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

Abstract

Chronic cardiovascular disease is associated with air pollution exposure in epidemiology and toxicology studies. Inhaled toxicants can induce changes in serum bioactivity that impact endothelial inflammatory gene expression in vitro and impair vasorelaxation ex vivo, which are common precursors to atherosclerosis. Comparisons between single pollutants and common combustion mixtures, in terms of driving such serum inflammatory and vasoactive effects, have not been characterized. Healthy C57BL/6 mice were exposed to a single 6h period of contrasting pollutant atmospheres: road dust, mixed vehicle emissions (MVE; a combination of gasoline and diesel engine emissions) particulate matter (MVE-PM), mixed vehicle emissions gases (MVE-G), road dust plus ozone, road dust plus MVE, and hardwood smoke. Serum obtained from mice 24h after these exposures was used as a stimulus to assess inflammatory potential in two assays: incubated with primary murine cerebrovascular endothelial cells for 4h to measure inflammatory gene expression, or applied to naïve aortic rings in an ex vivo myographic preparation. Road dust and wood smoke exposures were most potent at inducing inflammatory gene expression, while MVE atmospheres and wood smoke were most potent at impairing vasorelaxation to acetylcholine. Responses are consistent with recent reports on MVE toxicity, but reveal novel serum bioactivity related to wood smoke and road dust. These studies suggest that the compositional changes in serum and resultant bioactivity following inhalation exposure to pollutants may be highly dependent on the composition of mixtures.

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

“…The breadth of metabolomic outcomes is consistent with findings of serum-borne inflammatory bioactivity (Aragon et al, 2015), in that numerous metabolites were altered, but the outcomes fail to clearly identify potential intermediate drivers of vascular pathology. More extensive and comprehensive characterization of circulatory alterations following inhalation exposures to particles and gases, along with linkages to functional outcomes, is therefore necessary.…”

“…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.…”

“…MVE specifically has been extensively characterized in mouse models and has clear vasculotoxic effects (Aragon et al, 2015; Lund et al, 2011; Vedal et al, 2013). The underlying mechanism for such changes appears to be indirect, as particulates directly applied to vessels or cultured endothelial cells or directly injected intravenously often fail to recapitulate the vascular effects of relevant concentrations of inhaled particulates.…”

Inhalation exposure to three-dimensional printer emissions stimulates acute hypertension and microvascular dysfunction

“…However, single toxicant based studies do not accurately relate to the complexity of emissions generated by the 3D printing process. Fortunately, other groups have reported similar vascular consequences after exposure to complex mixtures of respirable PM and emission gases (Aragon et al , 2016). A lack of proper endothelium-dependent dilation in any microvascular bed results in the inability to adjust or maintain tissue perfusion with a variety of homeostatic processes (Pohl et al , 1994; Durand and Gutterman, 2013).…”

Serum from obstructive sleep apnea patients induces inflammatory responses in coronary artery endothelial cells

“…Additionally, we have used this serum cumulative inflammatory potential (SCIP) assay to show that prolonged use of a grape seed extract (principally resveratrol) could significantly lower inflammatory potential relative to placebo, while no changes were noted in circulating chemokines or acute phase proteins [24]. These studies suggests that serum factors altered by diseased states may induce changes in naïve cell behavior, and animal studies have confirmed that changes in endothelial mRNA gene expression are consistent with endothelial dysfunction, including decreased barrier integrity, increased leukocyte extravasation through the endothelium and downstream foam cell formation [25, 26]. …”