Recent studies suggest that particulate matter (PM) derived from different sources with necessarily different physicochemical make up may differ in toxicity. It is important to investigate what components impact human health to assist the regulatory agencies to impose emission standards to reduce the health risk. The goal of this study is to use collected and characterized fine ambient particles, to determine the in vivo systemic vascular dysfunction in a murine model. Particles have been collected over the period of one month from 10 cities within the U.S. and 2 that are in Germany, (Hettstedt and Zerbst). Preliminary data on size and particle composition, as well as cellular response studies that focus on oxidative stress have been completed in our laboratory;these data will be utilized as our foundation for this study. Wild type (WT) and endothelial nitric oxide synthesis knockout (eNOS -/-) mice will be exposed, via trans-oral aspiration, to single or repeated doses of coarse, fine, and ultrafine particles from these locations to determine radical oxidative species formation and subsequent inflammation response and vascular dysfunction. We hypothesize that PM-induced pulmonary inflammation leads to uncoupling of eNOS in the systemic vasculature, which in turn will lead to NOS-generated intracellular radical oxidative stress (ROS). Intracellular oxidative stress induced by PM exposure causes endothelial nitric oxide synthesis inhibition and increases neutrophil adhesion to endothelial cells, causing inflammatory damage. The inflammation-related responses can then be correlated to vascular dysfunction by measuring polymorphonuclear leukocytes (PMN) in the lung in comparison to measurements of PMN in the circulation in WT vs. eNOS -/- mice. The characterization of systemic insult will be assessed by comparing vascular markers of oxidative stress (iNOS, eNOS activities and gene expression, glutathione levels, etc) and dysfunction (contraction response to agonists) in eNOS -/- to WT mice. Usage of the eNOS -/- mice will aid in understanding the mechanisms behind this uncoupling and, to verify this ROS generating pathway.
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