Faculty Bibliography

Inhalation of ozone (O3), a common environmental pollutant, causes pulmonary injury, pulmonary inflammation, and airway hyperresponsiveness (AHR) in healthy individuals and exacerbates many of these same sequelae in individuals with preexisting lung disease. However, the mechanisms underlying these phenomena are poorly understood. Consequently, we sought to determine the contribution of osteopontin (OPN), a hormone and a pleiotropic cytokine, to the development of O3-induced pulmonary injury, pulmonary inflammation, and AHR. To that end, we examined indices of these aforementioned sequelae in mice genetically deficient in OPN and in wild-type, C57BL/6 mice 24 h following the cessation of an acute (3 h) exposure to filtered room air (air) or O3 (2 parts/million). In wild-type mice, O3 exposure increased bronchoalveolar lavage fluid (BALF) OPN, whereas immunohistochemical analysis demonstrated that there were no differences in the number of OPN-positive alveolar macrophages between air- and O3-exposed wild-type mice. O3 exposure also increased BALF epithelial cells, protein, and neutrophils in wild-type and OPN-deficient mice compared with genotype-matched, air-exposed controls. However, following O3 exposure, BALF neutrophils were significantly reduced in OPN-deficient compared with wild-type mice. When airway responsiveness to inhaled acetyl-beta-methylcholine chloride (methacholine) was assessed using the forced oscillation technique, O3 exposure caused hyperresponsiveness to methacholine in the airways and lung parenchyma of wild-type mice, but not OPN-deficient mice. These results demonstrate that OPN is increased in the air spaces following acute exposure to O3 and functionally contributes to the development of O3-induced pulmonary inflammation and airway and lung parenchymal hyperresponsiveness to methacholine.

RATIONALE: Epidemiological studies indicate that exposure to fine particulate matter air pollution mass (PM_2.5) is associated with an increased risk of mortality; Pope et al., noted elevated total and cardiovascular mortality risks of long-term PM_2.5 in the U.S. nationwide American Cancer Society CP-II cohort (2002,2004). However, it is desirable to test these results in another large cohort that addresses participant mobility and estimates pollution exposures on a finer geographic scale. This research seeks to address these issues in the NIH-AARP Diet and Health Cohort. METHODS: The NIH-AARP cohort is an ongoing prospective mortality study of more than a half million people from locations across the U.S. It was begun in 1995-1996, when questionnaires eliciting information on demographic and health related behaviors were mailed to 3.5 million AARP members aged 50 to 71 years residing in 6 U.S. States (California, Florida, Louisiana, New Jersey, North Carolina, and Pennsylvania) and 2 metropolitan areas (Atlanta, GA; and Detroit, MI). Subject residence data were available at the census tract level at study entry. Subjects were censored from the analysis if they changed residence. Using available central site data to interpolate exposures on a census tract level, we fitted the Cox proportional hazard model to estimate hazard ratios and 95% confidence intervals for pollution and mortality using time-dependent exposure of PM_2.5, one-year prior. For this analysis, follow-up began January 1, 2000 and extended to 2006. The individual subject variables included in the model were age, sex, BMI, smoking status, race, alcohol consumption, education level, marital status, and residence region (6 States and 2 metropolitan areas). RESULTS: During the study period, more than 50,000 deaths occurred, including more than 15,000 from cardiovascular disease. Univariate analyses showed weak correlations (R2 < .05) between (log) PM_2.5 and the individual subject covariates of age, race, gender, education, marital status, tobacco use and BMI. Contextual spatial-related variables based on census tract data were not strongly correlated with PM_2.5 (household income, education, income diversity), with the exception of region of residence (R2 < .40). After inclusion of above-noted potential confounders, excess risks (p < .05) were found with increasing PM_2.5 exposure for all-cause and cardiovascular mortality. CONCLUSION: An analysis of mortality among US residents of the NIH-AARP cohort confirms excess total and cardiovascular mortality risks to be associated with long-term exposure to PM_2.5 air pollution

Rationale: The prevalence of obesity continues to increase, and obesity has been associated with increased risk of new incident asthma in children. Ambient air pollution has also been associated with increases in asthma incidence and morbidity. Since asthma and obesity are both inflammatory states it is possible that the adverse effects of air pollution may be enhanced among children with obesity. This potential effect modification of obesity on the association between air pollution and increased asthma morbidity merits further investigation. Methods: We studied the effects of ambient ozone exposure on pulmonary function in a cohort of 2,239 children with asthma, ages 6 to 18, in New York State. Pulmonary function testing occurred over a 4 year period from January 2006 to May 2012. Body mass index (BMI) percentiles were calculated for each child. Those with a BMI from the 85th up to the 95th percentile were considered overweight and those at the 95th percentile or greater were considered obese. Eight-hour maximum ozone levels were obtained from U.S. Environmental Protection Agency's local area monitoring stations on day of and 1, 2 and 3 days (lag 0- to 3-day) prior to the day of testing for each subject. Generalized estimating equations were used to assess the effect of ozone exposures (average lag-0 to lag-3, 8-hour maximum) on pulmonary function as well as to determine whether obesity status modified these effects. Results: The mean age of the study population was 10.5 +/- 3.3 (SD); 53% of subjects were male; 18.7% of subjects were overweight and 22.4% were obese. Average pulmonary function measures for children with normal BMI and for the combination of overweight and obese subjects are shown in Table 1. Conclusions: Acute exposures to ambient ozone were associated with changes in pulmonary function among children with asthma. Increased obstruction following acute exposures to ambient ozone is positively modified by weight status. These results indicate that overweight or obese children may have increased sensitivity to the adverse pulmonary effects of air pollution exposure. (Figure Presented)

