IL-17A neutralization fails to attenuate airway remodeling and potentiates a proinflammatory lung microenvironment in diacetyl-exposed rats.

Bronchiolitis obliterans (BO) is a devastating lung disease that can develop following inhalation exposure to certain chemicals. Diacetyl (DA) is one chemical commonly associated with BO development when inhaled at occupational levels. Previous studies in rats have shown that repetitive DA vapor exposures increased lung CD4+CD25+ T cells and bronchoalveolar (BAL) interleukin-17A (IL-17A) concentrations concurrent with the development of airway remodeling. We hypothesized that IL-17A neutralization would attenuate the severity of airway remodeling after repetitive DA vapor exposures. Sprague-Dawley rats were exposed to 200 parts-per-million DA vapor or filtered air (RA) for 6 h/day × 5 days and monitored for 2 wk postexposure. Treatment with IL-17A neutralization (αIL-17A) or IgG (control) began immediately following exposures and continued twice weekly until study's end. Lungs were harvested for histology, flow cytometry, and BAL analyses. Survival, oxygen saturations, and percent weight change decreased significantly in DA-exposed versus RA-exposed rats, but did not differ significantly between DA + αIL-17A versus DA + IgG. Similarly, the number nor severity of airway lesions did not differ significantly between DA + αIL-17A versus DA + IgG rats despite the percentage of lung regulatory T cells increasing with decreased BAL IL-17A concentrations. Ashcroft scoring of the distal lung parenchyma suggested worse parenchymal remodeling in DA + αIL-17A versus DA + IgG rats with increased expression of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), and nuclear factor-kappa B (NF-κB). Collectively, IL-17A neutralization in DA-exposed rats failed to attenuate airway remodeling with increased expression of pro-inflammatory cytokines TNF-α, IL-1ß, and NF-κB.NEW & NOTEWORTHY Interleukin-17A (IL-17A) neutralization has shown benefit previously in preclinical models of transplant-associated bronchiolitis obliterans (BO), yet it remains unknown whether IL-17A neutralization has similar benefit for other forms of BO. Here, IL-17A neutralization fails to prevent severe airway remodeling in rats exposed repetitively to the flavoring chemical diacetyl, and instead, promotes a proinflammatory microenvironment with increased expression of TNF-α, IL-1ß, and NF-κB within the lung.

Triggering of ST-elevation myocardial infarction by ultrafine particles in New York: Changes following Tier 3 vehicle introduction.

BACKGROUND: Previously, we found increased rates of ST-elevation myocardial infarction (STEMI) associated with increased ultrafine particle (UFP; <100 nm) concentrations in the previous few hours in Rochester, New York. Relative rates were higher after air quality policies and a recession reduced pollutant concentrations (2014-2016 versus 2005-2013), suggesting PM composition had changed and the same PM mass concentration had become more toxic. Tier 3 light duty vehicles, which should produce less primary organic aerosols and oxidizable gaseous compounds, likely making PM less toxic, were introduced in 2017. Thus, we hypothesized we would observe a lower relative STEMI rate in 2017-2019 than 2014-2016. METHODS: Using STEMI events treated at the University of Rochester Medical Center (2014-2019), UFP and other pollutants measured in Rochester, a case-crossover design, and conditional logistic regression models, we estimated the rate of STEMI associated with increased UFP and other pollutants in the previous hours and days in the 2014-2016 and 2017-2019 periods. RESULTS: An increased rate of STEMI was associated with each 3111 particles/cm3 increase in UFP concentration in the previous hour in 2014-2016 (lag hour 0: OR = 1.22; 95% CI = 1.06, 1.39), but not in 2017-2019 (OR = 0.94; 95% CI = 0.80, 1.10). There were similar patterns for black carbon, UFP11-50nm, and UFP51-100nm. In contrast, increased rates of STEMI were associated with each 0.6 ppb increase in SO2 concentration in the previous 120 h in both periods (2014-2016: OR = 1.26, 95% CI = 1.03, 1.55; 2017-2019: OR = 1.21, 95% CI = 0.87, 1.68). CONCLUSIONS: Greater rates of STEMI were associated with short term increases in concentrations of UFP and other motor vehicle related pollutants before Tier 3 introduction (2014-2016), but not afterwards (2017-2019). This change may be due to changes in PM composition after Tier 3 introduction, as well as to increased exposure misclassification and greater underestimation of effects from 2017 to 2019.

The potential involvement of inhaled iron (Fe) in the neurotoxic effects of ultrafine particulate matter air pollution exposure on brain development in mice.

