Dataset Information

Exposure to diesel exhaust up-regulates iNOS expression in ApoE knockout mice.

ABSTRACT: Traffic related particulate matter air pollution is a risk factor for cardiovascular events; however, the biological mechanisms are unclear. We hypothesize that diesel exhaust (DE) inhalation induces up-regulation of inducible nitric oxide synthase (iNOS), which is known to contribute to vascular dysfunction, progression of atherosclerosis and ultimately cardiovascular morbidity and mortality.ApoE knockout mice (30-week) were exposed to DE (at 200 ?g/m³ of particulate matter) or filtered-air (control) for 7 weeks (6 h/day, 5 days/week). iNOS expression in the blood vessels and heart was evaluated by immunohistochemistry and western blotting analysis. To examine iNOS activity, thoracic aortae were mounted in a wire myograph, and vasoconstriction stimulated by phenylephrine (PE) was measured with and without the presence of the specific inhibitor for iNOS (1400 W). NF-?B (p65) activity was examined by ELISA. The mRNA expression of iNOS and NF-?B (p65) was determined by real-time PCR.DE exposure significantly enhanced iNOS expression in the thoracic aorta (4-fold) and heart (1.5 fold). DE exposure significantly attenuated PE-stimulated vasoconstriction by ~20%, which was partly reversed by 1400 W. The mRNA expression of iNOS and NF-?B was significantly augmented after DE exposure. NF-?B activity was enhanced 2-fold after DE inhalation, and the augmented NF-?B activity was positively correlated with iNOS expression (R²=0.5998).We show that exposure to DE increases iNOS expression and activity possibly via NF-?B-mediated pathway. We suspect that DE exposure-caused up-regulation of iNOS contributes to vascular dysfunction and atherogenesis, which could ultimately lead to urban air pollution-associated cardiovascular morbidity and mortality.

SUBMITTER: Bai N

PROVIDER: S-EPMC4528958 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Exposure to diesel exhaust up-regulates iNOS expression in ApoE knockout mice.

Bai Ni N Kido Takashi T Kavanagh Terrance J TJ Kaufman Joel D JD Rosenfeld Michael E ME van Breemen Cornelis C van Eeden Stephan F SF

Toxicology and applied pharmacology 20110623 2

<h4>Unlabelled</h4>Traffic related particulate matter air pollution is a risk factor for cardiovascular events; however, the biological mechanisms are unclear. We hypothesize that diesel exhaust (DE) inhalation induces up-regulation of inducible nitric oxide synthase (iNOS), which is known to contribute to vascular dysfunction, progression of atherosclerosis and ultimately cardiovascular morbidity and mortality.<h4>Methods</h4>ApoE knockout mice (30-week) were exposed to DE (at 200 μg/m³ of part ...[more]

PMID: 21722660

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Project description:BackgroundWhile exposure to diesel exhaust particles has been linked to aberrant immune responses in allergic diseases such as asthma, little attention has been paid to their effects on the airway epithelial barrier. In this study, we sought to determine the effect of diesel exhaust exposure on airway epithelial barrier function and composition using in vitro and in vivo model systems.Methods16HBE14o- human bronchial epithelial cells were grown on collagen coated Transwell inserts and exposed to 5 to 50 μg/cm2 SRM 2975 diesel particulate matter (DEP) suspended in cell culture medium or vehicle controls. Changes in barrier function were assessed by measuring transepithelial electrical resistance (TEER) and permeability to 4 kDa FITC Dextran. Neonatal BALB/c mice were exposed to aerosolized DEP (255 ± 89 μg/m3; 2 h per day for 5 days) and changes in the tight junction protein Tricellulin were assessed 2 weeks post exposure.ResultsA six-hour incubation of epithelial cells with diesel exhaust particles caused a significant concentration-dependent reduction in epithelial barrier integrity as measured by decreased TEER and increased permeability to 4 kDa FITC-Dextran. This reduction in epithelial barrier integrity corresponded to a significant reduction in expression of the tight junction protein Tricellulin. siRNA mediated knockdown of Tricellulin recapitulated changes in barrier function caused by DEP exposure. Neonatal exposure to aerosolized DEP caused a significant reduction in lung Tricellulin 2 weeks post exposure at both the protein and mRNA level.ConclusionShort term exposure to DEP causes a significant reduction in epithelial barrier integrity through a reduction in the tight junction protein Tricellulin. Neonatal exposure to aerosolized DEP caused a significant and sustained reduction in Tricellulin protein and mRNA in the lung, suggesting that early life exposure to inhaled DEP may cause lasting changes in airway epithelial barrier function.

Project description:BackgroundRecent epidemiological studies indicate early-life exposure to pollution particulate is associated with adverse neurodevelopmental outcomes. The need is arising to evaluate the risks conferred by individual components and sources of air pollution to provide a framework for the regulation of the most relevant components for public health protection. Previous studies in rodent models have shown diesel particulate matter has neurotoxic potential and could be a health concern for neurodevelopment. The present study shows an evaluation of pathological and protracted behavioral alterations following neonatal exposure to aerosolized diesel exhaust particles (NIST SRM 1650b). The particular behavioral focus was on temporal control learning, a broad and fundamental cognitive domain in which reward delivery is contingent on a fixed interval schedule. For this purpose, C57BL/6?J mice were exposed to aerosolized NIST SRM 1650b, a well-characterized diesel particulate material, from postnatal days 4-7 and 10-13, for four hours per day. Pathological features, including glial fibrillary-acidic protein, myelin basic protein expression in the corpus callosum, and ventriculomegaly, as well as learning alterations were measured to determine the extent to which NIST SRM 1650b would induce developmental neurotoxicity.ResultsTwenty-four hours following exposure significant increases in glial-fibrillary acidic protein (GFAP) in the corpus callosum and cortex of exposed male mice were present. Additionally, the body weights of juvenile and early adult diesel particle exposed males were lower than controls, although the difference was not statistically significant. No treatment-related differences in males or females on overall locomotor activity or temporal learning during adulthood were observed in response to diesel particulate exposure.ConclusionWhile some sex and regional-specific pathological alterations in GFAP immunoreactivity suggestive of an inflammatory reaction to SRM 1650b were observed, the lack of protracted behavioral and pathological deficits suggests further clarity is needed on the developmental effects of diesel emissions prior to enacting regulatory guidelines.

Dataset Information

Exposure to diesel exhaust up-regulates iNOS expression in ApoE knockout mice.

Publications

Exposure to diesel exhaust up-regulates iNOS expression in ApoE knockout mice.

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