Norbert Staimer

Circulating Biomarkers of Inflammation, Antioxidant Activity, and Platelet Activation Are Associated with Primary Combustion Aerosols in Subjects with Coronary Artery Disease

Background Biomarkers of systemic inflammation have been associated with risk of cardiovascular morbidity and mortality. Objectives We aimed to clarify associations of particulate matter (PM) air pollution with systemic inflammation using models based on size-fractionated PM mass and markers of primary and secondary aerosols. Methods We followed a panel of 29 nonsmoking elderly subjects with a history of coronary artery disease (CAD) living in retirement communities in the Los Angeles, California, air basin. Blood plasma biomarkers were measured weekly over 12 weeks and included C-reactive protein (CRP), fibrinogen, tumor necrosis factor-α (TNF-α) and its soluble receptor-II (sTNF-RII), interleukin-6 (IL-6) and its soluble receptor (IL-6sR), fibrin D-dimer, soluble platelet selectin (sP-selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1), intracellular adhesion molecule-1 (sICAM-1), and myeloperoxidase (MPO). To assess changes in antioxidant capacity, we assayed erythrocyte lysates for glutathione peroxidase-1 (GPx-1) and copper-zinc superoxide dismutase (Cu,Zn-SOD) activities. We measured indoor and outdoor home daily size-fractionated PM mass, and hourly pollutant gases, total particle number (PN), fine PM elemental carbon (EC) and organic carbon (OC), estimated secondary organic aerosol (SOA) and primary OC (OCpri) from total OC, and black carbon (BC). We analyzed data with mixed models controlling for temperature and excluding weeks with infections. Results We found significant positive associations for CRP, IL-6, sTNF-RII, and sP-selectin with outdoor and/or indoor concentrations of quasi-ultrafine PM ≤ 0.25 μm in diameter, EC, OCpri, BC, PN, carbon monoxide, and nitrogen dioxide from the current-day and multiday averages. We found consistent positive but largely nonsignificant coefficients for TNF-α, sVCAM-1, and sICAM-1, but not fibrinogen, IL-6sR, or D-dimer. We found inverse associations for erythrocyte Cu,Zn-SOD with these pollutants and other PM size fractions (0.25–2.5 and 2.5–10 μm). Inverse associations of GPx-1 and MPO with pollutants were largely nonsignificant. Indoor associations were often stronger for estimated indoor EC, OCpri, and PN of outdoor origin than for uncharacterized indoor measurements. There was no evidence for positive associations with SOA. Conclusions Results suggest that traffic emission sources of OCpri and quasi-ultrafine particles lead to increased systemic inflammation and platelet activation and decreased antioxidant enzyme activity in elderly people with CAD.

Air Pollution Exposures and Circulating Biomarkers of Effect in a Susceptible Population: Clues to Potential Causal Component mixtures and mechanisms

Background Mechanisms involving oxidative stress and inflammation have been proposed to explain associations of ambient air pollution with cardiovascular morbidity and mortality. Experimental evidence suggests that organic components and ultrafine particles (UFP) are important. Methods We conducted a panel study of 60 elderly subjects with coronary artery disease living in retirement communities within the Los Angeles, California, air basin. Weekly biomarkers of inflammation included plasma interleukin-6, tumor necrosis factor-α soluble receptor II (sTNF-RII), soluble platelet selectin (sP-selectin), and C-reactive protein (CRP). Biomarkers of erythrocyte antioxidant activity included glutathione peroxidase-1 and superoxide dismutase. Exposures included outdoor home daily particle mass [particulate matter < 0.25, 0.25–2.5, and 2.5–10 μm in aerodynamic diameter (PM0.25, PM0.25–2.5, PM2.5–10)], and hourly elemental and black carbon (EC–BC), estimated primary and secondary organic carbon (OCpri, SOC), particle number (PN), carbon monoxide (CO), and nitrogen oxides–nitrogen dioxide (NOx–NO2). We analyzed the relation of biomarkers to exposures with mixed effects models adjusted for potential confounders. Results Primary combustion markers (EC–BC, OCpri, CO, NOx–NO2), but not SOC, were positively associated with inflammatory biomarkers and inversely associated with erythrocyte anti-oxidant enzymes (n = 578). PN and PM0.25 were more strongly associated with biomarkers than PM0.25–2.5. Associations for all exposures were stronger during cooler periods when only OCpri, PN, and NOx were higher. We found weaker associations with statin (sTNF-RII, CRP) and clopidogrel use (sP-selectin). Conclusions Traffic-related air pollutants are associated with increased systemic inflammation, increased platelet activation, and decreased erythrocyte antioxidant enzyme activity, which may be partly behind air pollutant–related increases in systemic inflammation. Differences in association by particle size, OC fraction, and seasonal period suggest components carried by UFP are important.