BACKGROUND: Air pollution has been associated with neurodevelopmental disorders in epidemiological studies. In our studies in mice, developmental exposures to ambient ultrafine particulate (UFP) matter either postnatally or gestationally results in neurotoxic consequences that include brain metal dyshomeostasis, including significant increases in brain Fe. Since Fe is redox active and neurotoxic to brain in excess, this study examined the extent to which postnatal Fe inhalation exposure, might contribute to the observed neurotoxicity of UFPs. Mice were exposed to 1 µg/m3 Fe oxide nanoparticles alone, or in conjunction with sulfur dioxide (Fe (1 µg/m3) + SO2 (SO2 at 1.31 mg/m3, 500 ppb) from postnatal days 4-7 and 10-13 for 4 h/day. RESULTS: Overarching results included the observations that Fe + SO2 produced greater neurotoxicity than did Fe alone, that females appeared to show greater vulnerability to these exposures than did males, and that profiles of effects differed by sex. Consistent with metal dyshomeostasis, both Fe only and Fe + SO2 exposures altered correlations of Fe and of sulfur (S) with other metals in a sex and tissue-specific manner. Specifically, altered metal levels in lung, but particularly in frontal cortex were found, with reductions produced by Fe in females, but increases produced by Fe + SO2 in males. At PND14, marked changes in brain frontal cortex and striatal neurotransmitter systems were observed, particularly in response to combined Fe + SO2 as compared to Fe only, in glutamatergic and dopaminergic functions that were of opposite directions by sex. Changes in markers of trans-sulfuration in frontal cortex likewise differed in females as compared to males. Residual neurotransmitter changes were limited at PND60. Increases in serum glutathione and Il-1a were female-specific effects of combined Fe + SO2. CONCLUSIONS: Collectively, these findings suggest a role for the Fe contamination in air pollution in the observed neurotoxicity of ambient UFPs and that such involvement may be different by chemical mixture. Translation of such results to humans requires verification, and, if found, would suggest a need for regulation of Fe in air for public health protection.

Repetitive diacetyl vapor exposure promotes ubiquitin proteasome stress and precedes bronchiolitis obliterans pathology.

Bronchiolitis obliterans (BO) is a devastating lung disease seen commonly after lung transplant, following severe respiratory tract infection or chemical inhalation exposure. Diacetyl (DA; 2,3-butanedione) is a highly reactive alpha-diketone known to cause BO when inhaled, however, the mechanisms of how inhalation exposure leads to BO development remains poorly understood. In the current work, we combined two clinically relevant models for studying the pathogenesis of DA-induced BO: (1) an in vivo rat model of repetitive DA vapor exposures with recovery and (2) an in vitro model of primary human airway epithelial cells exposed to pure DA vapors. Rats exposed to 5 consecutive days 200 parts-per-million DA 6 h per day had worsening survival, persistent hypoxemia, poor weight gain, and histologic evidence of BO 14 days after DA exposure cessation. At the end of exposure, increased expression of the ubiquitin stress protein ubiquitin-C accumulated within DA-exposed rat lung homogenates and localized primarily to the airway epithelium, the primary site of BO development. Lung proteasome activity increased concurrently with ubiquitin-C expression after DA exposure, supportive of significant proteasome stress. In primary human airway cultures, global proteomics identified 519 significantly modified proteins in DA-exposed samples relative to controls with common pathways of the ubiquitin proteasome system, endosomal reticulum transport, and response to unfolded protein pathways being upregulated and cell-cell adhesion and oxidation-reduction pathways being downregulated. Collectively, these two models suggest that diacetyl inhalation exposure causes abundant protein damage and subsequent ubiquitin proteasome stress prior to the development of chemical-induced BO pathology.

Wavelength-Dependent Photochemistry and Biological Relevance of a Bilirubin Dipyrrinone Subunit.

Phototherapy is a standard treatment for severe neonatal jaundice to remove toxic bilirubin from the blood. Here, the wavelength-dependent photochemistry of vinylneoxanthobilirubic acid methyl ester, a simplified model of a bilirubin dipyrrinone subunit responsible for a lumirubin-like structural rearrangement, was thoroughly investigated by liquid chromatography and mass and absorption spectroscopies, with the application of a multivariate curve resolution analysis method supplemented with quantum chemical calculations. Irradiation of the model chromophore leads to reversible Z → E photoisomerization followed by reversible photocyclization to a seven-membered ring system (formed as a mixture of diastereomers). Both the isomerization processes are efficient (ΦZE ∼ ΦEZ ∼ 0.16) when irradiated in the wavelength range of 360-410 nm, whereas the E-isomer cyclization (Φc = 0.006-0.008) and cycloreversion (Φ-c = 0.002-0.004) reactions are significantly less efficient. The quantum yields of all processes were found to depend strongly on the wavelength of irradiation, especially when lower energy photons were used. Upon irradiation in the tail of the absorption bands (490 nm), both the isomers exhibit more efficient photoisomerization (ΦZE ∼ ΦEZ ∼ 0.30) and cyclization (Φc = ∼0.07). In addition, the isomeric bilirubin dipyrrinone subunits were found to possess important antioxidant activities while being substantially less toxic than bilirubin.

