Browsing by Subject "Air pollution"
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Item Air Pollution Exposure and the Lung-Brain Axis: Implications for Alzheimer's Disease(2022-03) Greve, Hendrik Jacob; Oblak, Adrian; Block, Michelle; Nass, Richard; Landreth, GaryAlzheimer’s disease (AD) is a devastating neurodegenerative disease that is expected to affect approximately 6.2 million Americans. Despite its high prevalence, the mechanisms underlying AD remain poorly understood. In recent years, increasing reports indicate that exposure to urban air pollution is a risk factor for the development of AD. However, the mechanistic underpinnings of this association are not well studied. Rats exposed to diesel exhaust (DE) showed neuroinflammation and impaired expression of TREM2 and disease-associated microglia (DAM), a cell subtype hypothesized to play beneficial roles during neurodegeneration, markers. Microglia in the cortex of rats exposed to DE, also showed decreased association with the vasculature, providing a novel link between the microglia and the brain vasculature. Examining the functional role of TREM2 during DE exposures, Trem2-/- mice showed an altered pro-inflammatory profile in both the brain and lungs in response to DE particles as well as altered phagocytic oxidase related gene expression. Examining another prominent component of air pollution, ozone (O3), in a mouse model of AD, it was discovered that subchronic O3 exposure exacerbates amyloid pathology through impaired microglial-plaque association in 5xFAD mice. 5xFAD mice exposed to O3 also showed increased expression of pro-inflammatory cytokines, increased markers of dystrophic neurites, and decreased expression of key acetylcholinergic pathway components. Examining the peri-plaque microenvironment, it was discovered that O3 dysregulates key DAM proteins and amyloid processing proteins. In the lung, it was found that O3 exacerbated immune cell infiltration in 5xFAD mice compared to WT controls, suggesting that ongoing amyloid pathology regulates pulmonary immune response to air pollution. To examine how O3-induced pulmonary immune responses may be signaling to the CNS, we examined the serum of 5xFAD mice, where HMGB1, VEGF, and IL-9 were upregulated. Injection of rHMGB1 into mice showed similar gene changes to 5xFAD mice exposed to O3, along with impaired Trem2 expression. Using a peripheral myeloid specific knock-out model of HMGB1, we also show that HMGB1 regulates O3-induced Trem2 expression impairment. Taken together, these data support that air pollution exposure impairs TREM2, DAM cells, and the microglial plaque response through a bidirectional lung-brain axis to exacerbate AD-like pathology.Item Associations between air pollution indicators and prevalent and incident diabetes in an African American cohort, the Jackson Heart Study(Wolters Kluwer, 2021-04-22) Weaver, Anne M.; Bidulescu, Aurelian; Wellenius, Gregory A.; Hickson, DeMarc A.; Sims, Mario; Vaidyanathan, Ambarish; Wu, Wen-Chih; Correa, Adolfo; Wang, Yi; Environmental Health Science, School of Public HealthBackground: Diabetes is especially prevalent among African Americans. Prior studies suggest that long-term exposure to ambient air pollution may be associated with greater incidence of diabetes, but results remain heterogeneous. Few studies have included large numbers of African Americans. Methods: We assessed diabetes status and concentrations of 1- and 3-year fine particulate matter (PM2.5) and ozone (O3) among African American participants of the Jackson Heart Study at visits 1 (2000-2004, N = 5128) and 2 (2005-2008, N = 2839). We used mixed-effect modified Poisson regression to estimate risk ratios (RRs) and 95% confidence intervals (CIs) of incidence of diabetes by visit 2 and prevalence ratios (PRs) of the association between air pollution exposure and prevalent diabetes at visits 1 and 2. We adjusted for potential confounding by patient characteristics, as well as inverse probability weights of diabetes at visit 2, accounting for clustering by census tract. Results: We observed associations between incident diabetes and interquartile range increase in 1-year O3 (RR 1.34, 95% CI = 1.11, 1.61) and 3-year O3 (RR 0.88, 95% CI = 0.76, 1.02). We observed associations between prevalent diabetes and 1-year PM2.5 (PR 1.08, 95% CI = 1.00, 1.17), 1-year O3 (PR 1.18, 95% CI = 1.10, 1.27), and 3-year O3 (PR 0.95, 95% CI = 0.90, 1.01) at