Faculty Bibliography

Rescue workers and residents exposed to the environment surrounding the collapse of the World Trade Center (WTC) on September 11, 2001, have suffered a disproportionate incidence of chronic lung disease attributed to the inhalation of airborne dust. To date, the pathophysiology of this lung disease is poorly understood. The aim of this study was to examine whether airborne dust contaminants recovered from the surrounding area 24-48 h after the collapse of the WTC demonstrate direct cytotoxicity to two airway cell types that were most directly exposed to inhaled dust, airway epithelial and smooth muscle cells. It was also of interest to determine whether the presence of these dusts could modulate the effects of cigarette smoke on these cell types in that some of the individuals who responded to the collapse site were also smokers. Human cultured airway epithelial (BEAS-2B) cells were exposed to 10% cigarette smoke extract (CSE), WTC dust particles (10-53 mum; 0.01-0.5 mug/mul), or a combination of the two for 2-24 h. Cell viability was measured by determining mitochondrial integrity (MTT assays) and apoptosis (poly-ADP-ribose polymerase [PARP] immunoblotting). Conditioned cell culture media recovered from the CSE- and/or WTC dust-exposed BEAS-2B cells were then applied to cultured human airway smooth muscle cells that were subsequently assayed for mitochondrial integrity and their ability to synthesize cyclic AMP (a regulator of airway smooth muscle constriction). BEAS-2B cells underwent necrotic cell death following exposure to WTC dust or CSE for 2-24 h without evidence of apoptosis. Smooth muscle cells demonstrated cellular toxicity and enhanced cyclic AMP synthesis following exposure to conditioned media from WTC- or CSE-exposed epithelial cells. These acute toxicity assays of WTC dust and CSE offer insights into lung cell toxicity that may contribute to the pathophysiology of chronic lung disease in workers and residents exposed to WTC dust. These studies clearly showed that WTC dust (at least the supercoarse particle fraction) or CSE alone exerted direct adverse effects on airway epithelial and smooth muscle cells, and altered the signaling properties of airway smooth muscle cells. In addition the combination of CSE and WTC exerted an interactive effect on cell toxicity. It remains to be determined whether these initial cell death events might account, in part, for the chronic lung effects associated with WTC dust exposure among First Responders and others

BACKGROUND: The use of nanoparticles (NPs) in technological applications is rapidly expanding, but the potential health effects associated with NP exposure are still largely unknown. Given epidemiological evidence indicating an association between inhaled ambient ultrafine particles and increased risk of cardiovascular disease morbidity and mortality, it has been suggested that exposure to NPs via inhalation may induce similar cardiovascular responses. METHODS: Male C57BL/6 mice were exposed via whole-body inhalation to either filtered air (FA) or nickel hydroxide (NH) NPs (100, 150, or 900 microg/m(3)) for 1, 3, or 5 consecutive days (5 h/day). At 24-h post-exposure, vascular function in response to a vasoconstrictor, phenylephrine (PE), and a vasodilator, acetylcholine (ACh), was measured in the carotid artery. RESULTS: Carotid arteries from mice exposed to all concentrations of NH-NPs showed statistically significant differences in graded doses of PE-induced contractile responses compared with those from FA mice. Similarly, vessels from NH-NP-exposed mice also demonstrated impaired vasorelaxation following graded doses of ACh as compared with FA mice. CONCLUSIONS: These results suggest that short-term exposure to NH-NPs can induce acute endothelial disruption and alter vasoconstriction and vasorelaxation. These findings are consistent with other studies assessing vascular tone and function in the aorta, coronary, and mesenteric vessels from mice exposed to motor vehicular exhaust and concentrated ambient particles

