Endothelial inflammatory transcriptional responses to an altered plasma exposome following inhalation of diesel emissions

Abstract

Background: Air pollution, especially emissions derived from traffic sources, is associated with adverse cardiovascular outcomes. However, it remains unclear how inhaled factors drive extrapulmonary pathology.

Objectives: Previously, we found that canonical inflammatory response transcripts were elevated in cultured endothelial cells treated with plasma obtained after exposure compared with pre-exposure samples or filtered air (sham) exposures. While the findings confirmed the presence of bioactive factor(s) in the plasma after diesel inhalation, we wanted to better examine the complete genomic response to investigate (1) major responsive transcripts and (2) collected response pathways and ontogeny that may help to refine this method and inform the pathogenesis.

Methods: We assayed endothelial RNA with gene expression microarrays, examining the responses of cultured endothelial cells to plasma obtained from six healthy human subjects exposed to 100 μg/m³ diesel exhaust or filtered air for 2 h on separate occasions. In addition to pre-exposure baseline samples, we investigated samples obtained immediately-post and 24 h-post exposure.

Results: Microarray analysis of the coronary artery endothelial cells challenged with plasma identified 855 probes that changed over time following diesel exhaust exposure. Over-representation analysis identified inflammatory cytokine pathways were upregulated both at the 2 and 24 h conditions. Novel pathways related to FOXO transcription factors and secreted extracellular factors were also identified in the microarray analysis.

Conclusions: These outcomes are consistent with our recent findings that plasma contains bioactive and inflammatory factors following pollutant inhalation and provide a novel pathway to explain the well-reported extrapulmonary toxicity of ambient air pollutants.

• Air pollution
• diesel
• endothelium
• inflammation
• particulate matter
• plasma

Acknowledgements

The views expressed in this document are solely those of the authors and the U.S. EPA does not endorse any products or commercial services mentioned in this publication.

Declaration of interest

This study was funded by grants from the National Institutes of Health (ES014639) and the Environmental Protection Agency (RD-83479601-0). The authors declare no financial conflicts of interest with the content of the present manuscript.