RESUMEN
Carbon nanotubes (CNTs) are important materials in advanced industries. It is a concern that pulmonary exposure to CNTs may induce carcinogenic responses. It has been recently reported that CNTs scavenge ROS though non-carbon fibers generate ROS. A comprehensive evaluation of ROS scavenging using various kinds of CNTs has not been demonstrated well. The present work specifically investigates ROS scavenging capabilities with a series of CNTs and their derivatives that were physically treated, and with the number of commercially available CNTs. CNT concentrations were controlled at 0.2 through 0.6 wt%. The ROS scavenging rate was measured by ESR with DMPO. Interestingly, the ROS scavenging rate was not only influenced by physical treatments, but was also dependent on individual manufacturing methods. Ratio of CNTs to DMPO/ hydrogen peroxide is a key parameter to obtain appropriate ROS quenching results for comparison of CNTs. The present results suggest that dangling bonds are not a sole factor for scavenging, and electron transfer on the CNT surface is not clearly determined to be the sole mechanism to explain ROS scavenging.
RESUMEN
Due to the fibrous shape and durability of multi-walled carbon nanotubes (MWCNT), concerns regarding their potential for producing environmental and human health risks, including carcinogenesis, have been raised. This study sought to investigate how previously identified lung cancer prognostic biomarkers and the related cancer signaling pathways are affected in the mouse lung following pharyngeal aspiration of well-dispersed MWCNT. A total of 63 identified lung cancer prognostic biomarker genes and major signaling biomarker genes were analyzed in mouse lungs (n=80) exposed to 0, 10, 20, 40, or 80µg of MWCNT by pharyngeal aspiration at 7 and 56days post-exposure using quantitative PCR assays. At 7 and 56days post-exposure, a set of 7 genes and a set of 11 genes, respectively, showed differential expression in the lungs of mice exposed to MWCNT vs. the control group. Additionally, these significant genes could separate the control group from the treated group over the time series in a hierarchical gene clustering analysis. Furthermore, 4 genes from these two sets of significant genes, coiled-coil domain containing-99 (Ccdc99), muscle segment homeobox gene-2 (Msx2), nitric oxide synthase-2 (Nos2), and wingless-type inhibitory factor-1 (Wif1), showed significant mRNA expression perturbations at both time points. It was also found that the expression changes of these 4 overlapping genes at 7days post-exposure were attenuated at 56days post-exposure. Ingenuity Pathway Analysis (IPA) found that several carcinogenic-related signaling pathways and carcinogenesis itself were associated with both the 7 and 11 gene signatures. Taken together, this study identifies that MWCNT exposure affects a subset of lung cancer biomarkers in mouse lungs.
Asunto(s)
Expresión Génica/efectos de los fármacos , Pulmón/efectos de los fármacos , Nanotubos de Carbono/toxicidad , Animales , Biomarcadores , Redes Reguladoras de Genes , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Exposición Profesional/efectos adversosRESUMEN
AIM: Liraglutide is a long-acting glucagon-like peptide-1 (GLP-1) mimetic which is a treatment option for type 2 diabetes. GLP-1 peptides, including Liraglutide, cross the blood-brain barrier and may additionally act to improve brain function. The present study tested the hypothesis that, in addition to its antihyperglycaemic actions, peripheral administration of Liraglutide exerts positive actions on cognitive function in mice with high fat dietary-induced obesity and insulin resistance. METHODS: Young Swiss TO mice maintained on high fat diet for 20 weeks received twice-daily injections of Liraglutide (200 µg/kg bw; sc) or saline vehicle over 28 days. An additional group of mice on standard diet received twice-daily saline injections. Energy intake, bodyweight, non-fasting plasma glucose and insulin concentrations were monitored at regular intervals. Glucose tolerance, open field assessment, object recognition testing and electrophysiological long-term potentiation (LTP) were performed at termination of the study. RESULTS: Liraglutide treatment resulted in significant time-dependent reduction in bodyweight and energy intake, whilst improving non-fasting glucose and normalizing glucose tolerance. Although Liraglutide did not alter general behaviour, treated mice exhibited marked increase in recognition index (RI) during object recognition testing, indicative of enhanced learning and memory ability. Furthermore, Liraglutide rescued the deleterious effects of high fat diet on hippocampal LTP of neurotransmission following both chronic and direct intracerebroventricular (icv) administration. CONCLUSION: Liraglutide administered peripherally not only improves metabolic parameters but exerts additional beneficial effects on cognitive function and hippocampal synaptic plasticity. Whether therapy with GLP-1 mimetics has similar effects in humans with type 2 diabetes needs to be established.