OBJECTIVE: To evaluate the role of early-life exposure to airborne fine particulate matter (diameter, <2.5 mum [PM(2.5)]) 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: PM(2.5) 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 p47(phox) (p47(phox-/-)) 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. PM(2.5)-exposed C57BL/6 mice fed a normal diet exhibited metabolic abnormalities after exposure to PM(2.5) 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 PM(2.5)-exposed mice. p47(phox-/-) mice exhibited an improvement in parameters of insulin resistance, vascular function, and visceral inflammation in response to PM(2.5). CONCLUSIONS: Early-life exposure to high levels of PM(2.5) 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

While many studies found associations between ambient particulate matter (PM) and morbidity or mortality outcomes, it is unclear whether these associations were dependent on the composition of PM, which varies with the source of that PM. We address this knowledge gap by conducting a time-series PM-health effects assessment that specifically investigates the role of source-apportioned fine PM (PM2.5) on the oxidant generation capacity that might be responsible for respiratory and cardiovascular health outcomes. Daily PM2.5 composition speciation and black carbon (BC) measurements, conducted in rural New York for 303 days between March 2003 and January 2005, were analyzed using factor analysis source-apportionment model, and five source categories (transported aerosol/secondary sulfate, resuspended soil, metals, residual oil combustion, and industrial/incineration) were identified. After the exposure of human epithelial cells (BEAS-2B) to these PM2.5 samples, cellular nuclear factor-kappaB (NF-kappaB) activation showed a relatively significant association Ni (concentration averaging 38 ng/m(3)), and weaker but still significant correlations with Ba (13 ng/m(3)), Mn (9 ng/m(3)), and Fe (500 ng/m(3)). The single-source regression analysis of NF-kappaB signal showed significant association with metal source only. Our results showed that metals in PM2.5 were the important source for cellular oxidant generation and may be responsible for subsequent health effects associate with particle air pollution

INTRODUCTION: Particulate matter (PM), specifically nickel (Ni) found on or in PM, has been associated with an increased risk of mortality in human population studies and significant increases in vascular inflammation, generation of reactive oxygen species, altered vasomotor tone, and potentiated atherosclerosis in murine exposures. Recently, murine inhalation of Ni nanoparticles have been shown to cause pulmonary inflammation that affects cardiovascular tissue and potentiates atherosclerosis. These adverse cardiovascular outcomes may be due to the effects of Ni on endothelial progenitor cells (EPCs), endogenous semi-pluripotent stem cells that aid in endothelial repair. Thus, we hypothesize that Ni nanoparticle exposures decrease cell count and cause impairments in function that may ultimately have significant effects on various cardiovascular diseases, such as, atherosclerosis. METHODS: Experiments involving inhaled Ni nanoparticle exposures (2 days/5 h/day at approximately 1200 microg/m(3), 3 days/5 h/day at approximately 700 microg/m(3), and 5 days/5 h/day at approximately 100 microg/m(3)), were performed in order to quantify bone marrow resident EPCs using flow cytometry in C57BL/6 mice. Plasma levels of human stromal cell-derived factor 1alpha (SDF-1alpha) and vascular endothelial growth factor (VEGF) were assessed by enzyme-linked immunosorbent assay and in vitro functional assessments of cultured EPCs were conducted. RESULTS AND CONCLUSIONS: Significant EPC count differences between exposure and control groups for Ni nanoparticle exposures were observed. Differences in EPC tube formation and chemotaxis were also observed for the Ni nanoparticle exposed group. Plasma VEGF and SDF-1alpha differences were not statistically significant. In conclusion, this study shows that inhalation of Ni nanoparticles results in functionally impaired EPCs and reduced number in the bone marrow, which may lead to enhanced progression of atherosclerosis

