Fine particulate matter air pollution plus ozone impairs vascular function and raises diastolic blood pressure. We aimed to determine the mechanism and air pollutant responsible. The effects of pollution on heart rate variability, blood pressure, biomarkers, and brachial flow-mediated dilatation were determined in 2 randomized, double-blind, crossover studies. In Ann Arbor, 50 subjects were exposed to fine particles (150 μg/m ³ ) plus ozone (120 parts per billion) for 2 hours on 3 occasions with pretreatments of an endothelin antagonist (Bosentan, 250 mg), antioxidant (Vitamin C, 2 g), or placebo. In Toronto, 31 subjects were exposed to 4 different conditions (particles plus ozone, particles, ozone, and filtered air). In Toronto, diastolic blood pressure significantly increased (2.9 and 3.6 mm Hg) only during particle-containing exposures in association with particulate matter concentration and reductions in heart rate variability. Flow-mediated dilatation significantly decreased (2.0% and 2.9%) only 24 hours after particle-containing exposures in association with particulate matter concentration and increases in blood tumor necrosis factor α. In Ann Arbor, diastolic blood pressure significantly similarly increased during all of the exposures (2.5 to 4.0 mm Hg), a response not mitigated by pretreatments. Flow-mediated dilatation remained unaltered. Particulate matter, not ozone, was responsible for increasing diastolic blood pressure during air pollution inhalation, most plausibly by instigating acute autonomic imbalance. Only particles from urban Toronto additionally impaired endothelial function, likely via slower proinflammatory pathways. Our findings demonstrate credible mechanisms whereby fine particulate matter could trigger acute cardiovascular events and that aspects of exposure location may be an important determinant of the health consequences.

Background: Exposure to particulate matter ≤ 2.5 μm in diameter (PM2.5) increases blood pressure (BP) in humans and animal models. Abnormal activation of the sympathetic nervous system may have a role in the acute BP response to PM2.5 exposure. The mechanisms responsible for sympathetic nervous system activation and its role in chronic sustenance of hypertension in response to PM2.5 exposure are currently unknown. Objectives: We investigated whether central nervous system inflammation may be implicated in chronic PM2.5 exposure-induced increases in BP and sympathetic nervous system activation. Methods: C57BL/6J mice were exposed to concentrated ambient PM2.5 (CAPs) for 6 months, and we analyzed BP using radioactive telemetric transmitters. We assessed sympathetic tone by measuring low-frequency BP variability (LF-BPV) and urinary norepinephrine excretion. We also tested the effects of acute pharmacologic inhibitors of the sympathetic nervous system and parasympathetic nervous system. Results: Long-term CAPs exposure significantly increased basal BP, paralleled by increases in LF-BPV and urinary norepinephrine excretion. The increased basal BP was attenuated by the centrally acting α2a agonist guanfacine, suggesting a role of increased sympathetic tone in CAPs exposure–induced hypertension. The increase in sympathetic tone was accompanied by an inflammatory response in the arcuate nucleus of the hypothalamus, evidenced by increased expression of pro-inflammatory genes and inhibitor kappaB kinase (IKK)/nuclear factor–kappaB (NF-κB) pathway activation. Conclusion: Long-term CAPs exposure increases BP through sympathetic nervous system activation, which may involve hypothalamic inflammation. Citation: Ying Z, Xu X, Bai Y, Zhong J, Chen M, Liang Y, Zhao J, Liu D, Morishita M, Sun Q, Spino C, Brook RD, Harkema JR, Rajagopalan S. 2014. Long-term exposure to concentrated ambient PM2.5 increases mouse blood pressure through abnormal activation of the sympathetic nervous system: a role for hypothalamic inflammation. Environ Health Perspect 122:79–86; http://dx.doi.org/10.1289/ehp.1307151