Personal and Ambient Air Pollution is Associated with Increased Exhaled Nitric Oxide in Children with Asthma

Background Research has shown associations between pediatric asthma outcomes and airborne particulate matter (PM). The importance of particle components remains to be determined. Methods We followed a panel of 45 schoolchildren with persistent asthma living in Southern California. Subjects were monitored over 10 days with offline fractional exhaled nitric oxide (FeNO), a biomarker of airway inflammation. Personal active sampler exposures included continuous particulate matter < 2.5 μm in aerodynamic diameter (PM2.5), 24-hr PM2.5 elemental and organic carbon (EC, OC), and 24-hr nitrogen dioxide. Ambient exposures included PM2.5, PM2.5 EC and OC, and NO2. Data were analyzed with mixed models controlling for personal temperature, humidity and 10-day period. Results The strongest positive associations were between FeNO and 2-day average pollutant concentrations. Per interquartile range pollutant increase, these were: for 24 μg/m3 personal PM2.5, 1.1 ppb FeNO [95% confidence interval (CI), 0.1–1.9]; for 0.6 μg/m3 personal EC, 0.7 ppb FeNO (95% CI, 0.3–1.1); for 17 ppb personal NO2, 1.6 ppb FeNO (95% CI, 0.4–2.8). Larger associations were found for ambient EC and smaller associations for ambient NO2. Ambient PM2.5 and personal and ambient OC were significant only in subjects taking inhaled corticosteroids (ICS) alone. Subjects taking both ICS and antileukotrienes showed no significant associations. Distributed lag models showed personal PM2.5 in the preceding 5 hr was associated with FeNO. In two-pollutant models, the most robust associations were for personal and ambient EC and NO2, and for personal but not ambient PM2.5. Conclusion PM associations with airway inflammation in asthmatics may be missed using ambient particle mass, which may not sufficiently represent causal pollutant components from fossil fuel combustion.

Traffic-related air pollution and blood pressure in elderly subjects with coronary artery disease.

Background: Associations between blood pressure (BP) and ambient air pollution have been inconsistent. No studies have used ambulatory BP monitoring and outdoor home air-pollutant measurements with time-activity-location data. We address these gaps in a study of 64 elderly subjects with coronary artery disease, living in retirement communities in the Los Angeles basin. Methods: Subjects were followed up for 10 days with hourly waking ambulatory BP monitoring (n = 6539 total measurements), hourly electronic diaries for perceived exertion and location, and real-time activity monitors (actigraphs). We measured hourly outdoor home pollutant gases, particle number, PM2.5, organic carbon, and black carbon. Data were analyzed with mixed models controlling for temperature, posture, actigraph activity, hour, community, and season. Results: We found positive associations of systolic and diastolic BP with air pollutants. The strongest associations were with organic carbon (especially its estimated fossil-fuel- combustion fraction), multiday average exposures, and time periods when subjects were at home. An interquartile increase in 5-day average organic carbon (5.2 &mgr;g/m3) was associated with 8.2 mm Hg higher mean systolic BP (95% confidence interval = 3.0–13.4) and 5.8 mm Hg higher mean diastolic BP (3.0–8.6). Associations of BP with 1–8 hour average air pollution were stronger with reports of moderate to strenuous physical exertion but not with higher actigraph motion. Associations were also stronger among 12 obese subjects. Conclusions: Exposure to primary organic components of fossil fuel combustion near the home were strongly associated with increased ambulatory BP in a population at potential risk of heart attack. Low fitness or obesity may increase the effects of pollutants.

