Citation:

Farraj, A. Early Endothelial Bioactivity of Serum after Diesel Exhaust Inhalation: A Driver of Latent Impairment in Left Ventricular Pressure in the Heart? 2017 Annual Meeting of the Society of Toxicology, Baltimore, Maryland, March 12 - 16, 2017.

Impact/Purpose:

This work helps shed light on the uncertainty with respect to the mechanisms that mediate cardiovascular dysfunction after exposure to air pollution. This work suggests that cardiac effects in particular may potentially be driven by circulating soluble mediators of inflammation that target the heart and/or vasculature. These findings provide biological plausibility to the epidemiological evidence linking short and long term exposure to air pollution to increased cardiovascular morbidity and mortality.

Description:

Adverse cardiovascular effects of air pollution are often associated with a spike in systemic proinflammatory biomarkers, but causative linkage between circulating factors and deleterious outcomes following exposure remains elusive. Endothelial dysfunction is a consequence of systemic inflammation and precedes multiple cardiovascular pathologies. The purpose of this study was to examine the plausibility of serum-bound factors as initiators of an air pollution-induced pathologic sequelae beginning with endothelial injury, and later, cardiac dysfunction. We hypothesized that serum taken from diesel exhaust (DE)-exposed rats that develop cardiac dysfunction would alter aortic endothelial cell function in vitro. To assess cardiac function in vivo, left ventricular pressure (LVP) assessments were conducted in rats one day after a single 4 hour whole body exposure to 150 or 500 μg/m3 DE or filtered air. Rat aortic endothelial cells (RAEC) were then exposed to diluted serum (10%) collected 1 hour after exposure from a separate cohort of similarly exposed rats for measures of VCAM-1, cell viability, nitric oxide synthase (NOS) levels, and mRNA expression of key mediators of inflammation. Exposure of rats to 150 or 500 μg/m3 DE increased heart rate (HR) after exposure relative to rats exposed to filtered air, suggesting a shift towards increased sympathetic tone. LVP and HR in DE-exposed rats (500 μg/m3 DE) failed to recover to normal levels after challenge with the sympathomimetic dobutamine, suggesting dysregulation of mean arterial pressure, a response consistent with impaired post-exercise recovery of cardiac function in humans exposed to air pollution. Serum from DE-exposed rats caused a decrease in NOS activity (150, 500 μg/m3 DE) and cell viability (500 μg/m3 DE), and an increase in VCAM-1 (500 μg/m3 DE) in RAECs relative to cells treated with serum from rats exposed to filtered air. Thus, cardiac responses after DE exposure may stem from a shift in autonomic balance and/or endothelial dysfunction that may in part be triggered by exposure-induced increases in circulating proinflammatory mediators. Proteomic and lipid assessments in rat sera are currently being conducted to confirm the presence of a circulating proinflammatory milieu after exposure and to identify potential causative factors (this work is supported in part by NIH R01 ES019311 and K99 ES024392; this abstract does not reflect EPA policy).

Record Details: