Lung Chi Chen

Translocation and potential neurological effects of fine and ultrafine particles a critical update

Particulate air pollution has been associated with respiratory and cardiovascular disease. Evidence for cardiovascular and neurodegenerative effects of ambient particles was reviewed as part of a workshop. The purpose of this critical update is to summarize the evidence presented for the mechanisms involved in the translocation of particles from the lung to other organs and to highlight the potential of particles to cause neurodegenerative effects.Fine and ultrafine particles, after deposition on the surfactant film at the air-liquid interface, are displaced by surface forces exerted on them by surfactant film and may then interact with primary target cells upon this displacement. Ultrafine and fine particles can then penetrate through the different tissue compartments of the lungs and eventually reach the capillaries and circulating cells or constituents, e.g. erythrocytes. These particles are then translocated by the circulation to other organs including the liver, the spleen, the kidneys, the heart and the brain, where they may be deposited. It remains to be shown by which mechanisms ultrafine particles penetrate through pulmonary tissue and enter capillaries. In addition to translocation of ultrafine particles through the tissue, fine and coarse particles may be phagocytized by macrophages and dendritic cells which may carry the particles to lymph nodes in the lung or to those closely associated with the lungs. There is the potential for neurodegenerative consequence of particle entry to the brain. Histological evidence of neurodegeneration has been reported in both canine and human brains exposed to high ambient PM levels, suggesting the potential for neurotoxic consequences of PM-CNS entry. PM mediated damage may be caused by the oxidative stress pathway. Thus, oxidative stress due to nutrition, age, genetics among others may increase the susceptibility for neurodegenerative diseases. The relationship between PM exposure and CNS degeneration can also be detected under controlled experimental conditions. Transgenic mice (Apo E -/-), known to have high base line levels of oxidative stress, were exposed by inhalation to well characterized, concentrated ambient air pollution. Morphometric analysis of the CNS indicated unequivocally that the brain is a critical target for PM exposure and implicated oxidative stress as a predisposing factor that links PM exposure and susceptibility to neurodegeneration.Together, these data present evidence for potential translocation of ambient particles on organs distant from the lung and the neurodegenerative consequences of exposure to air pollutants.

Ambient Air Pollution Exaggerates Adipose Inflammation and Insulin Resistance in a Mouse Model of Diet-Induced Obesity

Background— There is a strong link between urbanization and type 2 diabetes mellitus. Although a multitude of mechanisms have been proposed, there are no studies evaluating the impact of ambient air pollutants and the propensity to develop type 2 diabetes mellitus. We hypothesized that exposure to ambient fine particulate matter (<2.5 &mgr;m; PM2.5) exaggerates diet-induced insulin resistance, adipose inflammation, and visceral adiposity. Methods and Results— Male C57BL/6 mice were fed high-fat chow for 10 weeks and randomly assigned to concentrated ambient PM2.5 or filtered air (n=14 per group) for 24 weeks. PM2.5-exposed C57BL/6 mice exhibited marked whole-body insulin resistance, systemic inflammation, and an increase in visceral adiposity. PM2.5 exposure induced signaling abnormalities characteristic of insulin resistance, including decreased Akt and endothelial nitric oxide synthase phosphorylation in the endothelium and increased protein kinase C expression. These abnormalilties were associated with abnormalities in vascular relaxation to insulin and acetylcholine. PM2.5 increased adipose tissue macrophages (F4/80+ cells) in visceral fat expressing higher levels of tumor necrosis factor-α/interleukin-6 and lower interleukin-10/N-acetyl-galactosamine specific lectin 1. To test the impact of PM2.5 in eliciting direct monocyte infiltration into fat, we rendered FVBN mice expressing yellow fluorescent protein (YFP) under control of a monocyte-specific promoter (c-fms, c-fmsYFP) diabetic over 10 weeks and then exposed these mice to PM2.5 or saline intratracheally. PM2.5 induced YFP cell accumulation in visceral fat and potentiated YFP cell adhesion in the microcirculation. Conclusion— PM2.5 exposure exaggerates insulin resistance and visceral inflammation/adiposity. These findings provide a new link between air pollution and type 2 diabetes mellitus.

Cardiovascular effects of nickel in ambient air.