Personal and Ambient Air Pollution Exposures and Lung Function Decrements in Children with Asthma

Background Epidemiologic studies have shown associations between asthma outcomes and outdoor air pollutants such as nitrogen dioxide and particulate matter mass < 2.5 μm in diameter (PM2.5). Independent effects of specific pollutants have been difficult to detect because most studies have relied on highly correlated central-site measurements. Objectives This study was designed to evaluate the relationship of daily changes in percent-predicted forced expiratory volume in 1 sec (FEV1) with personal and ambient air pollutant exposures. Methods For 10 days each, we followed 53 subjects with asthma who were 9–18 years of age and living in the Los Angeles, California, air basin. Subjects self-administered home spirometry in themorning, afternoon, and evening. We measured personal hourly PM2.5 mass, 24-hr PM2.5 elemental and organic carbon (EC–OC), and 24-hr NO2, and the same 24-hr average outdoor central-site(ambient) exposures. We analyzed data with transitional mixed models controlling for personal temperature and humidity, and as-needed β2-agonist inhaler use. Results FEV1 decrements were significantly associated with increasing hourly peak and daily average personal PM2.5, but not ambient PM2.5. Personal NO2 was also inversely associated with FEV1. Ambient NO2 was more weakly associated. We found stronger associations among 37 subjects not taking controller bronchodilators as follows: Personal EC–OC was inversely associated with morning FEV1; for an interquartile increase of 71 μg/m3 1-hr maximum personal PM2.5, overall percent-predicted FEV1 decreased by 1.32% [95% confidence interval (CI), −2.00 to −0.65%]; and for an interquartile increase of 16.8 ppb 2-day average personal NO2, overall percent-predicted FEV1 decreased by 2.45% (95% CI, −3.57 to −1.33%). Associations of both personal PM2.5 and NO2 with FEV1 remained when co-regressed, and both confounded ambient NO2. Conclusions Independent pollutant associations with lung function might be missed using ambient data alone. Different sets of causal components are suggested by independence of FEV1 associations with personal PM2.5 mass from associations with personal NO2.

Associations of primary and secondary organic aerosols with airway and systemic inflammation in an elderly panel cohort.

Background: Exposure-response information about particulate air-pollution constituents is needed to protect sensitive populations. Particulate matter <2.5 mm (PM2.5) components may induce oxidative stress through reactive-oxygen-species generation, including primary organics from combustion sources and secondary organics from photochemically oxidized volatile organic compounds. We evaluated differences in airway versus systemic inflammatory responses to primary versus secondary organic particle components, particle size fractions, and the potential of particles to induce cellular production of reactive oxygen species. Methods: A total of 60 elderly subjects contributed up to 12 weekly measurements of fractional exhaled nitric oxide (NO; airway inflammation biomarker), and plasma interleukin-6 (IL-6; systemic inflammation biomarker). PM2.5 mass fractions were PM0.25 (<0.25 &mgr;m) and PM0.25–2.5 (0.25–2.5 &mgr;m). Primary organic markers included PM2.5 primary organic carbon, and PM0.25 polycyclic aromatic hydrocarbons and hopanes. Secondary organic markers included PM2.5 secondary organic carbon, and PM0.25 water soluble organic carbon and n-alkanoic acids. Gaseous pollutants included carbon monoxide (CO) and nitrogen oxides (NOx; combustion emissions markers), and ozone (O3; photochemistry marker). To assess PM oxidative potential, we exposed rat alveolar macrophages in vitro to aqueous extracts of PM0.25 filters and measured reactive-oxygen-species production. Biomarker associations with exposures were evaluated with mixed-effects models. Results: Secondary organic markers, PM0.25–2.5, and O3 were positively associated with exhaled NO. Primary organic markers, PM0.25, CO, and NOx were positively associated with IL-6. Reactive oxygen species were associated with both outcomes. Conclusions: Particle effects on airway versus systemic inflammation differ by composition, but overall particle potential to induce generation of cellular reactive oxygen species is related to both outcomes.

