Air pollution, especially particulate matter (PM), has a substantial impact on global health, with the World Health Organization estimating 800,000 annual excess cardiopulmonary deaths through mechanisms that are not entirely clear. Ongoing work in our program has revealed potentiating interactions between combustion- source PM and associated gaseous components that can enhance systemic vascular toxicity. Despite the protective barrier afforded by the lung, the systemic vascular endothelium is a vulnerable target of air pollution toxicity and sensitive to the combinations of PM and gas components. Classic outcomes of inflammatory endothelial activation are observable in animals and humans exposed to a wide variety of pollutants; such responses are central to early development of atherosclerosis and also to late-stage events, such as plaque instability and rupture. What remains unclear is the pathway by which air pollution toxicity is transferred from the lung to the vasculature. We postulate that inflammatory endothelial activation arises following inhalation of air pollutants due to oxidative modifications of blood components, and reflects a common mode of action for many pollutants. Plasma obtained from humans exposed to diesel or nitrogen dioxide activates endothelial cells, suggesting that the transfer of toxicity from the lung to systemic vessels is carried in the blood stream. Multiligand scavenger and pattern recognition receptors on endothelial cells, including the lechtin-like receptor for oxidized LDL (LOX-1) and CD36, may represent a focal junction that reduces the complex serum alterations to common vascular pathological responses. The objectives of the renewed project are to expand on two key findings from the original project: 1) gases and PM interact to enhance vascular toxicity and 2) inhaled pollutants increase circulating inflammatory potential. Thus in Aim 1, we will elucidate interactions between PM and volatile organics in driving systemic vascular toxicity. Here, we hypothesize that combining PM with the gaseous portion of motor vehicle emissions will enhance vascular toxicity in a manner dependent on the surface area and composition of the PM.
In Aim 2, we will measure circulating inflammatory potential relative to components of combined engine emissions, and analyze results using novel statistical methods designed for complex mixtures. We hypothesize that the potency of acute endothelial cell activation by circulating factors will be dose-dependent, exacerbated by combined PM and gas phases, and will correlate with chronic vascular remodeling and oxidative stress. Lastly in Aim 3, we will delineate the relative contribution of CD36 and LOX-1 in driving pulmonary generation of and endothelial response to circulating factors induced by O3 and MVE. We hypothesize that despite the complex atmospheric chemistry and serum composition changes with pollution exposures, the multiligand receptors CD36 and LOX-1 mediate endothelial response and NOS inactivation. Successful completion of these Aims will identify new pathways that mediate transference of air pollution toxicity to systemic vasculature that contributes to cardiovascular morbidity.
Air pollution has a substantial impact on global health, with the World Health Organization estimating 800,000 annual excess cardiopulmonary deaths. We postulate inhalation of air pollutants cause's oxidative modifications to blood components that trigger inflammatory endothelial activation through multiligand receptors such as CD36 and LOX-1, which reflects a common mode of action for many pollutants.
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