Exposure to Fine Particulate Air Pollution Is Associated With Endothelial Injury and Systemic Inflammation

Abstract

Rationale: 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.

Objective: To examine whether acute exposure to PM2.5 is associated with endothelial injury and systemic inflammation.

Methods and results: 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], GROα [growth-regulated protein α], and VEGF [vascular endothelial growth factor]), and an increase in the levels of antiangiogenic (TNFα [tumor necrosis factor α], IP-10 [interferon γ-induced protein 10]), and proinflammatory cytokines (MCP-1 [monocyte chemoattractant protein 1], MIP-1α/β [macrophage inflammatory protein 1α/β], IL-6 [interleukin 6], and IL-1β [interleukin 1β]), 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.

Conclusions: 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.

Keywords: air pollution; cardiovascular disease; inflammation; particulate matter; vascular disease.

© 2016 American Heart Association, Inc.

Figures

Figure 1

PM2.5 concentrations and blood-draw dates plotted over study periods. Line plots indicate ambient PM2.5 concentrations for various sites and methods where: “1-d FRM” indicates daily concentrations based on the Federal Reference Method and “24-h Real time” indicates 24-hour average concentrations based on continuous monitors from the Department of Environmental Quality sites (Lindon, North Provo, and Spanish Fork). “FOB 24-h Real time” indicates 24-hr concentrations from monitor located adjacent to blood-draw building and “Blood draw room 24-h” indicates 24-hr concentrations from monitor inside the blood-draw room. Dots indicate the times of and PM2.5 concentrations at blood draws for each 12-subject blood-draw group.

Figure 2

Subject-mean adjusted values for endothelial microparticles (panel A), monocytes (panel B), TNFα (panel C), and sICAM-1(panel D) plotted over PM2.5 concentrations, with fitted regression lines, 95% confidence limits, and 95% prediction limits.

Figure 3

Associations between elevated PM2.5 exposures biomarkers of inflammation. The biomarkers include all 42 measured cytokines and 2 adhesion molecules. The results are presented as percent change (and 95% CIs) in each analyte per 10 μg/m3 increase in PM2.5 relative to the mean. Estimates are derived from the subject-mean adjusted regressions and are ordered from left to right based on t-values—resulting in the most statistically significant positive associations being on the left and the most statistically significant negative associations being on the right.

Figure 4

Schematic of the proposed mechanism by which PM2.5 induces vascular injury. Inhalation and deposition of PM2.5 in the lungs triggers inflammatory responses that lead to the release of inflammatory cytokines (TNFα, MCP-1 and IL-8); the recruitment of immune cells (CD14+ monocytes, CD16+ natural killer cells, CD4+ and CD8+ T cells); suppression of growth/angiogenic factors (EGF, CD40L, PDGF-AA, RANTES, GROα); and an increase in anti-angiogenic factors (TNFα and IP-10), resulting in endothelial cell apoptosis and the generation of endothelial microparticles in blood. These events are associated with an increase in circulating levels of soluble adhesion molecules (sICAM-1 and sVCAM-1) and platelet-monocyte aggregates. Collectively, these responses contribute to the pathogenic sequelae of atherogenesis and may increase thrombotic potential increasing risk of acute cardiovascular events.