Asunto(s)
Glucemia/efectos de los fármacos , Cognición/efectos de los fármacos , Péptido 1 Similar al Glucagón/análogos & derivados , Hipoglucemiantes/administración & dosificación , Memoria/efectos de los fármacos , Obesidad/tratamiento farmacológico , Animales , Cognición/fisiología , Diabetes Mellitus Tipo 2 , Péptido 1 Similar al Glucagón/administración & dosificación , Resistencia a la Insulina/fisiología , Liraglutida , Masculino , Memoria/fisiología , RatonesRESUMEN
Results from previous studies indicate that hyperthyroidism increases the risk of ozone-induced lung toxicity. This observation raised the possibility that pulmonary damage from other oxidant substances might be greater in a hyperthyroid state. To address this hypothesis, pulmonary responses to crystalline silica, a particulate with oxidant properties, were evaluated in normal or hyperthyroid adult male rats. To induce a hyperthyroid condition, time-release pellets containing thyroxine were implanted subcutaneously; control rats received placebo pellets. After 7 days, the animals were exposed to saline or silica (0.1mg/100g BW or 1.0mg/100g BW) by intratracheal instillation. Following silica treatment, there was a dose-related increase in bronchoalveolar lavage (BAL) albumin levels and neutrophil numbers. However, the effects of silica were similar in both normal and hyperthyroid rats. These findings were confirmed and contrasted with those regarding ozone (1ppm, 4h inhalation) in a subsequent experiment. The results indicated that, although exposure to either ozone or silica resulted in increases in BAL albumin levels and neutrophil numbers, only responses to ozone were enhanced in hyperthyroid rats. These findings suggest that specificity exists in regards to the modulation of oxidant-induced lung damage and inflammation by thyroid hormones.
Asunto(s)
Hipertiroidismo/complicaciones , Enfermedades Pulmonares/inducido químicamente , Pulmón/efectos de los fármacos , Oxidantes/toxicidad , Estrés Oxidativo/efectos de los fármacos , Dióxido de Silicio/toxicidad , Albúminas/análisis , Animales , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Relación Dosis-Respuesta a Droga , Hipertiroidismo/inducido químicamente , Intubación Intratraqueal , Recuento de Leucocitos , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patología , Masculino , Neutrófilos/patología , Ozono/toxicidad , Ratas , Ratas Sprague-Dawley , Tiroxina/administración & dosificación , Tiroxina/sangreRESUMEN
Previous studies demonstrated that ozone-induced lung damage and inflammation are much greater in hyperthyroid rats, compared to normal rats, at 18 h postexposure. The purpose of the present investigation was to study early events and mechanisms underlying the increased sensitivity to ozone in a hyperthyroid state. Specifically, the degree of lung epithelial cell barrier disruption, the antioxidant status of the extracellular lining fluid, and the release of inflammatory mediators were examined. To induce a hyperthyroid state, mature male Sprague-Dawley rats were implanted with time-release pellets containing thyroxine; control rats received placebo pellets. After 7 d, the animals were exposed to air or ozone (2 ppm, 3 h). Immediately following the end of the exposure, bronchoalveolar lavage (BAL) fluid and cells were harvested. BAL fluid albumin levels and total antioxidant status were examined. In addition, levels of prostaglandin E2 (PGE2), macrophage inflammatory protein (MIP)-2, MCP-1, and tumor necrosis factor (TNF)-alpha were determined in BAL fluid and in media samples following ex vivo culture of BAL cells harvested after in vivo inhalation exposures. The results of this study are consistent with the following hypotheses: (1) A marked increase in the permeability of the alveolar-capillary barrier is an early event following ozone exposure in a hyperthyroid state; however this does not appear to be due to overall changes in BAL fluid antioxidant potential. (2) Early increases in MIP-2, but not PGE2, are involved in the enhanced lung response to ozone in a hyperthyroid state. (3) Inflammatory mediator production (i.e., PGE2, MIP-2, MCP-1, and TNF-alpha) by alveolar macrophages plays a minimal role in the initial responses to ozone in a hyperthyroid state.