Background Fine particulate matter (FPM) in ambient air causes premature mortality due to cardiac disease in susceptible populations. Objective Our objective in this study was to determine the most influential FPM components. Methods A mouse model of atherosclerosis (ApoE−/−) was exposed to either filtered air or concentrated FPM (CAPs) in Tuxedo, New York (85 μg/m3 average, 6 hr/day, 5 days/week, for 6 months), and the FPM elemental composition was determined for each day. We also examined associations between PM components and mortality for two population studies: National Mortality and Morbidity Air Pollution Study (NMMAPS) and Hong Kong. Results For the CAPs-exposed mice, the average of nickel was 43 ng/m3, but on 14 days, there were Ni peaks at ~ 175 ng/m3 and unusually low FPM and vanadium. For those days, back-trajectory analyses identified a remote Ni point source. Electrocardiographic measurements on CAPs-exposed and sham-exposed mice showed Ni to be significantly associated with acute changes in heart rate and its variability. In NMMAPS, daily mortality rates in the 60 cities with recent speciation data were significantly associated with average Ni and V, but not with other measured species. Also, the Hong Kong sulfur intervention produced sharp drops in sulfur dioxide, Ni, and V, but not other components, corresponding to the intervention-related reduction in cardiovascular and pulmonary mortality. Conclusions Known biological mechanisms cannot account for the significant associations between Ni with the acute cardiac function changes in the mice or with cardiovascular mortality in people at low ambient air concentrations; therefore, further research is needed.

Effects of Metals within Ambient Air Particulate Matter (PM) on Human Health

We review literature providing insights on health-related effects caused by inhalation of ambient air particulate matter (PM) containing metals, emphasizing effects associated with in vivo exposures at or near contemporary atmospheric concentrations. Inhalation of much higher concentrations, and high-level exposures via intratracheal (IT) instillation that inform mechanistic processes, are also reviewed. The most informative studies of effects at realistic exposure levels, in terms of identifying influential individual PM components or source-related mixtures, have been based on (1) human and laboratory animal exposures to concentrated ambient particles (CAPs), and (2) human population studies for which both health-related effects were observed and PM composition data were available for multipollutant regression analyses or source apportionment. Such studies have implicated residual oil fly ash (ROFA) as the most toxic source-related mixture, and Ni and V, which are characteristic tracers of ROFA, as particularly influential components in terms of acute cardiac function changes and excess short-term mortality. There is evidence that other metals within ambient air PM, such as Pb and Zn, also affect human health. Most evidence now available is based on the use of ambient air PM components concentration data, rather than actual exposures, to determine significant associations and/or effects coefficients. Therefore, considerable uncertainties about causality are associated with exposure misclassification and measurement errors. As more PM speciation data and more refined modeling techniques become available, and as more CAPs studies involving PM component analyses are performed, the roles of specific metals and other components within PM will become clearer.

Chronic Fine Particulate Matter Exposure Induces Systemic Vascular Dysfunction via NADPH Oxidase and TLR4 Pathways

Rationale: Chronic exposure to ambient air-borne particulate matter of <2.5 &mgr;m (PM2.5) increases cardiovascular risk. The mechanisms by which inhaled ambient particles are sensed and how these effects are systemically transduced remain elusive. Objective: To investigate the molecular mechanisms by which PM2.5 mediates inflammatory responses in a mouse model of chronic exposure. Methods and Results: Here, we show that chronic exposure to ambient PM2.5 promotes Ly6Chigh inflammatory monocyte egress from bone-marrow and mediates their entry into tissue niches where they generate reactive oxygen species via NADPH oxidase. Toll-like receptor (TLR)4 and Nox2 (gp91phox) deficiency prevented monocyte NADPH oxidase activation in response to PM2.5 and was associated with restoration of systemic vascular dysfunction. TLR4 activation appeared to be a prerequisite for NAPDH oxidase activation as evidenced by reduced p47phox phosphorylation in TLR4 deficient animals. PM2.5 exposure markedly increased oxidized phospholipid derivatives of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC) in bronchioalveolar lavage fluid. Correspondingly, exposure of bone marrow–derived macrophages to oxPAPC but not PAPC recapitulated effects of chronic PM2.5 exposure, whereas TLR4 deficiency attenuated this response. Conclusions: Taken together, our findings suggest that PM2.5 triggers an increase in oxidized phospholipids in lungs that then mediates a systemic cellular inflammatory response through TLR4/NADPH oxidase–dependent mechanisms.