Background: Epidemiologic and experimental studies support an association between PM2.5 exposure and insulin resistance (IR). Innate immune cell activation has been suggested to play a role in the pathogenesis of these effects. Objectives: We sought to evaluate the role of CC-chemokine receptor 2 (CCR2) in PM2.5-mediated inflammation and IR. Methods: Wild-type C57BL/6 and CCR2–/– male mice were fed a high-fat diet and exposed to either concentrated ambient PM2.5 or filtered air for 17 weeks via a whole-body exposure system. We evaluated glucose tolerance and insulin sensitivity. At euthanasia, blood, spleen, and visceral adipose tissue (VAT) were collected, and inflammatory cells were measured using flow cytometry. We used standard immunoblots, immunohistochemical methods, and quantitative PCR (polymerase chain reaction) to assess pathways of interest involving insulin signaling, inflammation, and lipid and glucose metabolism in various organs. Vascular function was assessed using myography. Results: PM2.5 exposure resulted in whole-body IR and increased hepatic lipid accumulation in the liver, which was attenuated in CCR2–/– mice by inhibiting SREBP1c-mediated transcriptional programming, decreasing fatty acid uptake, and suppressing p38 MAPK activity. Abnormal phosphorylation levels of AKT, AMPK in VAT, and adipose tissue macrophage content in wild-type mice were not present in CCR2–/– mice. However, the impaired whole-body glucose tolerance and reduced GLUT-4 in skeletal muscle in response to PM2.5 was not corrected by CCR2 deficiency. Conclusions: PM2.5 mediates IR by regulating VAT inflammation, hepatic lipid metabolism, and glucose utilization in skeletal muscle via both CCR2-dependent and -independent pathways. These findings provide new mechanistic links between air pollution and metabolic abnormalities underlying IR. Citation: Liu C, Xu X, Bai Y, Wang TY, Rao X, Wang A, Sun L, Ying Z, Gushchina L, Maiseyeu A, Morishita M, Sun Q, Harkema JR, Rajagopalan S. 2014. Air pollution–mediated susceptibility to inflammation and insulin resistance: influence of CCR2 pathways in mice. Environ Health Perspect 122:17–26; http://dx.doi.org/10.1289/ehp.1306841

The World Health Organization attributes more than 4 million deaths per year to ambient fine (<2.5 μm in diameter) particulate matter (PM_2.5).¹ Short-term exposures (eg, days) increase risks for numerous cardiovascular (CV) events, including myocardial infarction, stroke, and heart failure.² Longer-term exposures (eg, years) amplify this risk and potentiate development of chronic cardiometabolic conditions (eg, type 2 diabetes, hypertension).²

We report on the research conducted by the Community Action Against Asthma (CAAA) in Detroit, Michigan, to evaluate personal and community-level exposures to particulate matter (PM) among children with asthma living in an urban environment. CAAA is a community-based participatory research collaboration among academia, health agencies, and community-based organizations. CAAA investigates the effects of environmental exposures on the residents of Detroit through a participatory process that engages participants from the affected communities in all aspects of the design and conduct of the research; disseminates the results to all parties involved; and uses the research results to design, in collaboration with all partners, interventions to reduce the identified environmental exposures. The CAAA PM exposure assessment includes four seasonal measurement campaigns each year that are conducted for a 2-week duration each season. In each seasonal measurement period, daily ambient measurements of PM2.5 and PM10 (particulate matter with a mass median aerodynamic diameter less than 2.5 microm and 10 microm, respectively) are collected at two elementary schools in the eastside and southwest communities of Detroit. Concurrently, indoor measurements of PM2.5 and PM10 are made at the schools as well as inside the homes of a subset of 20 children with asthma. Daily personal exposure measurements of PM10 are also collected for these 20 children with asthma. Results from the first five seasonal assessment periods reveal that mean personal PM10 (68.4 39.2 microg/m(3)) and indoor home PM10 (52.2 30.6 microg/m(3)) exposures are significantly greater (p < 0.05) than the outdoor PM10 concentrations (25.8 11.8 microg/m(3)). The same was also found for PM2.5 (indoor PM2.5 = 34.4 21.7 microg/m(3); outdoor PM2.5 = 15.6 8.2 microg/m(3)). In addition, significant differences (p < 0.05) in community-level exposure to both PM10 and PM2.5 are observed between the two Detroit communities (southwest PM10 = 28.9 14.4 microg/m(3)), PM2.5 = 17.0 9.3 microg/m(3); eastside PM10 = 23.8 12.1 microg/m(3), PM2.5 = 15.5 9.0 microg/m(3). The increased levels in the southwest Detroit community are likely due to the proximity to heavy industrial pollutant point sources and interstate motorways. Trace element characterization of filter samples collected over the 2-year period will allow a more complete assessment of the PM components. When combined with other project measures, including concurrent seasonal twice-daily peak expiratory flow and forced expiratory volume at 1 sec and daily asthma symptom and medication dairies for 300 children with asthma living in the two Detroit communities, these data will allow not only investigations into the sources of PM in the Detroit airshed with regard to PM exposure assessment but also the role of air pollutants in exacerbation of childhood asthma.