Association of Biomarkers of Systemic Inflammation with Organic Components and Source Tracers in Quasi-Ultrafine Particles

Background Evidence is needed regarding the air pollutant components and their sources responsible for associations between particle mass concentrations and human cardiovascular outcomes. We previously found associations between circulating biomarkers of inflammation and mass concentrations of quasi-ultrafine particles ≤ 0.25 μm in aerodynamic diameter (PM0.25) in a panel cohort study of 60 elderly subjects with coronary artery disease living in the Los Angeles Basin. Objectives We reassessed biomarker associations with PM0.25 using new particle composition data. Methods Weekly biomarkers of inflammation were plasma interleukin-6 (IL-6) and soluble tumor necrosis factor-α receptor II (sTNF-RII) (n = 578). Exposures included indoor and outdoor community organic PM0.25 constituents [polycyclic aromatic hydrocarbons (PAHs), hopanes, n-alkanes, organic acids, water-soluble organic carbon, and transition metals]. We analyzed the relation between biomarkers and exposures with mixed-effects models adjusted for potential confounders. Results Indoor and outdoor PAHs (low-, medium-, and high-molecular-weight PAHs), followed by hopanes (vehicle emissions tracer), were positively associated with biomarkers, but other organic components and transition metals were not. sTNF-RII increased by 135 pg/mL [95% confidence interval (CI), 45–225 pg/mL], and IL-6 increased by 0.27 pg/mL (95% CI, 0.10–0.44 pg/mL) per interquartile range increase of 0.56 ng/m3 outdoor total PAHs. Two-pollutant models of PM0.25 with PAHs showed that nominal associations of IL-6 and sTNF-RII with PM0.25 mass were completely confounded by PAHs. Vehicular emission sources estimated from chemical mass balance models were strongly correlated with PAHs (R = 0.71). Conclusions Traffic emission sources of organic chemicals represented by PAHs are associated with increased systemic inflammation and explain associations with quasi-ultrafine particle mass.

Airway inflammation and oxidative potential of air pollutant particles in a pediatric asthma panel

Airborne particulate matter (PM) components from fossil fuel combustion can induce oxidative stress initiated by reactive oxygen species (ROS). Reported associations between worsening asthma and PM2.5 mass could be related to PM oxidative potential to induce airway oxidative stress and inflammation (hallmarks of asthma pathology). We followed 45 schoolchildren with persistent asthma in their southern California homes daily over 10 days with offline fractional exhaled nitric oxide (FENO), a biomarker of airway inflammation. Ambient exposures included daily average PM2.5, PM2.5 elemental and organic carbon (EC, OC), NO2, O3, and endotoxin. We assessed PM2.5 oxidative potential using both an abiotic and an in vitro bioassay on aqueous extracts of daily particle filters: (1) dithiothreitol (DTT) assay (abiotic), representing chemically produced ROS; and (2) ROS generated intracellularly in a rat alveolar macrophage model using the fluorescent probe 2′7′-dicholorohidroflourescin diacetate. We analyzed relations of FENO to air pollutants in mixed linear regression models. FENO was significantly positively associated with lag 1-day and 2-day averages of traffic-related markers (EC, OC, and NO2), DTT and macrophage ROS, but not PM2.5 mass. DTT associations were nearly twice as strong as other exposures per interquartile range: median FENO increased 8.7–9.9% per 0.43 nmole/min/m3 DTT. Findings suggest that future research in oxidative stress-related illnesses such as asthma and PM exposure would benefit from assessments of PM oxidative potential and composition.