Asunto(s)
Hipertiroidismo/complicaciones , Oxidantes Fotoquímicos/toxicidad , Ozono/toxicidad , Animales , Antioxidantes/análisis , Técnicas de Cultivo de Célula , Quimiocina CCL4 , Quimiocina CXCL2 , Dinoprostona/análisis , Células Epiteliales , Inflamación , Pulmón/citología , Proteínas Inflamatorias de Macrófagos/análisis , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/fisiología , Masculino , Monocinas/análisis , Permeabilidad , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/fisiología , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/análisisRESUMEN
Stress interferes with the normal secretion of LH and FSH from the anterior pituitary gland and therefore exerts a deleterious effect on reproductive function. Evidence suggests that the stress-induced disruption of gonadal function is due to a central action of corticotrophin-releasing factor (CRF) to inhibit the release of LHRH into the hypophysial-portal circulation. The following studies were undertaken to investigate further the role of CRF in regulating gonadotrophin release in the sheep and to determine whether central administration of this peptide can alter the secretion of other hormones (e.g. prolactin and cortisol) known to be released under conditions of stress. In contrast to other species, injection of CRF into the third ventricle of the sheep brain caused a dose-related stimulation of LH secretion. The pulse frequency and mean levels of LH were increased significantly following central administration of CRF. In contrast to this effect, central administration of CRF did not alter the plasma concentration of FSH but caused a marked and dose-related stimulation of prolactin and cortisol secretion. The stimulatory effect of CRF on prolactin secretion was reversed by i.v. administration of the opioid antagonist naloxone, suggesting that endogenous opioid peptides mediate the central effect of CRF on the release of prolactin, but not cortisol. In conclusion, these data demonstrate that administration of CRF causes a dose-related stimulation of LH and prolactin release from the anterior pituitary gland and cortisol from the adrenal gland. In the case of prolactin, endogenous opioid peptides are likely to mediate this response.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Hormona Liberadora de Corticotropina/farmacología , Hidrocortisona/metabolismo , Hormona Luteinizante/metabolismo , Prolactina/metabolismo , Ovinos/sangre , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Femenino , Hidrocortisona/sangre , Hormona Luteinizante/sangre , Naloxona/farmacología , Adenohipófisis/efectos de los fármacos , Adenohipófisis/metabolismo , Prolactina/sangreRESUMEN
The results of several in vitro studies have suggested that the enzyme cystathionase gamma-lyase (EC 4.4.1.1) may function in the endogenous detoxification of cyanide; however, this possibility has not been investigated in vivo. If cystathionase gamma-lyase in involved in the endogenous detoxification of cyanide, it logically follows that inhibiting cystathionase gamma-lyase should increase the toxicity of cyanide. To test this hypothesis, the activity of cystathionase gamma-lyase was inhibited with a suicide inhibitor, 2-amino-4-pentynoic acid (propargyl-glycine). The activity of liver cystathionase gamma-lyase activity was decreased 96.8% by administration of propargylglycine, indicating that the propargylglycine treatment was effective. The propargylglycine treatment did not alter the activity of thiosulfate:cyanide sulfurtransferase (EC 2.8.1.1) or 3-mercaptopyruvate:cyanide sulfurtransferase (EC 2.8.1.2), two other enzymes that have been proposed to be involved in the detoxification of cyanide. The LD50 of cyanide in rats treated with propargylglycine was 5.14 +/- 0.029 mg NaCN/kg, which was significantly (P < 0.05) lower than the 5.98 +/- 0.008 mg NaCN/kg LD50 of cyanide determined in control rats. The results of these studies suggest that cystathionase gamma-lyase may participate in the detoxification of cyanide in vivo.