Diesel exhaust particle exposure reduces expression of the epithelial tight junction protein Tricellulin.

BACKGROUND: While exposure to diesel exhaust particles has been linked to aberrant immune responses in allergic diseases such as asthma, little attention has been paid to their effects on the airway epithelial barrier. In this study, we sought to determine the effect of diesel exhaust exposure on airway epithelial barrier function and composition using in vitro and in vivo model systems. METHODS: 16HBE14o- human bronchial epithelial cells were grown on collagen coated Transwell inserts and exposed to 5 to 50 µg/cm2 SRM 2975 diesel particulate matter (DEP) suspended in cell culture medium or vehicle controls. Changes in barrier function were assessed by measuring transepithelial electrical resistance (TEER) and permeability to 4 kDa FITC Dextran. Neonatal BALB/c mice were exposed to aerosolized DEP (255 ± 89 µg/m3; 2 h per day for 5 days) and changes in the tight junction protein Tricellulin were assessed 2 weeks post exposure. RESULTS: A six-hour incubation of epithelial cells with diesel exhaust particles caused a significant concentration-dependent reduction in epithelial barrier integrity as measured by decreased TEER and increased permeability to 4 kDa FITC-Dextran. This reduction in epithelial barrier integrity corresponded to a significant reduction in expression of the tight junction protein Tricellulin. siRNA mediated knockdown of Tricellulin recapitulated changes in barrier function caused by DEP exposure. Neonatal exposure to aerosolized DEP caused a significant reduction in lung Tricellulin 2 weeks post exposure at both the protein and mRNA level. CONCLUSION: Short term exposure to DEP causes a significant reduction in epithelial barrier integrity through a reduction in the tight junction protein Tricellulin. Neonatal exposure to aerosolized DEP caused a significant and sustained reduction in Tricellulin protein and mRNA in the lung, suggesting that early life exposure to inhaled DEP may cause lasting changes in airway epithelial barrier function.

Ambient wintertime particulate air pollution and hypertensive disorders of pregnancy in Monroe County, New York.

BACKGROUND: Previous studies have reported associations between ambient fine particle (PM2.5) concentrations and hypertensive disorders of pregnancy (HDP). However, none have examined whether ultrafine particles (UFP; < 100 nm), accumulation mode particles (AMP; 100-500 nm), markers of traffic pollution (black carbon; BC), or wood burning (Delta-C; (30% of ambient wintertime PM2.5 in Monroe County, NY is from wood burning)) are associated with an increased odds of HDP. We estimated the odds of HDP associated with increased concentrations of PM2.5, UFP, AMP, BC, and Delta-C in each gestational month during winter months. METHODS: Electronic medical records and birth certificate data were linked with land-use regression models in Monroe County, New York in 2009-2013 to predict monthly pollutant concentrations during winter (November-April) based on maternal residential address for 16,637 births. Using multivariable logistic regression, we estimated the odds of HDP associated with each interquartile range (IQR) increase in PM2.5, UFP, AMP, BC, and Delta-C concentrations during each gestational month, adjusting for maternal characteristics, birth hospital, temperature, and relative humidity. RESULTS: Each 0.52 µg/m3 increase in Delta-C concentration during the 7th gestational month was associated with an increased odds of HDP (odds ratio (OR) = 1.21; 95% confidence interval (CI) = 1.01, 1.45), with a similar sized estimate in month 8 (OR = 1.18; 95%CI = 0.98, 1.43). Non-statistically significant increased odds of HDP associated with IQR increases in BC concentrations during months 3 (OR = 1.12; 95%CI = 0.98, 1.28) and 7 (OR = 1.12; 95%CI = 0.96, 1.29) were observed. Increased odds of HDP were not observed for PM2.5, UFP, or AMP. CONCLUSIONS: Our findings suggest that maternal exposure to wood smoke in Monroe County during winter is associated with an increased odds of HDP during late gestation. Additional studies are needed to evaluate the effect of wood smoke on HDP and to explore effects on other pregnancy outcomes.

Changes in triggering of ST-elevation myocardial infarction by particulate air pollution in Monroe County, New York over time: a case-crossover study.