Electrocardiographic ST-segment depression and exposure to traffic-related aerosols in elderly subjects with coronary artery disease

Background Air pollutants have not been associated with ambulatory electrocardiographic evidence of ST-segment depression ≥ 1 mm (probable cardiac ischemia). We previously found that markers of primary (combustion-related) organic aerosols and gases were positively associated with circulating biomarkers of inflammation and ambulatory blood pressure in the present cohort panel study of elderly subjects with coronary artery disease. Objectives We specifically aimed to evaluate whether exposure markers of primary organic aerosols and ultrafine particles were more strongly associated with ST-segment depression of ≥ 1 mm than were secondary organic aerosols or PM2.5 (particulate matter with aerodynamic diameter ≤ 2.5 μm) mass. Methods We evaluated relations of air pollutants to ambulatory electrocardiographic evidence of cardiac ischemia over 10 days in 38 subjects without ST depression on baseline electrocardiographs. Exposures were measured outdoors in retirement communities in the Los Angeles basin, including daily size-fractionated particle mass and hourly markers of primary and secondary organic aerosols and gases. Generalized estimating equations were used to estimate odds of hourly ST-segment depression (≥ 1 mm) from hourly air pollution exposures and to estimate relative rates of daily counts of ST-segment depression from daily average exposures, controlling for potential confounders. Results We found significant positive associations of hourly ST-segment depression with markers of combustion-related aerosols and gases averaged 1-hr through 3–4 days, but not secondary (photochemically aged) organic aerosols or ozone. The odds ratio per interquartile increase in 2-day average primary organic carbon (5.2 μg/m3) was 15.4 (95% confidence interval, 3.5–68.2). Daily counts of ST-segment depression were consistently associated with primary combustion markers and 2-day average quasi-ultrafine particles < 0.25 μm. Conclusions Results suggest that exposure to quasi-ultrafine particles and combustion-related pollutants (predominantly from traffic) increase the risk of myocardial ischemia, coherent with our previous findings for systemic inflammation and blood pressure.

Mitochondrial Genetic Background Modifies the Relationship between Traffic-Related Air Pollution Exposure and Systemic Biomarkers of Inflammation

Background Mitochondria are the main source of reactive oxygen species (ROS). Human mitochondrial haplogroups are linked to differences in ROS production and oxidative-stress induced inflammation that may influence disease pathogenesis, including coronary artery disease (CAD). We previously showed that traffic-related air pollutants were associated with biomarkers of systemic inflammation in a cohort panel of subjects with CAD in the Los Angeles air basin. Objective We tested whether air pollutant exposure-associated inflammation was stronger in mitochondrial haplogroup H than U (high versus low ROS production) in this panel (38 subjects and 417 observations). Methods Inflammation biomarkers were measured weekly in each subject (≤12 weeks), including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein, interleukin-6 soluble receptor and tumor necrosis factor-soluble receptor II. We determined haplogroup by restriction fragment length polymorphism analysis. Air pollutants included nitrogen oxides (NOx), carbon monoxide (CO), organic carbon, elemental and black carbon (EC, BC); and particulate matter mass, three size fractions (<0.25 µm, 0.25–2.5 µm, and 2.5–10 µm in aerodynamic diameter). Particulate matter extracts were analyzed for organic compounds, including polycyclic aromatic hydrocarbons (PAH), and in vitro oxidative potential of aqueous extracts. Associations between exposures and biomarkers, stratified by haplogroup, were analyzed by mixed-effects models. Results IL-6 and TNF-α were associated with traffic-related air pollutants (BC, CO, NOx and PAH), and with mass and oxidative potential of quasi-ultrafine particles <0.25 µm. These associations were stronger for haplogroup H than haplogroup U. Conclusions Results suggest that mitochondrial haplogroup U is a novel protective factor for air pollution-related systemic inflammation in this small group of subjects.