Asunto(s)
Cianuros/metabolismo , Cistationina gamma-Liasa/farmacología , Hígado/efectos de los fármacos , Liasas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Abstract Injection of luteinizing hormone-releasing hormone (21 pmol) into the third cerebral ventricle of long-term ovariectomized ewes caused a marked inhibition of luteinizing hormone secretion. Mean luteinizing hormone levels and luteinizing hormone pulse frequency were reduced significantly when compared with the control responses to saline (50 mul). A notable characteristic of the response was the delayed and sustained nature of the luteinizing hormone-releasing hormone-induced inhibition. In the presence of the opioid antagonist naloxone (4 +/- 25 mg iv), the central administration of luteinizing hormone-releasing hormone still produced a marked inhibition of luteinizing hormone secretion. Again, mean luteinizing hormone levels and luteinizing hormone pulse frequency were reduced significantly. When naloxone was injected iv, there was a significant rise in mean luteinizing hormone levels as a consequence of an increase in pulse frequency (in four out of five ewes) and a significant increase in luteinizing hormone pulse amplitude. In conclusion, these data suggest that central opioid pathways sensitive to blockade by naloxone are not involved in the luteinizing hormone-releasing hormone-induced inhibition of luteinizing hormone release. Furthermore, in the long-term ovariectomized ewe, endogenous opioid peptides exert a tonic inhibitory influence on luteinizing hormone-releasing hormone/luteinizing hormone secretion.
RESUMEN
Neurons immunoreactive for neuropeptide Y (NPY) are abundant in the hypophysiotrophic areas of the brain. In particular, there is considerable anatomical evidence for the influence of this neuropeptide on the reproductive and hypothalamo-pituitary-adrenal axes. We therefore investigated whether central administration of NPY can alter the activities of the reproductive and hypothalamopituitary-adrenal axes in the ewe, and whether ovarian steroids are involved in the modulation of these events. We also attempted to investigate whether endogenous NPY is important in the control of luteinizing hormone-releasing hormone/luteinizing hormone (LHRH/LH) secretion in the sheep oestrous cycle. Central injection of NPY (0.15 and 1.5 nmol in 50 microliters saline), delivered by gravity flow into the third cerebral ventricle, had no effect on LH levels in ovariectomized (OVX) ewes (n = 6) or OVX ewes implanted with oestradiol (OVX/E2) (n = 7), nor was LH secretion altered by central NPY (1.5 nmol) in intact cycling animals in either the follicular or the luteal phase (n = 5). However, central administration of 1.5 nmol NPY to intact ewes during both the follicular (P < 0.05) and the luteal phase (P < 0.01), and in OVX/E2 ewes (P < 0.05) caused a large and significant increase in plasma cortisol levels. High titre antibodies were raised to NPY in sheep and the effects of peripheral and central (intracerebroventricular) administration of anti-NPY antibodies on the timing and/or characteristics of the E2-induced LH surge in anoestrous ewes and of the preovulatory surge of LH in cycling ewes were determined. Intravenous administration of anti-NPY antibodies (n = 6) had no effect on the oestradiol benzoate-induced LH surge, compared with the control injection of non-immune plasma (n = 6). Likewise, passive systemic immunization against NPY (n = 10) was without effect on the characteristics of the preovulatory LH surge, compared with the control group (n = 10). However, central (intracerebroventricular) administration of anti-NPY antibodies (n = 4) delayed or abolished the preovulatory LH surge when compared with non-immune plasma treatment in the same animals. In summary, tonic LHRH/LH secretion is unaffected by centrally administered NPY at the doses used in this study. However, the same doses of NPY activate the hypothalamo-pituitary-adrenal axis, thus lending clear support to the hypothesis that NPY is involved in the multifactorial regulation of adrenocorticotrophin and cortisol secretion in this species, probably by stimulating corticotrophin-releasing hormone and/or arginine vasopressin secretion within the hypothalamus.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Estro/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Hormona Luteinizante/metabolismo , Neuropéptido Y/farmacología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Animales , Estradiol/farmacología , Femenino , Hidrocortisona/sangre , Inmunización Pasiva , Inyecciones Intraventriculares , Hormona Luteinizante/sangre , Neuropéptido Y/inmunología , Neuropéptido Y/fisiología , Ovariectomía , OvinosRESUMEN
