The attack on the World Trade Center (WTC) created an acute environmental disaster of enormous magnitude. This study characterizes the environmental exposures resulting from destruction of the WTC and assesses their effects on health. Methods include ambient air sampling; analyses of outdoor and indoor settled dust; high-altitude imaging and modeling of the atmospheric plume; inhalation studies of WTC dust in mice; and clinical examinations, community surveys, and prospective epidemiologic studies of exposed populations. WTC dust was found to consist predominantly (95%) of coarse particles and contained pulverized cement, glass fibers, asbestos, lead, polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and polychlorinated furans and dioxins. Airborne particulate levels were highest immediately after the attack and declined thereafter. Particulate levels decreased sharply with distance from the WTC. Dust pH was highly alkaline (pH 9.0-11.0). Mice exposed to WTC dust showed only moderate pulmonary inflammation but marked bronchial hyperreactivity. Evaluation of 10,116 firefighters showed exposure-related increases in cough and bronchial hyperreactivity. Evaluation of 183 cleanup workers showed new-onset cough (33%), wheeze (18%), and phlegm production (24%). Increased frequency of new-onset cough, wheeze, and shortness of breath were also observed in community residents. Follow-up of 182 pregnant women who were either inside or near the WTC on 11 September showed a 2-fold increase in small-for-gestational-age (SGA) infants. In summary, environmental exposures after the WTC disaster were associated with significant adverse effects on health. The high alkalinity of WTC dust produced bronchial hyperreactivity, persistent cough, and increased risk of asthma. Plausible causes of the observed increase in SGA infants include maternal exposures to PAH and particulates. Future risk of mesothelioma may be increased, particularly among workers and volunteers exposed occupationally to asbestos. Continuing follow-up of all exposed populations is required to document the long-term consequences of the disaster.

BackgroundPopulation-based studies have estimated health risks of short-term exposure to fine particles using mass of PM2.5 (particulate matter ≤ 2.5 μm in aerodynamic diameter) as the indicator. Evidence regarding the toxicity of the chemical components of the PM2.5 mixture is limited.ObjectiveIn this study we investigated the association between hospital admission for cardiovascular disease (CVD) and respiratory disease and the chemical components of PM2.5 in the United States.MethodsWe used a national database comprising daily data for 2000–2006 on emergency hospital admissions for cardiovascular and respiratory outcomes, ambient levels of major PM2.5 chemical components [sulfate, nitrate, silicon, elemental carbon (EC), organic carbon matter (OCM), and sodium and ammonium ions], and weather. Using Bayesian hierarchical statistical models, we estimated the associations between daily levels of PM2.5 components and risk of hospital admissions in 119 U.S. urban communities for 12 million Medicare enrollees (≥ 65 years of age).ResultsIn multiple-pollutant models that adjust for the levels of other pollutants, an interquartile range (IQR) increase in EC was associated with a 0.80% [95% posterior interval (PI), 0.34–1.27%] increase in risk of same-day cardiovascular admissions, and an IQR increase in OCM was associated with a 1.01% (95% PI, 0.04–1.98%) increase in risk of respiratory admissions on the same day. Other components were not associated with cardiovascular or respiratory hospital admissions in multiple-pollutant models.ConclusionsAmbient levels of EC and OCM, which are generated primarily from vehicle emissions, diesel, and wood burning, were associated with the largest risks of emergency hospitalization across the major chemical constituents of PM2.5.

