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 6 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 24h-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 condition. Novel pathways related to FOX 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. The specific study design implicates a novel pathway related to inflammatory blood borne components that may drive the extrapulmonary toxicity of ambient air pollutants.

Inflammatory and Vasoactive Effects of Serum Following Inhalation of Varied Complex Mixtures

“…As recently postulated (Vedal et al , 2013), combining combustion-source gases from fresh emissions with aged or secondary particles may enhance particle toxicity. Furthermore, we have confirmed the clinical relevance of diesel-induced serum bioactivity in human studies, showing not only induction of genes used in the present study (IL-8, ICAM-1, VCAM-1), but also a more complete microarray analysis of the endothelial cell response to plasma post-exposure (Channell et al ., 2012; Schisler et al ., 2015). The microarray analysis noted induction of more global inflammatory pathways in the endothelial cells treated with plasma post-diesel exposure, as well as induction of transcription factors previously unassociated with air pollution effects, including FOXO4, FOXF2, and TCF3 (Schisler et al, 2015).…”

Residential proximity to abandoned uranium mines and serum inflammatory potential in chronically exposed Navajo communities

“…13,14 Furthermore, it has been reported that polyphenols (namely resveratrol), as a nutraceutical treatment, led to reduced serum inflammatory potential in healthy subjects, as compared with placebo. 15 Such studies are coherent with animal toxicological research showing that the inhalation of various toxicants, including gases and particles, leads to inflammatory and antidilatory alterations in the serum composition.…”

Metabolomic changes in murine serum following inhalation exposure to gasoline and diesel engine emissions

“…MVE exposure induced several factors reflective of oxidative stress (oxidized glutathione, 13-HODE, 9-HODE) and altered fatty acid metabolism. In recent human and rodent studies, inhalation exposure to a wide variety of pollutants renders a pro-inflammatory bioactivity in the serum that can cause induction of inflammatory genes in cultured endothelial cells or impair vasodilation in isolated arteries (Aragon et al, 2015; Channell et al, 2012; Robertson et al, 2013; Schisler et al, 2015a). Metabolomic findings in the present study are consistent with serum alterations resulting from inhalation exposures, but it remains unclear if any specific alterations described herein cause this bioactivity.…”

“…Diesel exhaust inhalation induced a pro-inflammatory activity in serum of healthy human subjects, in that the serum more potently elevated transcription of adhesion molecules and cytokines in cultured endothelial cells (Channell et al, 2012; Schisler et al, 2015b). More recently, we have noted that inhalation of ozone, which reacts completely in the lung and does not pass beyond the surfactant layer intact, led to changes in the serum that diminished endothelial-dependent vasodilation in rats and mice, and the scavenger receptor CD36 appears to have a prominent intermediary role (Paffett et al, 2015; Robertson et al, 2013).…”

“…While cytokines such as IL-6 or TGF-beta are plausible candidates for mediating vascular or neuroinflammation, both human and rodent studies infrequently find these and similar cytokines to be elevated (Mills et al, 2005; Schisler et al, 2015b). We therefore collected murine serum samples following exposure conditions known to induce bioactivity and assessed changes in small molecule metabolites in a high-throughput manner to test whether substantial changes in this category of serum components might inform the pathogenesis of extrapulmonary outcomes.…”