Background: Asthma is a growing epidemic in the United States. Associations of acute air pollution with asthma hospital admissions have been shown to be modified by co-morbid conditions. However, no known previous study has investigated the modifying effects of concurrent respiratory infections, specifically bronchitis and upper respiratory infection (URI), on these associations. Methods: Data for 105,914 unscheduled hospital admissions in New York City with a primary diagnosis of asthma were obtained for years 2003-2006. A Poisson generalized linear model was applied to determine the association of inter-quartile increases in daily ambient air pollution (i.e., PM2.5, NO2, SO2, and O3) exposures with asthma hospital admissions, after controlling for meteorological and temporal variables. Stratified analyses were conducted for admissions with secondary diagnoses of bronchitis and URI, respectively. Results: Air pollution associations of asthma admissions with a secondary diagnosis of bronchitis were significantly higher vs. admissions without a secondary diagnosis of bronchitis (e.g., PM2.5 risk ratios are 1.19 (95% CI = 1.07-1.30) with bronchitis vs. 1.05 (95% CI = 1.02-1.07) without bronchitis). However, secondary diagnoses of URI did not modify the associations of air pollutants with asthma hospital admissions. These results were observed across multiple pollutants and age groups. Discussion: There is an increased risk of air pollution related asthma hospital admission among individuals with bronchitis, but not with URI. The identification of differential risks based on infection of the bronchioles, but not the upper respiratory tract, provides an opportunity for further investigation into the mechanisms by which air pollution affects respiratory function

We describe spatial and temporal patterns of seven chemical elements commonly observed in fine particulate matter (PM) and thought to be linked to roadway emissions that were measured at residential locations in New York City (NYC). These elements, that is, Si, Al, Ti, Fe, Ba, Br, and black carbon (BC), were found to have significant spatial and temporal variability at our 10 residential PM(2.5) sampling locations. We also describe pilot study data of near-roadway samples of both PM(10-2.5) and PM(2.5) chemical elements of roadway emissions. PM(2.5) element concentrations collected on the George Washington Bridge (GWB) connecting NYC and New Jersey were higher that similar elemental concentration measured at residential locations. Coarse-particle elements (within PM(10-2.5)) on the GWB were 10-100 times higher in concentration than their PM(2.5) counterparts. Roadway elements were well correlated with one another in both the PM(2.5) and PM(10-2.5) fractions, suggesting common sources. The same elements in the PM(2.5) collected at residential locations were less correlated, suggesting either different sources or different processing mechanisms for each element. Despite the fact that these elements are only a fraction of total PM(2.5) or PM(10-2.5) mass, the results have important implications for near-roadway exposures where elements with known causal links to health effects are shown to be at elevated concentrations in both the PM(2.5) and PM(10-2.5) size ranges.

Palmitoyl-lysophosphatidylcholine promotes a transient calcium influx in lymphoma cells. Previously, it was observed that this influx was accompanied by a temporary increase in propidium iodide permeability that appeared linked to calcium entry. Those studies demonstrated that cobalt or nickel could block the response to lysophosphatidylcholine and raised the question of whether the calcium conductance involved specific channels. This communication describes a series of experiments to address that issue. The time dependence and structural specificity of the responses to lysophosphatidylcholine reinforced the hypothesis of a specific channel or transporter. Nevertheless, observations using patch clamp or calcium channel blockers suggested that this "channel" does not involve proteins. Alternative protein-mediated mechanisms such as indirect involvement of the sodium-calcium exchanger and the sodium-potassium ATPase were also excluded. Experiments with extracellular and intracellular calcium chelators suggested a common route of entry for calcium and propidium iodide. More directly, the ability of lysophosphatidylcholine to produce cobalt-sensitive permeability to propidium iodide was reproduced in protein-free artificial membranes. Finally, the transient nature of the calcium time course was rationalized quantitatively by the kinetics of lysophosphatidylcholine metabolism. These results suggest that physiological concentrations of lysophosphatidylcholine can directly produce membrane pores that mimic some of the properties of specific protein channels.