Recent studies have suggested a link between inhaled particulate matter (PM) exposure and increased mortality and morbidity associated with pulmonary and cardiovascular diseases. However, a precise understanding of the biological mechanism underlying PM-associated toxicity and pathogenesis remains elusive. Here, we investigated the impact of PM exposure in intracellular stress signaling pathways with animal models and cultured cells. Inhalation exposure of the mice to environmentally relevant fine particulate matter (aerodynamic diameter < 2.5 mum, PM(2.5)) induces endoplasmic reticulum (ER) stress and activation of unfolded protein response (UPR) in the lung and liver tissues as well as in the mouse macrophage cell line RAW264.7. Ambient PM(2.5) exposure activates double-strand RNA-activated protein kinase-like ER kinase (PERK), leading to phosphorylation of translation initiation factor eIF2alpha and induction of C/EBP homologous transcription factor CHOP/GADD153. Activation of PERK-mediated UPR pathway relies on the production of reactive oxygen species (ROS) and is critical for PM(2.5)-induced apoptosis. Furthermore, PM(2.5) exposure can activate ER stress sensor IRE1alpha, but it decreases the activity of IRE1alpha in splicing the mRNA encoding the UPR trans-activator X-box binding protein 1 (XBP1). Together, our study suggests that PM(2.5) exposure differentially activates the UPR branches, leading to ER stress-induced apoptosis through the PERK-eIF2alpha-CHOP UPR branch. This work provides novel insights into the cellular and molecular basis by which ambient PM(2.5) exposure elicits its cytotoxic effects that may be related to air pollution-associated pathogenesis

The World Trade Center (WTC) collapse on September 11, 2001 released copious amounts of particulate matter (PM) into the atmosphere of New York City. Follow-up studies on persons exposed to the dusts have revealed a severely increased rate for asthma and other respiratory illnesses. There have only been a few studies that have sought to discern the possible mechanisms underlying these untoward pathologies. In one study, an increased cytokine release was detected in cells exposed to WTC fine dusts (PM. fraction or WTC.). However, the mechanism(s) for these increases has yet to be fully defined. Because activation of the mitogen-activated protein kinase (MAPK) signaling pathways is known to cause cytokine induction, the current study was undertaken to analyze the possible involvement of these pathways in any increased cytokine formation by lung epithelial cells (as BEAS-2B cells) exposed to WTC.. Our results showed that exposure to WTC. for 5 hr increased interleukin-6 (IL-6) mRNA expression in BEAS-2B cells, as well as its protein levels in the culture media, in a dose-dependent manner. Besides IL-6, cytokine multiplex analyses revealed that formation of IL-8 and -10 was also elevated by the exposure. Both extracellular signal-regulated kinase (ERK) and p38, but not c-Jun N-terminal protein kinase, signaling pathways were found to be activated in cells exposed to WTC.. Inactivation of ERK signaling pathways by PD98059 effectively blocked IL-6, -8, and -10 induction by WTC.; the p38 kinase inhibitor SB203580 significantly decreased induction of IL-8 and -10. Together, our data demonstrated activation of MAPK signaling pathway(s) likely played an important role in the WTC.-induced formation of several inflammatory (and, subsequently, anti-inflammatory) cytokines. The results are important in that they help to define one mechanism via which the WTC dusts may have acted to cause the documented increases in asthma and other inflammation-associated respiratory dysfunctions in the individuals exposed to the dusts released from the WTC collapse

Ambient air PM(2.5) (particulate matter less than 2.5 mum in diameter) has been associated with cardiovascular diseases (CVDs), but the underlying mechanisms affecting CVDs are unknown. The authors investigated whether subchronic inhalation of concentrated ambient PM(2.5) (CAPs), whole diesel exhaust (WDE), or diesel exhaust gases (DEGs) led to exacerbation of atherosclerosis, pulmonary and systemic inflammation, and vascular dysfunction; and whether DEG interactions with CAPs alter cardiovascular effects. ApoE(-/-) mice were simultaneously exposed via inhalation for 5 hours/day, 4 days/week, for up to 5 months to one of five different exposure atmospheres: (1) filtered air (FA); (2) CAPs (105 microg/m(3)); (3) WDE (DEP = 436 microg/m(3)); (4) DEG (equivalent to gas levels in WDE group); and (5) CAPs+DEG (PM(2.5): 113 microg/m(3); with DEG equivalent to WDE group). After 3 and 5 months, lung lavage fluid and blood sera were analyzed, and atherosclerotic plaques were quantified by ultrasound imaging, hematoxylin and eosin (H&E stain), and en face Sudan IV stain. Vascular functions were assessed after 5 months of exposure. The authors showed that (1) subchronic CAPs, WDE, and DEG inhalations increased serum vascular cell adhesion molecule (VCAM)-1 levels and enhanced phenylephrine (PE)-induced vasoconstriction; (2) for plaque exacerbation, CAPs > WDE > DEG = FA, thus PM components (not present in WDE) were responsible for plaque development; (3) atherosclerosis can exacerbated through mechanistic pathways other than inflammation and vascular dysfunction; and (4) although there were no significant interactions between CAPs and DEG on plaque exacerbation, it is less clear whether the effects of CAPs on vasomotor dysfunction and pulmonary/systemic inflammation were enhanced by the DEG coexposure

Personal exposures to fine particulate matter air pollution (PM(2.5)), and to its traffic-related fraction, were investigated in a group of urban children with asthma. The relationships of personal and outdoor school-site measurements of PM(2.5) and elemental carbon (EC) were characterized for a total of 40 fifth-grade children. These students, from four South Bronx, NY schools, each carried air pollution monitoring equipment with them for 24 h per day for approximately 1 month. Daily EC concentrations were estimated using locally calibrated reflectance of the PM(2.5) samples. Personal EC concentration was more closely related to outdoor school-site EC (median subject-specific: r=0.64) than was personal PM(2.5) to school-site PM(2.5) concentration (median subject-specific: r=0.33). Regression models also showed a stronger, more robust association of school site with personal measurements for EC than those for PM(2.5). High traffic pollution exposure was found to coincide with the weekday early morning rush hour, with higher personal exposures for participants living closer to a highway (<500 ft). A significant linear relationship of home distance from a highway with personal EC pollution exposure was also found (up to 1000 ft). This supports the assumptions by previous epidemiological studies using distance from a highway as an index of traffic PM exposure. These results are also consistent with the assumption that traffic, and especially smoke emitted from diesel vehicles, is a significant contributor to personal PM exposure levels in children living in urban areas such as the South Bronx, NY

Ambient PM(2.5) (particulate matter with an aerodynamic diameters of less than 2.5 mum) is associated with alterations in the autonomic nervous system and cardiac function, but there are significant response variations. The authors simultaneously studied the effects of concentrated PM(2.5) (CAPs) in Sterling Forest (SF; dominated by long-range transported PM) and at the Mount Sinai School of Medicine (MS; rich in Ni and elemental/organic carbon [EC/OC]) in Manhattan, NY. ApoE(-/-) mice (n = 8/group) were exposed to filtered air or CAPs (average 133 and 123 microg/m(3) in SF and MS, respectively) for 6 h/day, 5 days/week for 6 months. Electrocardiogram (ECG) tracings were monitored using telemetry. At MS, current day CAPs mass was negatively associated with short-term changes in heart rate (HR), and positively with HR variability (HRV). At SF, CAPs mass was positively associated with HR, and negatively with HRV. At MS, HR and HRV changes were associated with PM(2.5) components associated with residual oil combustion > long-range transport > traffic > FeMn > incineration > soil, and fireworks had no associations. At SF, HR and HRV were associated with long-range transport > Ni refinery > soil > residual oil combustion/traffic. At both sites, there were cardiac function associations with PM(2.5), but not EC. At MS, there were associations with Ni and P, whereas at SF, they were with a mixture of long-range transported PM, crustal material, and combustion products. Thus subchronic CAPs exposures at locations with different particle compositions produced different effects on cardiac function in ApoE(-/-) mice