Pro-inflammation and pro-atherosclerotic responses to short-term air pollution exposure associated with alterations in sphingolipid ceramides and neutrophil extracellular traps

Abstract

Air pollution has been associated with the development of atherosclerosis; however, the pathophysiological mechanisms underlying pro-atherosclerotic effects of air pollution exposure remain unclear. We conducted a prospective panel study in Beijing and recruited 152 participants with four monthly visits from September 2019 to January 2020. Linear mixed-effect models were applied to estimate the associations linking short-term air pollution exposure to biomarkers relevant to ceramide metabolism, pro-inflammation (neutrophil extracellular traps formation and systemic inflammation) and pro-atherosclerotic responses (endothelial stimulation, plaque instability, coagulation activation, and elevated blood pressure). We further explored whether ceramides and inflammatory indicators could mediate the alterations in the profiles of pro-atherosclerotic responses. We found that significant increases in levels of circulating ceramides of 9.7% (95% CIs: 0.7, 19.5) to 96.9% (95% CIs: 23.1, 214.9) were associated with interquartile range increases in moving averages of ambient air pollutant metrics, including fine particulate matter (PM_2.5), black carbon, particles in size fractions of 100-560 nm, nitrogen dioxide, carbon monoxide and sulfur dioxide at prior up to 7 days. Higher air pollution levels were also associated with activated neutrophils (increases in citrullinated histone H3, neutrophil elastase, double-stranded DNA, and myeloperoxidase) and exacerbation of pro-atherosclerotic responses (e.g., increases in vascular endothelial growth factor, lipoprotein-associated phospholipase A2, matrix metalloproteinase-8, P-selectin, and blood pressure). Mediation analyses further showed that dysregulated ceramide metabolism and potentiated inflammation could mediate PM_2.5-associated pro-atherosclerotic responses. Our findings extend the understanding on potential mechanisms of air pollution-associated atherosclerosis, and suggest the significance of reducing air pollution as priority in urban environments.

Keywords: Atherosclerosis; Biomarkers; Ceramides; Neutrophil extracellular traps; Urban air pollution.