visit 2. Conclusions: Our results provide some evidence of positive associations between indicators of long-term PM2.5 and O3 exposure and diabetes. This study is particularly relevant to African Americans, who have higher prevalence of diabetes but relatively few studies of environmental pollution risk factors.Item Diesel exhaust impairs TREM2 to dysregulate neuroinflammation(BMC, 2020-11-22) Greve, Hendrik J.; Mumaw, Christen L.; Messenger, Evan J.; Kodavanti, Prasada R. S.; Royland, Joyce L.; Kodavanti, Urmila P.; Block, Michelle L.; Pharmacology and Toxicology, School of MedicineBACKGROUND: Air pollution has been linked to neurodegenerative diseases, including Alzheimer's disease (AD), and the underlying neuroimmune mechanisms remain poorly understood. TREM2 is a myeloid cell membrane receptor that is a key regulator of disease-associated microglia (DAM) cells, where loss-of-function TREM2 mutations are associated with an increased risk of AD. At present, the basic function of TREM2 in neuroinflammation is a point of controversy. Further, the impact of air pollution on TREM2 and the DAM phenotype is largely unknown. Using diesel exhaust (DE) as a model of urban air pollution exposure, we sought to address its impact on TREM2 expression, the DAM phenotype, the association of microglia with the neurovasculature, and the role of TREM2 in DE-induced neuroinflammation. METHODS: WYK rats were exposed for 4 weeks to DE (0, 50, 150, 500 μg/m3) by inhalation. DE particles (DEP) were administered intratracheally once (600 μg/mouse) or 8 times (100 μg/mouse) across 28 days to male mice (Trem2+/+, Trem2-/-, PHOX+/+, and PHOX-/-). RESULTS: Rats exposed to DE exhibited inverted-U patterns of Trem2 mRNA expression in the hippocampus and frontal cortex, while TREM2 protein was globally diminished, indicating impaired TREM2 expression. Analysis of DAM markers Cx3Cr1, Lyz2, and Lpl in the frontal cortex and hippocampus showed inverted-U patterns of expression as well, supporting dysregulation of the DAM phenotype. Further, microglial-vessel association decreased with DE inhalation in a dose-dependent manner. Mechanistically, intratracheal administration of DEP increased Tnf (TNFα), Ncf1 (p47PHOX), and Ncf2 (p67PHOX) mRNA expression in only Trem2+/+ mice, where Il1b (IL-1β) expression was elevated in only Trem2-/- mice, emphasizing an important role for TREM2 in DEP-induced neuroinflammation. CONCLUSIONS: Collectively, these findings reveal a novel role for TREM2 in how air pollution regulates neuroinflammation and provides much needed insight into the potential mechanisms linking urban air pollution to AD.Item Granzymes, IL-16, and poly(ADP-ribose) polymerase 1 increase during wildfire smoke exposure(Elsevier, 2023) Aguilera, Juan; Kaushik, Abhinav; Cauwenberghs, Nicholas; Heider, Anja; Ogulur, Ismail; Yazici, Duygu; Smith, Eric; Alkotob, Shifaa; Prunicki, Mary; Akdis, Cezmi A.; Nadeau, Kari C.; Graduate Medical Education, School of MedicineBackground: Given the increasing prevalence of wildfires worldwide, understanding the effects of wildfire air pollutants on human health-particularly in specific immunologic pathways-is crucial. Exposure to air pollutants is associated with cardiorespiratory disease; however, immune and epithelial barrier alterations require further investigation. Objective: We sought to determine the impact of wildfire smoke exposure on the immune system and epithelial barriers by using proteomics and immune cell phenotyping. Methods: A San Francisco Bay area cohort (n = 15; age 30 ± 10 years) provided blood samples before (October 2019 to March 2020; air quality index = 37) and during (August 2020; air quality index = 80) a major wildfire. Exposure samples were collected 11 days (range, 10-12 days) after continuous exposure to wildfire smoke. We determined alterations in 506 proteins, including zonulin family peptide (ZFP); immune cell phenotypes by cytometry by time of flight (CyTOF); and their interrelationship using a correlation matrix. Results: Targeted proteomic analyses (n = 15) revealed a decrease of spondin-2 and an increase of granzymes A, B, and H, killer cell immunoglobulin-like receptor 3DL1, IL-16, nibrin, poly(ADP-ribose) polymerase 1, C1q TNF-related protein, fibroblast growth factor 19, and von Willebrand factor after 11 days' average continuous exposure to smoke from a large wildfire (P < .05). We also observed a large correlation cluster between