BACKGROUND: Previous studies have reported that fine particle (PM2.5) concentrations triggered ST elevation myocardial infarctions (STEMI). In Rochester, NY, multiple air quality policies and economic changes/influences from 2008 to 2013 led to decreased concentrations of PM2.5 and its major constituents (SO42-, NO3-, elemental and primary organic carbon). This study examined whether the rate of STEMI associated with increased ambient gaseous and PM component concentrations was different AFTER these air quality policies and economic changes (2014-2016), compared to DURING (2008-2013) and BEFORE these polices and changes (2005-2007). METHODS: Using 921 STEMIs treated at the University of Rochester Medical Center (2005-2016) and a case-crossover design, we examined whether the rate of STEMI associated with increased PM2.5, ultrafine particles (UFP, < 100 nm), accumulation mode particles (AMP, 100-500 nm), black carbon, SO2, CO, and O3 concentrations in the previous 1-72 h was modified by the time period related to these pollutant source changes (BEFORE, DURING, AFTER). RESULTS: Each interquartile range (3702 particles/cm3) increase in UFP concentration in the previous 1 h was associated with a 12% (95% CI = 3%, 22%) increase in the rate of STEMI. The effect size was larger in the AFTER period (26%) than the DURING (5%) or BEFORE periods (9%). There were similar patterns for black carbon and SO2. CONCLUSIONS: An increased rate of STEMI associated with UFP and other pollutant concentrations was higher in the AFTER period compared to the BEFORE and DURING periods. This may be due to changes in PM composition (e.g. higher secondary organic carbon and particle bound reactive oxygen species) following these air quality policies and economic changes.

Hourly land-use regression models based on low-cost PM monitor data.

Land-use regression (LUR) models provide location and time specific estimates of exposure to air pollution and thereby improve the sensitivity of health effects models. However, they require pollutant concentrations at multiple locations along with land-use variables. Often, monitoring is performed over short durations using mobile monitoring with research-grade instruments. Low-cost PM monitors provide an alternative approach that increases the spatial and temporal resolution of the air quality data. LUR models were developed to predict hourly PM concentrations across a metropolitan area using PM concentrations measured simultaneously at multiple locations with low-cost monitors. Monitors were placed at 23 sites during the 2015/16 heating season. Monitors were externally calibrated using co-located measurements including a reference instrument (GRIMM particle spectrometer). LUR models for each hour of the day and weekdays/weekend days were developed using the deletion/substitution/addition algorithm. Coefficients of determination for hourly PM predictions ranged from 0.66 and 0.76 (average 0.7). The hourly-resolved LUR model results will be used in epidemiological studies to examine if and how quickly, increases in ambient PM concentrations trigger adverse health events by reducing the exposure misclassification that arises from using less time resolved exposure estimates.

Associations between ambient wood smoke and other particulate pollutants and biomarkers of systemic inflammation, coagulation and thrombosis in cardiac patients.

BACKGROUND: Increased particulate air pollution has been associated with both an increased risk of myocardial infarction (MI) and adverse changes in cardiac biomarkers. Up to 30% of ambient wintertime fine particles (PM2.5) in Rochester, NY are from wood burning. Our study examined associations between ambient levels of a marker of wood smoke (Delta-C) and other particulate air pollutants and biomarkers of inflammation, coagulation and thrombosis. METHODS: We measured blood concentrations of C-reactive protein (CRP), D-dimer, fibrinogen, P-selectin, platelet factor 4 (PF-4), von Willebrand factor (vWF), and myeloperoxidase (MPO) of 135 patients undergoing cardiac catheterization during the winters of 2011-2013. We coupled these data with hourly ambient concentrations of Delta-C, black carbon (BC; marker of traffic pollution), and ultrafine (10-100nm; UFP), accumulation mode (100-500nm; AMP), and fine particles (<2.5µm; PM2.5). Using linear regression models, we estimated the change in each biomarker associated with increased pollutant concentrations at intervals between 1 and 96h preceding blood collection. RESULTS: Each 0.13µg/m3 increase in Delta-C concentration in the prior 12h was associated with a 0.91% increase in fibrinogen levels (95% CI=0.23%, 1.59%), but unexpectedly in the prior 48h, each 0.17µg/m3 increase in Delta-C concentration was associated with a 2.75% decrease in MPO levels (95% CI=-5.13%,-0.37%). We did not see associations between Delta-C concentrations and any other biomarkers. Interquartile range (IQR) increases in PM2.5, BC, UFP, and AMP concentrations were generally associated with increased CRP and fibrinogen, but not PF4, D-dimer, vWF, or P-selectin. CONCLUSIONS: In a population of cardiac patients, we noted adverse changes in fibrinogen associated with increased concentrations of a marker of wood smoke. Increases in PM2.5, BC, AMP, and UFP concentrations in the previous 96h were also associated with adverse changes in markers of systemic inflammation and coagulation, but not with markers of endothelial cell dysfunction or platelet activation.