Corticotrophin-releasing factor (CRF) and arginine vasopressin (AVP) are the primary neuropeptides regulating the secretion of ACTH from the anterior pituitary gland during fetal and adult life. However, a number of other neuropeptides including neuropeptide-Y (NPY) appear to modulate the activity of this system. The potential role of NPY in the regulation of pituitary-adrenal function was examined in fetal and adult sheep. Administration of NPY (6.5 micrograms) as a bolus injection into the third cerebral ventricle of adult ewes elicited a significant (P < 0.05) increase in plasma concentrations of ACTH. In fetal sheep at day 125 gestation (term = 145 days) a five-fold higher dose (30 micrograms) of NPY injected into the lateral cerebral ventricles also caused a significant increase in plasma concentrations of ACTH. The potential of NPY to influence ACTH secretion directly from the pituitary gland was investigated using primary cultures of fetal (day 130 gestation) and adult pituitary cells. CRF (10(-10)-10(-7) M) caused a significant (P < 0.01) dose-related increase in ACTH secretion from both fetal and adult pituitary cells. Furthermore, the secretion of ACTH from adult cells was significantly greater (P < 0.05) than that from fetal cells. NPY (10(-10)-10(-7) M) had no effect on basal or CRF-stimulated ACTH secretion from fetal or adult pituitary cells. Pre-incubation of pituitary cells with cortisol (10(-9) and 10(-7) M) for three days significantly inhibited CRF-stimulated ACTH secretion but had no effect on basal ACTH release. The simultaneous addition of NPY did not alter the ability of cortisol to inhibit CRF-stimulated ACTH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Neuropéptido Y/farmacología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Hormona Adrenocorticotrópica/sangre , Animales , Células Cultivadas , Retroalimentación , Femenino , Feto/fisiología , Glucocorticoides/sangre , Inyecciones Intraventriculares , Neuropéptido Y/administración & dosificación , Adenohipófisis/citología , Adenohipófisis/efectos de los fármacos , Adenohipófisis/metabolismo , Embarazo , Ovinos , Estimulación QuímicaRESUMEN
Inhalation of silica dust is associated with pulmonary fibrosis. Therefore, substitute abrasive materials have been suggested for use in abrasive blasting operations. To date, toxicological evaluation of most substitute abrasives has been incomplete. Therefore, the objective of this study was to compare the pulmonary toxicity of a set of substitute abrasives (garnet, staurolite, coal slag, specular hematite, and treated sand) to that of blasting sand. Rats were exposed to blasting sand or an abrasive substitute by intratracheal instillation and pulmonary responses to exposure were monitored 4 weeks postexposure. Pulmonary damage was monitored as lactate dehydrogenase (LDH) in the acellular lavage fluid. Pulmonary inflammation was evaluated from the yield of polymorphonuclear leukocytes (PMN) obtained by bronchoalveolar lavage. The activity of alveolar macrophages was determined by measuring zymosan-stimulated chemiluminescence. Blasting sand caused lung damage and showed histologic evidence for inflammation and fibrosis. Garnet, staurolite, and treated sand exhibited toxicity and inflammation that were similar to blasting sand, while coal slag caused greater pulmonary damage and inflammation than blasting sand. In contrast, specular hematite did not significantly elevate LDH or PMN levels and did not stimulate macrophage activity 4 weeks postexposure.