immune regulation pathways (IL-16, granzymes A, B, and H, and killer cell immunoglobulin-like receptor 3DL1), DNA repair [poly(ADP-ribose) 1, nibrin], and natural killer cells. We did not observe changes in ZFP levels suggesting a change in epithelial barriers. However, ZFP was associated with immune cell phenotypes (naive CD4+, TH2 cells). Conclusion: We observed functional changes in critical immune cells and their proteins during wildfire smoke exposure. Future studies in larger cohorts or in firefighters exposed to wildfire smoke should further assess immune changes and intervention targets.Item Smoggy with a Chance of Altruism: The Effects of Ozone Alerts on Outdoor Recreation and Driving in Atlanta(2014-02) Noonan, Douglas S.Metropolitan smog alerts are prominent public information campaigns designed to enhance public health and to curb driving and other emissions. Unlike many other voluntary information-based environmental policies, air quality alerts target household behavior via forecast information about ambient concentrations rather than firm or product characteristics. This paper explores behaviors with high emissions (driving) and with high exposure (outdoor recreation) and underscores the difference between altruistic and risk aversion motivations. Behavioral impacts are identified using the threshold nature of daily air quality forecasts. A regression discontinuity (RD) design finds elderly users and exercisers tend to curtail their use of a major park following smog alerts. The RD design also reveals that households do not drive less on smog alert days. Juxtaposing high emissions behavior with high exposure behavior in the same study highlights how public forecast information may better trigger some responses and struggle to trigger others.Item The bidirectional lung brain-axis of amyloid-β pathology: ozone dysregulates the peri-plaque microenvironment(Oxford University Press, 2023) Greve, Hendrik J.; Dunbar, August L.; Garza Lombo, Carla; Ahmed, Chandrama; Thang, Morrent; Messenger, Evan J.; Mumaw, Christen L.; Johnson, James A., Jr.; Kodavanti, Urmila P.; Oblak, Adrian L.; Block, Michelle L.; Pharmacology and Toxicology, School of MedicineThe mechanisms underlying how urban air pollution affects Alzheimer's disease (AD) are largely unknown. Ozone (O3) is a reactive gas component of air pollution linked to increased AD risk, but is confined to the respiratory tract after inhalation, implicating the peripheral immune response to air pollution in AD neuropathology. Here, we demonstrate that O3 exposure impaired the ability of microglia, the brain's parenchymal immune cells, to associate with and form a protective barrier around Aβ plaques, leading to augmented dystrophic neurites and increased Aβ plaque load. Spatial proteomic profiling analysis of peri-plaque proteins revealed a microenvironment-specific signature of dysregulated disease-associated microglia protein expression and increased pathogenic molecule levels with O3 exposure. Unexpectedly, 5xFAD mice exhibited an augmented pulmonary cell and humoral immune response to O3, supporting that ongoing neuropathology may regulate the peripheral O3 response. Circulating HMGB1 was one factor upregulated in only 5xFAD mice, and peripheral HMGB1 was separately shown to regulate brain Trem2 mRNA expression. These findings demonstrate a bidirectional lung-brain axis regulating the central and peripheral AD immune response and highlight this interaction as a potential novel therapeutic target in AD.Item The Use of Standardized Diesel Exhaust Particles in Alzheimer’s Disease Research(IOS Press, 2021) Block, Michelle L.; Kodavanti, Urmila P.; Pharmacology and Toxicology, School of MedicineThe mechanisms underlying how urban air pollution exposure conveys Alzheimer's disease risk and affects plaque pathology is largely unknown. Because particulate matter, the particle component of urban air pollution, varies across location, pollution source, and time, a single model representative of all ambient particulate matter is unfeasible for research investigating the role of ar pollution in central nervous system diseases. More specifically, the investigation of several models of particulate matter with enrichment of source-specific components are essential to employ, in order to more fully understand what characteristics of particulate matter affects Alzheimer's disease, including standardized diesel exhaust particles.