RESUMEN
Short-term increases in particulate matter (PM) are associated with heightened morbidity and mortality from cardiovascular causes. Inhalation of PM is known to increase endothelin (ET)-1 levels. Yet, less is known about particle composition-related changes at the molecular level including the endothelinergic system and relationship with cardiovascular function changes. In this work, adult Wistar male rats were exposed for 4 h by nose-only inhalation to clean air, Ottawa urban particles (EHC-93, 48 mg/m3) and water-leached (EHC-93L, 49 mg/m3) particles, to examine the effect of particle compositional changes on oxidative stress, circulating ETs, blood pressure, and heart electrophysiology. Particle deposition in the respiratory compartment was estimated at 85 µg (25 ng/cm2). Lung cell proliferation was low in both treatment groups, indicating absence of acute injury. Inhalation of EHC-93 caused statistically significant elevations (p < 0.05) of oxidative stress markers, ET-1, ET-3, blood pressure, and a decrease of ST-segment duration in the ECG at 1.5 days post-exposure. Leached particles (EHC-93L) caused rapid but transient elevation (p < 0.05) of oxidative stress, ET-1, ET-2, and ET-3 at earlier time points, with no changes in blood pressure or ST-segment. These results demonstrate that inhalation of urban particles at an internal dose inadequate to cause acute lung injury can induce oxidative stress, enhance vasoactive endothelins, leading to vasopressor response, affecting cardiac electrophysiology in Wistar rats, consistent with the cardiovascular impacts of ambient particles in human populations. Change in particle potency after removal of soluble species, notably cadmium, zinc and polar organics suggests that the toxicodynamics of cardiovascular effects can be modified by physicochemical properties of particles.
Asunto(s)
Contaminantes Atmosféricos , Material Particulado , Contaminantes Atmosféricos/análisis , Animales , Presión Sanguínea , Endotelina-1/farmacología , Exposición por Inhalación/efectos adversos , Pulmón , Masculino , Estrés Oxidativo , Tamaño de la Partícula , Material Particulado/farmacología , Ratas , Ratas WistarRESUMEN
Tumor necrosis factor (TNF)-alpha, a cytokine present in inflammed lungs, is known to mediate some of the adverse effects of ozone and inhaled particles. The authors evaluated transgenic mice with constitutive pulmonary expression of TNF-alpha under transcriptional regulation of the surfactant protein-C promoter as an animal model of biological susceptibility to air pollutants. To simulate a repeated, episodic exposure to air pollutants, wild-type and TNF mice inhaled air or a mixture of ozone (0.4 ppm) and urban particles (EHC-93, 4.8 mg/m3) for 4 h, once per week, for 12 consecutive weeks and were sacrificed 20 h after last exposure. TNF mice exhibited chronic lung inflammation with septal thickening, alveolar enlargement, and elevated protein and cellularity in bronchoalveolar lavage fluid (genotype main effect, p < .001). Repeated exposure to pollutants did not result in measurable inflammatory changes in wild-type mice and did not exacerbate the inflammation in TNF mice. The pollutants decreased recovery of alveolar macrophages in tavage fluid of both wild-type and TNF mice (exposure main effect, p < .001). Exacerbation of the rate of protein nitration reactions specifically in the lungs of TNF mice was revealed by the high ratio of 3-nitrotyrosine to L-DOPA after exposure to the air pollutants (Genotype x Exposure factor interaction, p = .014). Serum creatine kinase-MM isoform increased in TNF mice exposed to pollutants (Genotype X Exposure factor interaction, p = .043). The marked pollutant-related nitration in the lungs of the TNF mice reveals basic differences in free radical generation and scavenging in the inflamed lungs in response to pollutants. Furthermore, elevation of circulating creatine kinase-MM isoform specifically in TNF mice exposed to pollutants suggests systemic adverse impacts from lung inflammatory mediators, possibly on muscles and the cardiovascular system.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Exposición por Inhalación/efectos adversos , Pulmón/efectos de los fármacos , Neumonía/inducido químicamente , Factor de Necrosis Tumoral alfa/metabolismo , Administración por Inhalación , Animales , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Enfermedad Crónica , Creatina Quinasa/sangre , Forma MM de la Creatina-Quinasa , Modelos Animales de Enfermedad , Endotelinas/genética , Endotelinas/metabolismo , Femenino , Isoenzimas/sangre , Pulmón/metabolismo , Pulmón/patología , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neumonía/metabolismo , Neumonía/patología , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Pruebas de Toxicidad , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Altered cytokine production in the lung follows the deposition of urban air particles. The present study was designed to measure changes in tumor necrosis factoralpha (TNFalpha) and endothelin-1 (ET-1) levels in rat lung after instilling various fractions of the dust EHC-93, while in vitro, alveolar macrophages (AMs) and type 2 epithelial cells were studied to determine relative production of these molecules in response to the same particles. Whole dust and its soluble and leached components were instilled into rat lung and the animals were killed at intervals to 2 weeks; they received tritiated thymidine by intraperitoneal injection 1 hour before death. All samples induced some inflammation, with the highest cellular efflux being found by bronchoalveolar lavage 1 day after leached particles. Lung injury, illustrated by protein levels in lavage fluid, was maximal after instilling the soluble fraction and subsequently epithelial regeneration was also maximal in this group. TNFalpha levels were highest after instilling whole dust or its leached fraction at 4 hours and 1 day, and cell culture studies indicated a predominant AM source for this cytokine. ET-1 levels were also increased in BAL from 4 hours to 3 days and were mostly associated with the instillation of leached particles. The results demonstrate that the rapid production/release of TNFalpha and ET-1 after particle deposition is largely due to the insoluble particulate fraction. There appears to be a differential response to whole dust where the soluble components cause some inflammation and epithelial cell necrosis, whereas the leached particles are more likely to react with macrophages to induce the production of proinflammatory cytokines such as TNFalpha.