Asunto(s)
Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Carbón Mineral/toxicidad , Compuestos Férricos/toxicidad , L-Lactato Deshidrogenasa/química , Pulmón/citología , Pulmón/enzimología , Minerales/toxicidad , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/enzimología , Fibrosis Pulmonar/patología , Dióxido de Silicio/toxicidad , Animales , Carbón Mineral/análisis , Compuestos Férricos/análisis , Macrófagos Alveolares/enzimología , Macrófagos Alveolares/patología , Masculino , Microscopía Electrónica de Rastreo , Minerales/análisis , Neutrófilos/enzimología , Neutrófilos/patología , Ratas , Ratas Sprague-Dawley , Dióxido de Silicio/análisisRESUMEN
Exposure of the lung to lipopolysaccharide (LPS) or silica results in an activation of alveolar macrophages (AMs), recruitment of polymorphonuclear leukocytes (PMNs) into bronchoalveolar spaces, and the production of free radicals. Nitric oxide (NO) is one of the free radicals generated by bronchoalveolar lavage (BAL) cell populations following either LPS or silica exposure. The purpose of the present study was to assess the relative contributions of AMs and PMNs to the amounts of NO produced by BAL cells following intratracheal (IT) instillation of either LPS or silica. Male Sprague Dawley rats (265-340 g body wt.) were given LPS (10 mg/100 g body wt.) or silica (5 mg/100 g body wt.). BAL cells were harvested 18-24 h post-IT and enriched for AMs or PMNs using density gradient centrifugation. Media levels of nitrate and nitrite (NOx; the stable decomposition products of NO) were then measured 18 h after ex vivo culture of these cells. Following IT exposure to either LPS or silica, BAL cell populations were approximately 20% AMs and approximately 80% PMNs. After density gradient centrifugation of BAL cells from LPS- or silica-treated rats, cell fractions were obtained which were relatively enriched for AMs (approximately 60%) or PMNs (approximately 90%). The amounts of NOx produced by the AM-enriched fractions from LPS- or silica-treated rats were approximately 2-4-fold greater than that produced by the PMN-enriched fractions. Estimations of the relative contribution of AMs or PMNs to the NOx produced indicated that: (i) following LPS treatment, 75%-89% of the NOx was derived from AMs and 11%-25% from PMNs; and (ii) following silica treatment, 76%-100% of the NOx was derived from AMs and 0-24% from PMNs. Immunohistochemistry for inducible NO synthase on lung tissue sections supported these findings. We conclude that AMs are the major source of the NO produced by BAL cells during acute pulmonary inflammatory responses to LPS or silica.
Asunto(s)
Lipopolisacáridos/toxicidad , Macrófagos Alveolares/metabolismo , Neutrófilos/metabolismo , Óxido Nítrico/biosíntesis , Dióxido de Silicio/toxicidad , Animales , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Recuento de Células , Células Cultivadas , Inmunohistoquímica , Lipopolisacáridos/administración & dosificación , Macrófagos Alveolares/efectos de los fármacos , Masculino , Neutrófilos/efectos de los fármacos , Neutrófilos/enzimología , Nitratos/análisis , Óxido Nítrico Sintasa/metabolismo , Nitritos/análisis , Ratas , Ratas Sprague-Dawley , Dióxido de Silicio/administración & dosificación , Factores de TiempoRESUMEN
Chronic inflammation is a key step in the pathogenesis of particle-elicited fibrosis and lung cancer in rats, and possibly in humans. In this study, we compute the excess risk estimates for lung cancer in humans with occupational exposure to crystalline silica, using both rat and human data, and using both a threshold approach and linear models. From a toxicokinetic/dynamic model fit to lung burden and pulmonary response data from a subchronic inhalation study in rats, we estimated the minimum critical quartz lung burden (Mcrit) associated with reduced pulmonary clearance and increased neutrophilic inflammation. A chronic study in rats was also used to predict the human excess risk of lung cancer at various quartz burdens, including mean Mcrit (0.39 mg/g lung). We used a human kinetic lung model to link the equivalent lung burdens to external exposures in humans. We then computed the excess risk of lung cancer at these external exposures, using data of workers exposed to respirable crystalline silica and using Poisson regression and lifetable analyses. Finally, we compared the lung cancer excess risks estimated from male rat and human data. We found that the rat-based linear model estimates were approximately three times higher than those based on human data (e.g., 2.8% in rats vs. 0.9-1% in humans, at mean Mcrit lung burden or associated mean working lifetime exposure of 0.036 mg/m3). Accounting for variability and uncertainty resulted in 100-1000 times lower estimates of human critical lung burden and airborne exposure. This study illustrates that assumptions about the relevant biological mechanism, animal model, and statistical approach can all influence the magnitude of lung cancer risk estimates in humans exposed to crystalline silica.
