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Air Pollution Exposure with Fine Dust. Responses in the Pulmonary Vasculature and the Right Heart

ABSTRACT: Detrimental effects of air pollution with fine dust (particulate matter ?2.5 ?m in aerodynamic diameter, or PM2.5) on the systemic circulation and the left heart have been studied intensely during the past decade. In comparison, knowledge regarding the effects of exposure to air pollution with PM2.5 on the pulmonary vasculature and the right heart lags far behind. A report on severe lung disease and right heart failure in coal miners was published nearly 170 years ago. However, today, we still do not have a clear picture of how the effect of air pollution on the pulmonary circulation or the right heart should be viewed from a clinical, mechanistic biological, therapeutic, or economic angle. In the laboratory, we have established a model of immune response–induced vascular remodeling that is significantly worsened by adding PM2.5 to the intranasal antigen challenge solution. Importantly, the PM2.5 is given at a concentration that by itself does not induce significant inflammation or pulmonary vascular remodeling. However, when added to antigen, this low-dose PM2.5 exposure induces severe pulmonary vascular remodeling, significantly increased right ventricular pressures, and significant molecular changes in the right heart. Our data also show that these PM2.5-exaggerated responses are dependent on interleukin-13, interleukin-17A, and antigen-specific antibody. The experimental model is being used to address a few questions:1. Which mechanism protects the animals from severe right ventricular failure despite the severity of the pulmonary artery remodeling?2. What is the mechanism by which PM2.5 worsens the response to antigen?3. How does PM2.5 exert its effects across the small airways to the small blood vessels? In conclusion, further investigation is urgently needed to understand the effects of exposure to ambient or occupational air pollution on the pulmonary vasculature, because better knowledge could lead to immediate beneficial actions for patients with pulmonary hypertension and persons at risk.

SUBMITTER: Durmus N

PROVIDER: S-EPMC5955039 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Project description:BackgroundEpidemiological evidence suggests that exposure to ambient air fine particulate matter (PM2.5) increases the risk of developing type 2 diabetes and cardiovascular disease. However, the mechanisms underlying these effects of PM2.5 remain unclear.ObjectivesWe tested the hypothesis that PM2.5 exposure decreases vascular insulin sensitivity by inducing pulmonary oxidative stress.MethodsMice fed control (10-13% kcal fat) and high-fat (60% kcal fat, HFD) diets, treated with 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) or mice overexpressing lung-specific extracellular superoxide dismutase (ecSOD) were exposed to HEPA-filtered air or to concentrated PM2.5 (CAP) for 9 or 30 days, and changes in systemic and organ-specific insulin sensitivity and inflammation were measured.ResultsIn control diet-fed mice, exposure to CAP for 30 days decreased insulin-stimulated Akt phosphorylation in lung, heart, and aorta but not in skeletal muscle, adipose tissue, and liver and did not affect adiposity or systemic glucose tolerance. In HFD-fed mice, 30-day CAP exposure suppressed insulin-stimulated endothelial nitric oxide synthase (eNOS) phosphorylation in skeletal muscle and increased adipose tissue inflammation and systemic glucose intolerance. In control diet-fed mice, a 9-day CAP exposure was sufficient to suppress insulin-stimulated Akt and eNOS phosphorylation and to decrease IκBα (inhibitor of the transcription factor NF-κB levels in the aorta. Treatment with the antioxidant TEMPOL or lung-specific overexpression of ecSOD prevented CAP-induced vascular insulin resistance and inflammation.ConclusionsShort-term exposure to PM2.5 induces vascular insulin resistance and inflammation triggered by a mechanism involving pulmonary oxidative stress. Suppression of vascular insulin signaling by PM2.5 may accelerate the progression to systemic insulin resistance, particularly in the context of diet-induced obesity. Citation: Haberzettl P, O'Toole TE, Bhatnagar A, Conklin DJ. 2016. Exposure to fine particulate air pollution causes vascular insulin resistance by inducing pulmonary oxidative stress. Environ Health Perspect 124:1830-1839; http://dx.doi.org/10.1289/EHP212.

Project description:Epidemiological evidence indicates that exposures to fine particulate matter air pollution (PM2.5) contribute to global burden of disease, primarily as a result of increased risk of cardiovascular morbidity and mortality. However, mechanisms by which PM2.5 exposure induces cardiovascular injury remain unclear. PM2.5-induced endothelial dysfunction and systemic inflammation have been implicated, but direct evidence is lacking.To examine whether acute exposure to PM2.5 is associated with endothelial injury and systemic inflammation.Blood was collected from healthy, nonsmoking, young adults during 3 study periods that included episodes of elevated PM2.5 levels. Microparticles and immune cells in blood were measured by flow cytometry, and plasma cytokine/growth factors were measured using multiplexing laser beads. PM2.5 exposure was associated with the elevated levels of endothelial microparticles (annexin V+/CD41-/CD31+), including subtypes expressing arterial-, venous-, and lung-specific markers, but not microparticles expressing CD62+. These changes were accompanied by suppressed circulating levels of proangiogenic growth factors (EGF [epidermal growth factor], sCD40L [soluble CD40 ligand], PDGF [platelet-derived growth factor], RANTES [regulated on activation, normal T-cell-expressed and secreted], GRO? [growth-regulated protein ?], and VEGF [vascular endothelial growth factor]), and an increase in the levels of antiangiogenic (TNF? [tumor necrosis factor ?], IP-10 [interferon ?-induced protein 10]), and proinflammatory cytokines (MCP-1 [monocyte chemoattractant protein 1], MIP-1?/? [macrophage inflammatory protein 1?/?], IL-6 [interleukin 6], and IL-1? [interleukin 1?]), and markers of endothelial adhesion (sICAM-1 [soluble intercellular adhesion molecule 1] and sVCAM-1 [soluble vascular cellular adhesion molecule 1]). PM2.5 exposure was also associated with an inflammatory response characterized by elevated levels of circulating CD14+, CD16+, CD4+, and CD8+, but not CD19+ cells.Episodic PM2.5 exposures are associated with increased endothelial cell apoptosis, an antiangiogenic plasma profile, and elevated levels of circulating monocytes and T, but not B, lymphocytes. These changes could contribute to the pathogenic sequelae of atherogenesis and acute coronary events.

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Air Pollution Exposure with Fine Dust. Responses in the Pulmonary Vasculature and the Right Heart

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