Estimating Hourly Concentrations of PM2.5 across a Metropolitan Area Using Low-Cost Particle Monitors.

There is concern regarding the heterogeneity of exposure to airborne particulate matter (PM) across urban areas leading to negatively biased health effects models. New, low-cost sensors now permit continuous and simultaneous measurements to be made in multiple locations. Measurements of ambient PM were made from October to April 2015-2016 and 2016-2017 to assess the spatial and temporal variability in PM and the relative importance of traffic and wood smoke to outdoor PM concentrations in Rochester, NY, USA. In general, there was moderate spatial inhomogeneity, as indicated by multiple pairwise measures including coefficient of divergence and signed rank tests of the value distributions. Pearson correlation coefficients were often moderate (~50% of units showed correlations >0.5 during the first season), indicating that there was some coherent variation across the area, likely driven by a combination of meteorological conditions (wind speed, direction, and mixed layer heights) and the concentration of PM2.5 being transported into the region. Although the accuracy of these PM sensors is limited, they are sufficiently precise relative to one another and to research grade instruments that they can be useful is assessing the spatial and temporal variations across an area and provide concentration estimates based on higher-quality central site monitoring data.

Does total antioxidant capacity modify adverse cardiac responses associated with ambient ultrafine, accumulation mode, and fine particles in patients undergoing cardiac rehabilitation?

BACKGROUND: Previous studies suggest that pathways reducing oxidative stress may have a protective effect against adverse cardiac responses associated with ambient PM. However, few studies have directly assessed total antioxidant capacity (TAC) as a potential effect modifier of cardiac responses to increased ambient PM. OBJECTIVES: We examined if TAC modifies the association between ambient PM and markers of heart rate variability (HRV), repolarization, systemic inflammation, and systolic blood pressure (SBP) in post-infarction patients. METHODS: We recruited 76 patients with a recent coronary event (myocardial infarction or unstable angina) who participated in a cardiac rehabilitation program from June 2006 to November 2009 in Rochester, New York. Ambient fine particle (PM2.5,≤2.5µm in aerodynamic diameter), accumulation mode particle (AMP, 100-500nm) and ultrafine particle (UFP, 10-100nm) concentrations were measured continuously by fixed-site monitors. Markers of HRV and repolarization were measured by continuous Holter electrocardiogram (ECG) recordings before and during exercise sessions of the rehabilitation program. Blood pressure was measured and venous blood samples were collected before exercise to measure TAC and inflammation markers. We applied linear mixed models to assess changes in markers of HRV, repolarization, systemic inflammation, and SBP associated with increased PM concentrations in the low, medium and high TAC tertile groups, after adjusting for covariates including temperature, calendar time since the beginning of the study, visit number, month of year, and hour of day. RESULTS: Based on subject-visits with available TAC, we observed increases in SBP, C-reactive protein, and fibrinogen, and decreases in rMSSD (square root of the mean of the sum of the squared differences between adjacent normal to normal intervals) and SDNN (standard deviation of normal to normal beat intervals) associated with increased PM2.5, AMP and UFP in the previous 6-120h (e.g. change in SBP associated with each interquartile range (IQR) increase in PM2.5 lagged 0-5h was 1.27mmHg [95%CI: 0.09, 2.46mmHg]). However, we did not observe a consistent pattern of effect measure modification by TAC for any combination of pollutant and outcome (e.g. changes in SBP associated with each IQR increase in PM2.5 lagged 0-5h for the low, medium and high TAC tertile groups were 1.93mmHg [95%CI: 0.23, 3.63 mmHg], -0.31 mmHg [95%CI: -2.62, 2.01 mmHg], and 1.29mmHg [95%CI: -0.64, 3.21 mmHg], respectively. P for interaction=0.28). CONCLUSIONS: In a post-infarction population, total antioxidant capacity does not appear to modify the association between biomarkers of heart rate variability, repolarization, systemic inflammation, and systolic blood pressure and ambient PM concentrations in the previous 6-120h.

Increases in ambient particulate matter air pollution, acute changes in platelet function, and effect modification by aspirin and omega-3 fatty acids: A panel study.