Asunto(s)
Contaminantes Ocupacionales del Aire/efectos adversos , Interpretación Estadística de Datos , Neoplasias Pulmonares/etiología , Enfermedades Profesionales/etiología , Exposición Profesional/efectos adversos , Dióxido de Silicio/efectos adversos , Animales , Carga Corporal (Radioterapia) , Modelos Animales de Enfermedad , Humanos , Modelos Lineales , Modelos Biológicos , Ratas , Medición de Riesgo , Factores de Riesgo , Valores Limites del UmbralRESUMEN
Previous studies have determined that alpha-quartz (crystalline silica) can cause pulmonary inflammation, damage, and fibrosis. However, the temporal relationship between silica inhalation and pulmonary inflammation, damage, and fibrosis has not been fully examined. To address this gap in our knowledge of silica-induced pulmonary fibrosis, a chronic inhalation study using rats was designed. Specifically, rats were exposed to a silica aerosol (15 mg/m3 silica, 6 h/d, 5 d/wk, 116 d), and measurements of pulmonary inflammation, damage, and fibrosis were monitored throughout the study. We report (1) data demonstrating that the silica aerosol generation and exposure system produced a consistent silica aerosol of respirable size particles; (2) the time course of silica deposition in the lung; (3) calculations that demonstrate that the rats were not in pulmonary overload; (4) histopathological data demonstrating time-dependent enhancement of silica-induced alveolitis, epithelial hypertrophy and hyperplasia, alveolar lipoproteinosis, and pulmonary fibrosis in the absence of overload; and (5) biochemical data documenting the development of lipidosis, lung damage, and fibrosis.
Asunto(s)
Contaminantes Ocupacionales del Aire/toxicidad , Pulmón/efectos de los fármacos , Fibrosis Pulmonar/inducido químicamente , Dióxido de Silicio/toxicidad , Administración por Inhalación , Animales , Carga Corporal (Radioterapia) , Lavado Broncoalveolar , Lipidosis/inducido químicamente , Pulmón/patología , Masculino , Tamaño de la Partícula , Fibrosis Pulmonar/patología , Ratas , Ratas Endogámicas F344 , Dióxido de Silicio/administración & dosificación , Organismos Libres de Patógenos Específicos , Factores de TiempoRESUMEN
Although endotoxin is a known potent stimulant of inflammatory responses, the magnitude of pulmonary response following exposure to various organic dusts does not always correlate with endotoxin content of the dusts alone. Other components, such as 1-->3-beta-glucans, derived from the inner cell wall of yeasts and fungi, have been implicated in organic dust toxic syndrome. However, animal studies report conflicting results concerning the inflammatory potency of 1-->3-beta-glucan. In this experiment, the pulmonary reaction of rats to 1-->3-beta-glucan (zymosan A) exposure was assessed. Male Sprague-Dawley rats were exposed via intratracheal instillation (IT) to zymosan A (dose range 0-5 mg/kg body weight). Rats were sacrificed 1-7 d postexposure and the following pulmonary responses were monitored: (1) breathing frequency, (2) differential cell counts of hronchoalveolar lavage (BAL) cells, (3) chemiluminescence (CL) as a measure of alveolar macrophage activation, (4) nitric oxide production by alveolar macrophages, (5) albumin levels, and (6) lactate dehydrogenase (LDH) activity in the first acellular lavage fluid. Upon challenge with zymosan A, rats exhibited a dose-dependent pulmonary response at 1 d post IT that was significantly higher than the control level at a dose of 1-2.5 mg/kg body weight for each of these pulmonary parameters. Post-IT enhancement of breathing frequencies and polymorphonuclear leukocytes (PMN) obtained by BAL both correlated very well with zymosan A concentration (r = .95 and .99, respectively). Elevation of albumin levels and LDH activity of the acellular BAL fluid also correlated (r = .80) with the dose of zymosan. The recovery from a single intratracheal administration of zymosan A (2.5 mg/kg body weight) was monitored over 7 d. PMN and CL showed significant recovery from d 1 level by 3 d postexposure. Breathing frequencies and nitric oxide production showed significant recovery from d 1 level by 4 d postexposure. A good correlation (r2= .8) between recovery of PMN in BAL, CL, or nitric oxide production and the days postexposure was observed.