Air Pollution Exposure Potentiates Hypertension Through Reactive Oxygen Species-Mediated Activation of Rho/ROCK

Objective—Fine particulate matter <2.5 &mgr;m (PM2.5) has been implicated in vasoconstriction and potentiation of hypertension in humans. We investigated the effects of short-term exposure to PM2.5 in the angiotensin II (AII) infusion model. Methods and Results—Sprague-Dawley rats were exposed to PM2.5 or filtered air (FA) for 10 weeks. At week 9, minipumps containing AII were implanted and the responses studied over a week. Mean concentration of PM2.5 inside the chamber was 79.1±7.4 &mgr;g/m3. After AII infusion, mean arterial pressure was significantly higher in PM2.5-AII versus FA-AII group. Aortic vasoconstriction to phenylephrine was potentiated with exaggerated relaxation to the Rho-kinase (ROCK) inhibitor Y-27632 and increase in ROCK-1 mRNA levels in the PM2.5-AII group. Superoxide (O2·−) production in aorta was increased in the PM2.5-AII compared to the FA group, inhibitable by apocynin and L-NAME with coordinate upregulation of NAD(P)H oxidase subunits p22phox and p47phox and depletion of tetrahydrobiopterin. In vitro exposure to ultrafine particles (UFP) and PM2.5 was associated with an increase in ROCK activity, phosphorylation of myosin light chain, and myosin phosphatase target subunit (MYPT1). Pretreatment with the nonspecific antioxidant N-Acetylcysteine and the Rho kinase inhibitors (Fasudil and Y-27632) prevented MLC and MYPT-1 phosphorylation by UFP suggesting a O2·−-mediated mechanism for PM2.5 and UFP effects. Conclusions—Short-term air pollution exaggerates hypertension through O2·−-mediated upregulation of the Rho/ROCK pathway.

Effects of Subchronic Exposures to Concentrated Ambient Particles (CAPs) in Mice: V. CAPs Exacerbate Aortic Plaque Development in Hyperlipidemic Mice

Abstract Recent epidemiological studies suggest that long-term exposure to particulate matter (PM) causes chronic effects on the cardiovascular system that result in cumulative increases cardiovascular morbidity and mortality. Since atherosclerosis is a progressive irreversible condition and an underlying cause of many cardiovascular diseases, we hypothesized that long-term exposure to PM causes adverse cardiovascular effects by exacerbating atherosclerosis. In this study, we exposed C57- and ApoE-deficient (ApoE−/−) and ApoE, LDLr (DK)-deficient mice to concentrated ambient PM2.5 for 6 h/day, 5 days/wk, for up to 5 mo. The overall mean exposure concentration for these groups of animals was 110 μ g/m3. The cross-sectional area of the aorta root of DK mice was examined morphologically using confocal microscopy for the severity of lesion, extent of cellularity, and lipid contents. Aortas from the arch to the iliac bifurcations were also sectioned longitudinally and lesion areas were stained with Sudan IV. All DK mice regardless of exposure had developed extensive lesions in the aortic sinus regions, with lesion areas that covered more than 79% of the total area. In male DK mice, the lesion areas in the aortic sinus regions appeared to be enhanced by concentrated ambient particles (CAPs), with changes approaching statistical significance (p = .06). In addition, plaque cellularity was increased by 28% (p = .014, combined), whereas there were no CAPs-associated changes in the lipid content in these mice. When examining the entire aorta opened longitudinally, both the ApoE−/− and DK mice had prominent areas of severe atherosclerosis covering 40% or more of the lumenal surface. Visual examination of all images suggested that plaques tend to form in clusters concentrating near the aortic arch and the iliac bifurcations. Quantitative measurements showed that CAPs exposure increased the percentage of aortic intimal surface covered by grossly discernible atherosclerotic lesion by 57% in the ApoE−/− mice (p = .03). Changes produced by CAPs in male (10% increase) or female DK mice (8% decrease) were not statistically significant. In this study, we have demonstrated that subchronic exposure to CAPs in mice prone to develop atherosclerotic lesions had a significant impact on the size, severity, and composition of aortic plaque.

