indications that the olfactory bulb of the brain was targeted. Our objective in this follow-up study, therefore, was to determine whether translocation of inhaled ultrafine solid particles to regions of the brain takes place, hypothesizing that UFP depositing on the olfactory mucosa of the nasal region will translocate along the olfactory nerve into the olfactory bulb. This should result in significant increases in that region on the days following the exposure as opposed to other areas of the central nervous system (CNS). We generated ultrafine elemental (13)C particles (CMD = 36 nm; GSD = 1.66) from [(13)C] graphite rods by electric spark discharge in an argon atmosphere at a concentration of 160 microg/m(3). Rats were exposed for 6 h, and lungs, cerebrum, cerebellum and olfactory bulbs were removed 1, 3, 5, and 7 days after exposure. (13)C concentrations were determined by isotope ratio mass spectroscopy and compared to background (13)C levels of sham-exposed controls (day 0). The background corrected pulmonary (13)C added as ultrafine (13)C particles on day 1 postexposure was 1.34 microg/lung. Lung (13)C concentration decreased from 1.39 microg/g (day 1) to 0.59 microg/g by 7 days postexposure. There was a significant and persistent increase in added (13)C in the olfactory bulb of 0.35 microg/g on day 1, which increased to 0.43 microg/g by day 7. Day 1 (13)C concentrations of cerebrum and cerebellum were also significantly increased but the increase was inconsistent, significant only on one additional day of the postexposure period, possibly reflecting translocation across the blood-brain barrier in certain brain regions. The increases in olfactory bulbs are consistent with earlier studies in nonhuman primates and rodents that demonstrated that intranasally instilled solid UFP translocate along axons of the olfactory nerve into the CNS. We conclude from our study that the CNS can be targeted by airborne solid ultrafine particles and that the most likely mechanism is from deposits on the olfactory mucosa of the nasopharyngeal region of the respiratory tract and subsequent translocation via the olfactory nerve. Depending on particle size, >50% of inhaled UFP can be depositing in the nasopharyngeal region during nasal breathing. Preliminary estimates from the present results show that approximately 20% of the UFP deposited on the olfactory mucosa of the rat can be translocated to the olfactory bulb. Such neuronal translocation constitutes an additional not generally recognized clearance pathway for inhaled solid UFP, whose significance for humans, however, still needs to be established. It could provide a portal of entry into the CNS for solid UFP, circumventing the tight blood-brain barrier. Whether this translocation of inhaled UFP can cause CNS effects needs to be determined in future studies.
Assuntos
Poluentes Atmosféricos/farmacocinética , Encéfalo/metabolismo , Exposição por Inalação/efeitos adversos , Animais , Carbono/administração & dosagem , Carbono/farmacocinética , Cerebelo/metabolismo , Pulmão/metabolismo , Masculino , Bulbo Olfatório/metabolismo , Tamanho da Partícula , Ratos , Ratos Endogâmicos F344 , Telencéfalo/metabolismo , Distribuição TecidualRESUMO
PTFE (polytetrafluoroethylene) fumes consisting of large numbers of ultrafine (uf) particles and low concentrations of gas-phase compounds can cause severe acute lung injury. Our studies were designed to test three hypotheses: (i) uf PTFE fume particles are causally involved in the induction of acute lung injury, (ii) uf PTFE elicit greater pulmonary effects than larger sized PTFE accumulation mode particles, and (iii) preexposure to the uf PTFE fume particles will induce tolerance. We used uf Teflon (PTFE) fumes (count median particle size approximately 16 nm) generated by heating PTFE in a tube furnace to 486 degrees C to evaluate principles of ultrafine particle toxicity. Teflon fumes at ultrafine particle concentrations of 50 microg/m(3) were extremely toxic to rats when inhaled for only 15 min. We found that when generated in argon, the ultrafine Teflon particles alone are not toxic at these exposure conditions; neither were Teflon fume gas-phase constituents when generated in air. Only the combination of both phases when generated in air caused high toxicity, suggesting either the existence of radicals on the surface or a carrier mechanism of the ultrafine particles for adsorbed gas compounds. Aging of the fresh Teflon fumes for 3.5 min led to a predicted coagulation to >100 nm particles which no longer caused toxicity in exposed animals. This result is consistent with a greater toxicity of ultrafine particles compared to accumulation mode particles, although changes in particle surface chemistry during the aging process may have contributed to the diminished toxicity. Furthermore, the pulmonary toxicity of the ultrafine Teflon fumes could be prevented by adapting the animals with short 5-min exposures on 3 days prior to a 15-min exposure. Messages encoding antioxidants and chemokines were increased substantially in nonadapted animals, yet were unaltered in adapted animals. This study shows the importance of preexposure history for the susceptibility to acute ultrafine particle effects.
Assuntos
Pneumopatias/induzido quimicamente , Politetrafluoretileno/toxicidade , Administração por Inalação , Animais , Lavagem Broncoalveolar , Fluoretos/toxicidade , Masculino , Neutrófilos/efeitos dos fármacos , Tamanho da Partícula , Politetrafluoretileno/administração & dosagem , RNA Mensageiro/biossíntese , Ratos , Ratos Endogâmicos F344 , Fatores de TempoRESUMO
Epidemiological studies demonstrate associations between increasing levels of ambient particles and morbidity in the elderly with cardiopulmonary disease. Such findings have been challenged partly because particles may not act alone to cause these effects. We hypothesized that carbonaceous ambient ultrafine particles and ozone can act together to induce greater oxidative stress and inflammation in the lung than when administered alone and that these effects would be amplified in the compromised, aging lung. Two models of a compromised lung were used: endotoxin priming and old-age emphysema (TSK mice). Young (10 wk) and old (22 mo) male F344 rats and male TSK mice (14-17 mo) were exposed to ultrafine carbon particles (count median diameter 25 nm, 110 micrograms/m3) and to ozone (1 ppm) alone and in combination for 6 h. Inhalation of low-dose endotoxin (70 and 7.5 units estimated alveolar deposited dose in rats and mice, respectively) was used to model respiratory-tract infection. Cellular and biochemical lavage parameters and oxidant release from lung lavage cells were assessed 24 h after exposure. Inflammatory cell influx into the alveolar space was observed for both species and age groups: The combination of inhaled ultrafine carbon and ozone after endotoxin priming resulted in the greatest increase in lavage-fluid neutrophils. In general, the unstimulated and stimulated release of reactive oxygen species (ROS) from lavage inflammatory cells correlated well with the neutrophil response. There were significant effects of carbon particles as well as a consistent interaction between carbon and ozone as determined by analysis of variance (ANOVA). However, this interaction was in the opposite direction in young rats versus old rats and old TSK mice: Carbon and ozone interacted such that ROS activity was depressed in young rats, whereas it was enhanced in old rats and old TSK mice, indicating age-dependent functional differences in elicited pulmonary inflammatory cells. These results demonstrate that ultrafine carbonaceous particles inhaled for short periods of time can induce significant pulmonary inflammation and oxidative stress that are modified by age, copollutants, and a compromised respiratory tract.