Asunto(s)
Inflamación , Macrófagos Alveolares/efectos de los fármacos , Respiración/efectos de los fármacos , Zimosan/efectos adversos , Animales , Lavado Broncoalveolar , Relación Dosis-Respuesta a Droga , Polvo , Mediciones Luminiscentes , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Óxido Nítrico/análisis , Ratas , Ratas Sprague-Dawley , Albúmina Sérica/análisis , Tráquea/efectos de los fármacos , Zimosan/farmacologíaRESUMEN
Several cases of interstitial lung disease have been diagnosed among workers at a nylon flock plant, but the etiologic agent for the disease outbreak was unknown. The results of a medical survey and industrial hygiene study indicated that the dust present in the plant may be responsible. Thus, airborne dust collected at the plant was examined for its inflammatory potential in rat lungs. The endpoints measured were: (1) breathing rates, (2) differential cell counts of bronchoalveolar lavage cells, (3) alveolar macrophage (AM) chemiluminescence, (4) albumin concentration and matrix metalloprotease activities in the acellular fluid from the initial bronchoalveolar lavage, and (5) pulmonary histopathology. In the first study, rats received a single dose of the airborne dust sample (10 mg/kg body weight) by intratracheal (IT) instillation. At 1 d post-IT, all inflammatory endpoints were significantly increased versus controls, but by 29 d post-IT they did not differ significantly from controls. Histopathology demonstrated mild to moderate, multifocal, suppurative pneumonia, usually centered around bronchioles, at 1 d post-IT. At 29 d post-IT, pulmonary inflammation was minimal to mild and characterized by alveolar histocytosis usually restricted to the immediate area of retained bire-fringent fibers. In subsequent experiments, airborne dust was extracted with water and the dust (washed airborne dust) and water extract (soluble fraction) were separated by centrifugation for further study. Nylon tow dust was prepared in the laboratory by milling uncut nylon strands (called tow) that had not been treated with the finish or dyes that are commonly used in the flock plants. Rats were administered a single dose of a dust sample (10 mg/kg body weight) or the soluble fraction (1.3 ml/kg body weight) by IT administration and the same endpoints were measured at 1 d post-IT. The dust samples caused significant increases in all of the inflammatory endpoints; however, the soluble fraction was much less active. Histological analysis of the lungs 1 d post-IT confirmed lung inflammation was occurring and tended to center around bronchioles. The results suggest that: (1) nylon flocking generates particles of respirable size that can interact with AM in the lung and can be detected in the lung 29 d after exposure, (2) the dust samples examined cause an inflammatory response, (3) water-extractable agent(s) from airborne dust contribute only minimally to the inflammatory response, and (4) the acute inflammatory response to these dusts is substantial when compared to other pathologic occupational dusts previously examined in our laboratory.
Asunto(s)
Contaminantes Ocupacionales del Aire/toxicidad , Enfermedades Pulmonares Intersticiales/inducido químicamente , Nylons/toxicidad , Industria Textil , Enfermedad Aguda , Contaminantes Ocupacionales del Aire/análisis , Animales , Líquido del Lavado Bronquioalveolar/citología , Endotoxinas/análisis , Endotoxinas/toxicidad , Mediciones Luminiscentes , Pulmón/metabolismo , Pulmón/patología , Macrófagos Alveolares/efectos de los fármacos , Masculino , Metaloendopeptidasas/metabolismo , Nylons/análisis , Ratas , Ratas Sprague-Dawley , Albúmina Sérica/metabolismoRESUMEN
While it is widely believed that taurine may play an important role in protecting cells against toxic injury by functioning as an antioxidant, there is a lack of evidence to support this hypothesis. In this study, electron spin resonance (ESR) was used to investigate the reaction of taurine and hypotaurine with hydroxyl radicals (.OH). The Fenton reaction (Fe(II) + H2O2-->Fe(III) + .OH + OH-) and the Cr(V)-mediated Fenton-like reaction (Cr(V) + H2O2-->Cr(VI) + .OH + OH-) were used as sources of .OH radicals. The results show that hypotaurine but not taurine effectively scavenges .OH radicals with a reaction rate constant of k = 1.6 x 10(10) M-1s-1. That is comparable with other efficient .OH radical scavengers. The effect of taurine and hypotaurine on silica-induced lipid peroxidation was evaluated using linoleic acid as a model lipid. Hypotaurine, but not taurine, caused a significant inhibition of silica-induced lipid peroxidation. The results show that hypotaurine is an excellent antioxidant and appears to have the potential for being a therapeutic agent against silica-induced lung injury.