Increased particulate matter (PM) air pollutant concentrations have been associated with platelet activation. It was postulated that elevated air pollutant concentrations would be associated with increases in measures of platelet function and that responses would be blunted when taking aspirin and/or fish oil. Data from a sequential therapy trial (30 subjects with type 2 diabetes mellitus), with 4 clinic visits (first: no supplements, second: aspirin, third: omega-3 fatty acid supplements, fourth: aspirin and omega-3 fatty acids) per subject, were utilized. Using linear mixed models, adjusted for relative humidity, temperature, visit number, and season, changes in three platelet function measures including (1) aggregation induced by adenosine diphosphate (ADP), (2) aggregation induced by collagen, and (3) thromboxane B2 production were associated with interquartile range (IQR) increases in mean concentrations of ambient PM2.5, black carbon, ultrafine particles (UFP; 10-100 nm), and accumulation mode particles (AMP; 100-500 nm) in the previous 1-96 h. IQR increases in mean UFP and AMP concentrations were associated with significant decreases in platelet response, with the largest being a -0.43 log(pg/ml) decrease in log(thromboxane B2) (95% CI = -0.8, -0.1) associated with each 582-particles/cm(3) increase in AMP, and a -1.7 ohm reduction in collagen-induced aggregation (95% CI = -3.1, -0.3) associated with each 2097-particles/cm(3) increase in UFP in the previous 72 h. This UFP effect on thromboxane B2 was significantly muted in diabetic subjects taking aspirin (-0.01 log[pg/ml]; 95% CI = -0.4, 0.3). The reason for this finding remains unknown, and needs to be investigated in future studies.

Triggering of myocardial infarction by increased ambient fine particle concentration: Effect modification by source direction.

BACKGROUND: Previously, we reported a 18% increased odds of ST-elevation myocardial infarction (STEMI) associated with each 7.1 µg/m(3) increase in PM2.5 concentration in the hour prior to MI onset. We found no association with non-ST elevation myocardial infarction (NSTEMI). We examined if this association was modified by PM2.5 source direction. METHODS: We used the NOAA HYbrid Single-Particle Lagrangian Trajectory (HYSPLIT) model to calculate each hourly air mass location for the 24 hours before each case or control time period in our previous PM2.5/STEMI case-crossover analysis. Using these data on patients with STEMI (n=338), hourly PM2.5 concentrations, and case-crossover methods, we evaluated whether our PM2.5/STEMI association was modified by whether the air mass passed through each of the 8 cardinal wind direction sectors in the previous 24h. RESULTS: When the air mass passed through the West-Southwest direction (WSW) any time in the past 24h, the odds of STEMI associated with each 7.1µg/m(3) increase in PM2.5 concentration in the previous hour (OR=1.27; 95% CI=1.08, 1.22) was statistically significantly (p=0.01) greater than the relative odds of STEMI associated with increased PM2.5 concentration when the wind arrived from any other direction (OR=0.99; 95% CI=0.80, 1.22). We found no other effect modification by any other source direction. Further, relative odds estimates were largest when the time spent in the WSW was 8-16 h, compared to ≤7 h or 17-24 h, suggesting that particles arising from sources in this direction were more potent in triggering STEMIs. CONCLUSIONS: Since relative odds estimates were higher when the air mass passed through the WSW octant in the past 24h, there may be specific components of the ambient aerosol that are more potent in triggering STEMIs. This direction is associated with substantial emissions from coal-fired power plants and other industrial sources of the Ohio River Valley, many of which are undergoing modifications to reduce their emissions.

Cardiovascular effects of ozone in healthy subjects with and without deletion of glutathione-S-transferase M1.

CONTEXT: Exposure to ozone has acute respiratory effects, but few human clinical studies have evaluated cardiovascular effects. OBJECTIVE: We hypothesized that ozone exposure alters pulmonary and systemic vascular function, and cardiac function, with more pronounced effects in subjects with impaired antioxidant defense from deletion of the glutathione-S-transferase M1 gene (GSTM1 null). METHODS: Twenty-four young, healthy never-smoker subjects (12 GSTM1 null) inhaled filtered air, 100 ppb ozone and 200 ppb ozone for 3 h, with intermittent exercise, in a double-blind, randomized, crossover fashion. Exposures were separated by at least 2 weeks. Vital signs, spirometry, arterial and venous blood nitrite levels, impedance cardiography, peripheral arterial tonometry, estimation of pulmonary capillary blood volume (Vc), and blood microparticles and platelet activation were measured at baseline and during 4 h after each exposure. RESULTS: Ozone inhalation decreased lung function immediately after exposure (mean ± standard error change in FEV1, air: -0.03 ± 0.04 L; 200 ppb ozone: -0.30 ± 0.07 L; p < 0.001). The immediate post-exposure increase in blood pressure, caused by the final 15-min exercise period, was blunted by 200 ppb ozone exposure (mean ± standard error change for air: 16.7 ± 2.6 mmHg; 100 ppb ozone: 14.5 ± 2.4 mmHg; 200 ppb ozone: 8.5 ± 2.5 mmHg; p = 0.02). We found no consistent effects of ozone on any other measure of cardiac or vascular function. All results were independent of the GSTM1 genotype. CONCLUSIONS: We did not find convincing evidence for early acute adverse cardiovascular consequences of ozone exposure in young healthy adults. The ozone-associated blunting of the blood pressure response to exercise is of unclear clinical significance.