Epidemiologic studies have linked exposure to airborne pollutant particulate matter (PM) with increased cardiopulmonary mortality and morbidity. The mechanisms of PM-mediated lung pathophysiology, however, remain unknown. We tested the hypothesis that PM, via enhanced oxidative stress, disrupts lung endothelial cell (EC) barrier integrity, thereby enhancing organ dysfunction. Using PM collected from Ft. McHenry Tunnel (Baltimore, MD), we assessed PM-mediated changes in transendothelial electrical resistance (TER) (a highly sensitive measure of barrier function), reactive oxygen species (ROS) generation, and p38 mitogen-activated protein kinase (MAPK) activation in human pulmonary artery EC. PM induced significant dose (10-100 mg/ml)-and time (0-10 h)-dependent EC barrier disruption reflected by reduced TER values. Exposure of human lung EC to PM resulted in significant ROS generation, which was directly involved in PM-mediated EC barrier dysfunction, as N-acetyl-cysteine (NAC, 5 mM) pretreatment abolished both ROS production and barrier disruption induced by PM. Furthermore, PM induced p38 MAPK activation and HSP27 phosphorylation, events that were both attenuated by NAC. In addition, PM-induced EC barrier disruption was partially prevented by the p38 MAP kinase inhibitor SB203580 (10 mM) as well as by reduced expression of either p38 MAPK b or HSP27 (siRNA). These results demonstrate that PM induces ROS generation in human lung endothelium, resulting in oxidative stress-mediated EC barrier disruption via p38 MAPK-and HSP27-dependent pathways. These findings support a novel mechanism for PM-induced lung dysfunction and adverse cardiopulmonary outcomes.Keywords: endothelial permeability; HSP27; particulate matter; p38 MAP kinase; ROS Growing epidemiologic evidence supports the linkage of exposure to ambient particulate matter (PM) to deleterious cardiopulmonary health effects and increased cardiopulmonary mortality and morbidity (1). Exposure risk is especially increased in susceptible populations including individuals with asthma, chronic obstructive pulmonary disease (COPD), cardiac arrhythmias, and congestive heart failure (CHF). Various mechanisms have been proposed to explain the cardiopulmonary health effects of PM, including pulmonary and systemic oxidative stress and inflammation (2), enhanced coagulation (3), and altered cardiac autonomic function (4).After inhalation, fine/ultrafine PM passes rapidly into systemic circulation, potentially interacting with endothelial cells (ECs) (5) with induction of atherosclerotic plaque formation (6), endothelium-dependent dilation in the systemic microcirculation (7), and increased oxidative stress in vascular EC via NAD(P)H oxidase and mitochondrial pathways (8). Although the actual mechanism(s) for PM-mediated acceleration of cardiopulmonary events is unknown, it is likely to be multifaceted, with endothelial dysfunction as a critical component.We recently described in a murine model strong evidence for PM-mediated vascular barrier dysfunction with increased prote...

Nitrous acid (HONO) may be generated by heterogeneous reactions of nitrogen dioxide and direct emission from combustion sources. Interactions among nitrogen oxides and ozone are important for outdoor photochemical reactions. However, little is known of indoor HONO levels or the relationship between residential HONO, NO(2), and O(3) concentrations in occupied houses. Six-day integrated indoor and outdoor concentrations of the three pollutants were simultaneously measured in two communities in Southern California using passive samplers. The average indoor HONO concentration was 4.6 ppb, compared to 0.9 ppb for outdoor HONO. Average indoor and outdoor NO(2)concentrations were 28 and 20.1 ppb, respectively. Indoor O(3) concentrations were low (average 14.9 ppb) in comparison to the outdoor levels (average 56.5 ppb). Housing characteristics, including community and presence of a gas range, were significantly associated with indoor NO(2) and HONO concentrations. Indoor HONO levels were closely correlated with indoor NO(2) levels and were about 17% of indoor NO(2) concentrations. Indoor HONO levels were inversely correlated with indoor O(3) levels. The measurements demonstrated the occurrence of substantial residential indoor HONO concentrations and associations among the three indoor air pollutants.

BackgroundExposure to particulate matter (PM) is a significant risk factor for increased cardiopulmonary morbidity and mortality. The mechanism of PM-mediated pathophysiology remains unknown. However, PM is proinflammatory to the endothelium and increases vascular permeability in vitro and in vivo via ROS generation.ObjectivesWe explored the role of tight junction proteins as targets for PM-induced loss of lung endothelial cell (EC) barrier integrity and enhanced cardiopulmonary dysfunction.MethodsChanges in human lung EC monolayer permeability were assessed by Transendothelial Electrical Resistance (TER) in response to PM challenge (collected from Ft. McHenry Tunnel, Baltimore, MD, particle size >0.1 μm). Biochemical assessment of ROS generation and Ca2+ mobilization were also measured.ResultsPM exposure induced tight junction protein Zona occludens-1 (ZO-1) relocation from the cell periphery, which was accompanied by significant reductions in ZO-1 protein levels but not in adherens junction proteins (VE-cadherin and β-catenin). N-acetyl-cysteine (NAC, 5 mM) reduced PM-induced ROS generation in ECs, which further prevented TER decreases and atteneuated ZO-1 degradation. PM also mediated intracellular calcium mobilization via the transient receptor potential cation channel M2 (TRPM2), in a ROS-dependent manner with subsequent activation of the Ca2+-dependent protease calpain. PM-activated calpain is responsible for ZO-1 degradation and EC barrier disruption. Overexpression of ZO-1 attenuated PM-induced endothelial barrier disruption and vascular hyperpermeability in vivo and in vitro.ConclusionsThese results demonstrate that PM induces marked increases in vascular permeability via ROS-mediated calcium leakage via activated TRPM2, and via ZO-1 degradation by activated calpain. These findings support a novel mechanism for PM-induced lung damage and adverse cardiovascular outcomes.