THE TOXICOLOGY OF INHALED WOODSMOKE

In addition to developing nations relying almost exclusively upon biomass fuels, such as wood for cooking and home heating, North Americans, particularly in Canada and the northwestern and northeastern sections of the United States, have increasingly turned to woodburning as an alternate method for domestic heating because of increasing energy costs. As a result, the number of households using woodburning devices has increased dramatically. This has resulted in an increase in public exposure to indoor and outdoor woodsmoke-associated pollutants, which has prompted widespread concern about the adverse human health consequences that may be associated with prolonged woodsmoke exposure. This mini-review article brings together many of the human and animal studies performed over the last three decades in an attempt to better define the toxicological impact of inhaled woodsmoke on exposed children and adults; particular attention is given to effects upon the immune system. General information regarding occurrence and woodsmoke chemistry is provided so as to set the stage for a better understanding of the toxicological impact. It can be concluded from this review that exposure to woodsmoke, particularly for children, represents a potential health hazard. However, despite its widespread occurrence and apparent human health risks, relatively few studies have focused upon this particular area of research. More laboratory studies aimed at understanding the effects and underlying mechanisms of woodsmoke exposure, particularly on those individuals deemed to be at greatest risk, are badly needed, so that precise human health risks can be defined, appropriate regulatory standards can be set, and accurate decisions can be made concerning the use of current and new woodburning devices.

Effect of Early Particulate Air Pollution Exposure on Obesity in Mice. Role of p47phox

Objective—To evaluate the role of early-life exposure to airborne fine particulate matter (diameter, <2.5 &mgr;m [PM2.5]) pollution on metabolic parameters, inflammation, and adiposity; and to investigate the involvement of oxidative stress pathways in the development of metabolic abnormalities. Methods and Results—PM2.5 inhalation exposure (6 h/d, 5 d/wk) was performed in C57BL/6 mice (wild type) and mice deficient in the cytosolic subunit of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p47phox (p47phox−/−) beginning at the age of 3 weeks for a duration of 10 weeks. Both groups were simultaneously fed a normal diet or a high-fat diet for 10 weeks. PM2.5-exposed C57BL/6 mice fed a normal diet exhibited metabolic abnormalities after exposure to PM2.5 or FA for 10 weeks. Consistent with insulin resistance, these abnormalities included enlarged subcutaneous and visceral fat contents, increased macrophage infiltration in visceral adipose tissue, and vascular dysfunction. Ex vivo-labeled and infused monocytes demonstrated increased adherence in the microcirculation of normal diet- or high-fat diet-fed PM2.5-exposed mice. p47phox−/− mice exhibited an improvement in parameters of insulin resistance, vascular function, and visceral inflammation in response to PM2.5. Conclusion—Early-life exposure to high levels of PM2.5 is a risk factor for subsequent development of insulin resistance, adiposity, and inflammation. Reactive oxygen species generation by NADPH oxidase appears to mediate this risk.

Metal Fume Fever : Characterization of Clinical and Plasma IL-6 Responses in Controlled Human Exposures to Zinc Oxide Fume at and Below the Threshold Limit Value

Results from animal and preliminary human exposure studies have called into question whether the 5 mg/m3 8-hour time-weighted average threshold limit value (TLV) for zinc oxide fume is sufficient to protect workers against metal fume fever. The objectives of this study were to determine the clinical effects of exposures to low concentrations of zinc oxide and to ascertain whether these exposures elevated circulating levels of specific cytokines, which could account for the symptoms of the metal fume fever syndrome. Thirteen resting naive subjects inhaled, on separate days, air and 2.5 and 5 mg/m3 of furnace-generated zinc oxide fume for 2 hours. Subjects recorded symptoms and temperature and had blood drawn before and after each exposure. The mean (+/- SE) maximum rise in oral temperature at 6 to 12 hours after exposure was 1.4 +/- 0.3 degrees F after 5 mg/m3, compared with 0.6 +/- 0.5 degrees F after air exposure (P < 0.05). Mean temperature was also elevated after exposure to 2.5 mg/m3 zinc oxide (1.2 +/- 0.3 degrees F). In a parallel fashion, plasma levels of interleukin 6 (IL-6), a pyrogen, were significantly elevated after exposure to 5 mg/m3 zinc oxide. Mean IL-6 values (pg/mL) at pre-exposure and at 3 and 6 hours post-exposure were 1.9 (+/- 0.6), 2.8 (+/- 0.7), and 2.9 (+/- 0.6), respectively, on the air day and 1.6 (+/- 0.6), 4.4 (+/- 1.2), and 6.4 (+/- 1.1) on the 5 mg/m3 zinc oxide day. Zinc oxide exposure did not significantly affect plasma levels of tumor necrosis factor. Total symptom scores peaked 9 hours after the 5 mg/m3 zinc oxide exposure. Myalgias, cough, and fatigue were the predominant symptoms reported. Inhalation of zinc oxide for 2 hours at the current TLV of 5 mg/m3 produces fever and symptoms along with elevation in plasma IL-6 levels.