Inhalation of ultrafine carbon particles alters heart rate and heart rate variability in people with type 2 diabetes.

BACKGROUND: Diabetes may confer an increased risk for the cardiovascular health effects of particulate air pollution, but few human clinical studies of air pollution have included people with diabetes. Ultrafine particles (UFP, ≤100 nm in diameter) have been hypothesized to be an important component of particulate air pollution with regard to cardiovascular health effects. METHODS: 17 never-smoker subjects 30-60 years of age, with stable type 2 diabetes but otherwise healthy, inhaled either filtered air (0-10 particles/cm3) or elemental carbon UFP (~107 particles/cm3, ~50 ug/m3, count median diameter 32 nm) by mouthpiece, for 2 hours at rest, in a double-blind, randomized, crossover study design. A digital 12-lead electrocardiogram (ECG) was recorded continuously for 48 hours, beginning 1 hour prior to exposure. RESULTS: Analysis of 5-minute segments of the ECG during quiet rest showed reduced high-frequency heart rate variability with UFP relative to air exposure (p = 0.014), paralleled by non-significant reductions in time-domain heart rate variability parameters. In the analysis of longer durations of the ECG, we found that UFP exposure increased the heart rate relative to air exposure. During the 21- to 45-hour interval after exposure, the average heart rate increased approximately 8 beats per minute with UFP, compared to 5 beats per minute with air (p = 0.045). There were no UFP effects on cardiac rhythm or repolarization. CONCLUSIONS: Inhalation of elemental carbon ultrafine particles alters heart rate and heart rate variability in people with type 2 diabetes. Our findings suggest that effects may occur and persist hours after a single 2-hour exposure.

Ambient fine particulate air pollution triggers ST-elevation myocardial infarction, but not non-ST elevation myocardial infarction: a case-crossover study.

BACKGROUND: We and others have shown that increases in particulate air pollutant (PM) concentrations in the previous hours and days have been associated with increased risks of myocardial infarction, but little is known about the relationships between air pollution and specific subsets of myocardial infarction, such as ST-elevation myocardial infarction (STEMI) and non ST-elevation myocardial infarction (NSTEMI). METHODS: Using data from acute coronary syndrome patients with STEMI (n = 338) and NSTEMI (n = 339) and case-crossover methods, we estimated the risk of STEMI and NSTEMI associated with increased ambient fine particle (<2.5 um) concentrations, ultrafine particle (10-100 nm) number concentrations, and accumulation mode particle (100-500 nm) number concentrations in the previous few hours and days. RESULTS: We found a significant 18% increase in the risk of STEMI associated with each 7.1 µg/m³ increase in PM2.5 concentration in the previous hour prior to acute coronary syndrome onset, with smaller, non-significantly increased risks associated with increased fine particle concentrations in the previous 3, 12, and 24 hours. We found no pattern with NSTEMI. Estimates of the risk of STEMI associated with interquartile range increases in ultrafine particle and accumulation mode particle number concentrations in the previous 1 to 96 hours were all greater than 1.0, but not statistically significant. Patients with pre-existing hypertension had a significantly greater risk of STEMI associated with increased fine particle concentration in the previous hour than patients without hypertension. CONCLUSIONS: Increased fine particle concentrations in the hour prior to acute coronary syndrome onset were associated with an increased risk of STEMI, but not NSTEMI. Patients with pre-existing hypertension and other cardiovascular disease appeared particularly susceptible. Further investigation into mechanisms by which PM can preferentially trigger STEMI over NSTEMI within this rapid time scale is needed.

Long term trends in source apportioned particle number concentrations in Rochester NY.