Particulate matter (PM) in ambient air is a risk factor for human respiratory and cardiovascular diseases. The delivery of PM to airway epithelial cells has been linked to release of proinflammatory cytokines; however, the mechanisms of PM-induced inflammatory responses are not well-characterized. This study demonstrates that PM induces cyclooxygenase (COX)-2 expression and IL-6 release through both a reactive oxygen species (ROS)-dependent NF-kappaB pathway and an ROS-independent C/EBPbeta pathway in human bronchial epithelial cells (HBEpCs) in culture. Treatment of HBEpCs with Baltimore PM induced ROS production, COX-2 expression, and IL-6 release. Pretreatment with N-acetylcysteine (NAC) or EUK-134, in a dose-dependent manner, attenuated PM-induced ROS production, COX-2 expression, and IL-6 release. The PM-induced ROS was significantly of mitochondrial origin, as evidenced by increased oxidation of the mitochondrially targeted hydroethidine to hydroxyethidium by reaction with superoxide. Exposure of HBEpCs to PM stimulated phosphorylation of NF-kappaB and C/EBPbeta, while the NF-kappaB inhibitor, Bay11-7082, or C/EBPbeta siRNA attenuated PM-induced COX-2 expression and IL-6 release. Furthermore, NAC or EUK-134 attenuated PM-induced activation of NF-kappaB; however, NAC or EUK-134 had no effect on phosphorylation of C/EBPbeta. In addition, inhibition of COX-2 partly attenuated PM-induced Prostaglandin E2 and IL-6 release.

BackgroundAsthma is a complex disease characterized by airway hyperresponsiveness (AHR) and chronic airway inflammation. Epidemiologic studies have demonstrated that exposures to environmental factors such as ambient particulate matter (PM), a major air pollutant, contribute to increased asthma prevalence and exacerbations.ObjectiveWe investigated pathophysiologic responses to Baltimore, Maryland, ambient PM (median diameter, 1.78 μm) in a murine model of asthma and attempted to identify PM-specific genomic/molecular signatures.MethodsWe exposed ovalbumin (OVA)-sensitized A/J mice intratracheally to PM (20 mg/kg), and assayed both AHR and bronchoalveolar lavage (BAL) on days 1, 4, and 7 after PM exposure. Lung gene expression profiling was analyzed in OVA- and PM-challenged mice.ResultsConsistent with this murine model of asthma, we observed significant increases in airway responsiveness in OVA-treated mice, with PM exposure inducing significant changes in AHR in both naive mice and OVA-induced asthmatic mice. PM evoked eosinophil and neutrophil infiltration into airways, elevated BAL protein content, and stimulated secretion of type 1 T helper (TH1) cytokines [interferon-γ, interleukin-6 (IL-6), tumor necrosis factor-α] and TH2 cytokines (IL-4, IL-5, eotaxin) into murine airways. Furthermore, PM consistently induced expression of genes involved in innate immune responses, chemotaxis, and complement system pathways.ConclusionThis study is consistent with emerging epidemiologic evidence and indicates that PM exposure evokes proinflammatory and allergic molecular signatures that may directly contribute to the asthma susceptibility in naive subjects and increased severity in affected asthmatics.

Purpose Magnetic iron oxide nanoparticles (MNPs) are used as contrast agents for magnetic resonance imaging (MRI) and hyperthermia for cancer treatment. The relationship between MRI signal intensity and cellular iron concentration for many new formulations, particularly MNPs having magnetic properties designed for heating in hyperthermia, is lacking. In this study, we examine the correlation between MRI T2 relaxation time and iron content in cancer cells loaded with various MNP formulations. Materials and methods Human prostate carcinoma DU-145 cells were loaded with starch-coated bionised nanoferrite (BNF), iron oxide (Nanomag® D-SPIO), Feridex™, and dextran-coated Johns Hopkins University (JHU) particles at a target concentration of 50 pg Fe/cell using poly-D-lysine transfection reagent. T2-weighted MRI of serial dilutions of these labelled cells was performed at 9.4 T and iron content quantification was performed using inductively coupled plasma mass spectrometry (ICP-MS). Clonogenic assay was used to characterise cytotoxicity. Results No cytotoxicity was observed at twice the target intracellular iron concentration (~100 pg Fe/cell). ICP-MS revealed highest iron uptake efficiency with BNF and JHU particles, followed by Feridex and Nanomag-D-SPIO, respectively. Imaging data showed a linear correlation between increased intracellular iron concentration and decreased T2 times, with no apparent correlation among MNP magnetic properties. Conclusions This study demonstrates that for the range of nanoparticle concentrations internalised by cancer cells the signal intensity of T2-weighted MRI correlates closely with absolute iron concentration associated with the cells. This correlation may benefit applications for cell-based cancer imaging and therapy including nanoparticle-mediated drug delivery and hyperthermia.