During the past two decades, efforts have been made to further reduce particulate air pollution across New York State through various Federal and State policy implementations. Air quality has also been affected by economic drivers like the 2007-2009 recession and changing costs for different approaches to electricity generation. Prior work has focused on particulate matter with aerodynamic diameter ≤2.5 µm. However, there is also interest in the effects of ultrafine particles on health and the environment and analyses of changes in particle number concentrations (PNCs) are also of interest to assess the impacts of changing emissions. Particle number size distributions have been measured since 2005. Prior apportionments have been limited to seasonal analyses over a limited number of years because of software limitations. Thus, it has not been possible to perform trend analyses on the source-specific PNCs. Recent development have now permitted the analysis of larger data sets using Positive Matrix Factorization (PMF) including its diagnostics. Thus, this study separated and analyzed the hourly averaged size distributions from 2005 to 2019 into two data sets; October to March and April to September. Six factors were resolved for both data sets with sources identified as nucleation, traffic 1, traffic 2, fresh secondary inorganic aerosol (SIA), aged SIA, and O3-rich aerosol. The resulting source-specific PNCs were combined to provide continuous data sets and analyzed for trends. The trends were then examined with respect to the implementation of regulations and the timing of economic drivers. Nucleation was strongly reduced by the requirement of ultralow (<15 ppm) sulfur on-road diesel fuel in 2006. Secondary inorganic particles and O3-rich PNCs show strong summer peaks. Aged SIA was constant and then declined substantially in 2015 but rose in 2019. Traffic 1 and 2 have steadily declined bur rose in 2019.

The contributions of neonatal inhalation of copper to air pollution-induced neurodevelopmental outcomes in mice.

Exposures to ambient ultrafine particle (UFP) air pollution (AP) during the early postnatal period in mice (equivalent to human third trimester brain development) produce male-biased changes in brain structure, including ventriculomegaly, reduced brain myelination, alterations in neurotransmitters and glial activation, as well as impulsive-like behavioral characteristics, all of which are also features characteristic of male-biased neurodevelopmental disorders (NDDs). The purpose of this study was to ascertain the extent to which inhaled Cu, a common contaminant of AP that is also dysregulated across multiple NDDs, might contribute to these phenotypes. For this purpose, C57BL/6J mice were exposed from postnatal days 4-7 and 10-13 for 4 hr/day to inhaled copper oxide (CuxOy) nanoparticles at an environmentally relevant concentration averaging 171.9 ng/m3. Changes in brain metal homeostasis and neurotransmitter levels were determined following termination of exposure (postnatal day 14), while behavioral changes were assessed in adulthood. CuxOy inhalation modified cortical metal homeostasis and produced male-biased disruption of striatal neurotransmitters, with marked increases in dopaminergic function, as well as excitatory/inhibitory imbalance and reductions in serotonergic function. Impulsive-like behaviors in a fixed ratio (FR) waiting-for-reward schedule and a fixed interval (FI) schedule of food reward occurred in both sexes, but more prominently in males, effects which could not be attributed to altered locomotor activity or short-term memory. Inhaled Cu as from AP exposures, at environmentally relevant levels experienced during development, may contribute to impaired brain function, as shown by its ability to disrupt brain metal homeostasis and striatal neurotransmission. In addition, its ability to evoke impulsive-like behavior, particularly in male offspring, may be related to striatal dopaminergic dysfunction that is known to mediate such behaviors. As such, regulation of air Cu levels may be protective of public health.

Effects of outdoor air pollutants on platelet activation in people with type 2 diabetes.

Exposure to air pollution is associated with increased morbidity and mortality from cardiovascular disease. We hypothesized that increases in exposure to ambient air pollution are associated with platelet activation and formation of circulating tissue factor-expressing microparticles. We studied 19 subjects with type 2 diabetes, without clinical evidence of cardiovascular disease, who had previously participated in a human clinical study of exposure to ultrafine particles (UFP). Blood was obtained for measurements of platelet activation following an overnight stay in the Clinical Research Center, prior to each of their two pre-exposure visits. Air pollution and meteorological data, including UFP counts, were analyzed for the 5 days prior to the subjects' arrival at the Clinical Research Center. Contrary to expectations, increases in UFP were associated with decreases in surface expression of platelet activation markers. The number of platelet-leukocyte conjugates decreased by -80 (95% confidence interval (CI) -123 to -37, p = 0.001) on the first lag day (20-44 h prior to the blood draw) and by -85 (CI -139 to -31, p = 0.005) on combined lag days 1 to 5, per interquartile range (IQR) increase in UFP particle number (2482). However, levels of soluble CD40L increased 104 (CI 3 to 205, p = 0.04) pg/ml per IQR increase in UFP on lag day 1, a finding consistent with prior platelet activation. We speculate that, in people with diabetes, exposure to UFP activates circulating platelets within hours of exposure, followed by an increase in soluble CD40L and a rebound reduction in circulating platelet surface markers.