Date of Graduation

2015

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Jefferson C Frisbee

Committee Co-Chair

Timothy R Nurkiewicz

Committee Member

Aaron Barchowsky

Committee Member

Matthew A Boegehold

Committee Member

Dale W Porter

Committee Member

Edward M Sabolsky

Abstract

Cerium dioxide nanoparticles (CeO2 NP), an engineered nanomaterial, have great potential from a consumer and therapeutic perspective. Currently, CeO2 NP are added to diesel fuel to decrease the soot emissions commonly associated with diesel engines. CeO2 NP also have therapeutic applications (e.g. improve outcomes following stroke and radiation treatments) due to their anti-oxidant capabilities. These applications increase CeO2 NP exposure risk not only for manufacturers, but also for the general community; however, there are currently limited studies that investigated the effects of CeO2 NP exposure via multiple exposure routes. Furthermore, there are no studies that investigate the microvascular consequences of CeO2 NP exposure despite its importance in blood pressure and flow regulation.;Therefore, the aim of the first study was to determine the microvascular impacts of pulmonary CeO2 NP exposure. Based on previous studies with other nanoparticles, we predicted that CeO2 NP exposure would cause microvascular dysfunction that was dose and microvascular bed dependent. Microvascular function was assessed in mesenteric and coronary arterioles via isolated microvessels. Following exposure, endothelium-dependent and -independent arteriolar dilation was significantly impaired. CeO2 NP exposure also resulted in pulmonary inflammation (assessed via bronchoalveolar lavage). Finally, these impairments and inflammatory changes were dose dependent and microvascular bed dependent.;The aims of the second study were 1) determine the microvascular impacts of CeO2 NP exposure via non-pulmonary exposure routes (e.g. injection and ingestion) and 2) investigate the underlying mechanisms of microvascular dysfunction. Isolated mesenteric arterioles were analyzed 24 h post-exposure. Endothelium-dependent and -independent dilation was significantly impaired following the injection and ingestion of CeO2 NP and the severity of dysfunction was dose and exposure route dependent. Finally, this study determined that these impairments might be mechanistically linked to decreased soluble guanylyl cyclase activation, cyclic guanosine monophosphate responsiveness, and nitric oxide (NO) bioavailability. Finally, this study, along with the first study, established the dose, which caused a 50% impairment in arteriolar reactivity (EC50) for each exposure route.;The final study in this dissertation aimed to determine the in vivo anti-oxidant activity of CeO2 NP in the presence of a pre-existing pathology. Based on CeO2 NP catalytic activity, we predicted that exposure would decrease the microvascular dysfunction and oxidative stress associated with hypertension. Endothelium-dependent dilation was assessed via intravital microscopy and was significantly improved in spontaneously hypertensive (SH) rats following CeO2 NP exposure. Vascular oxidative stress was also significant reduced in the SH rats post-CeO2 NP exposure. Finally, CeO2 NP altered the expression of pro-inflammatory cytokines in the Wistar-Kyoto and SH groups.;In conclusion, these studies indicated that CeO2 NP exposure results in microvascular alterations, which are microvascular bed, exposure route, dose, and pathology dependent. Furthermore, these alterations may be due to changes in inflammation, oxidative stress, NO bioavailability, and/or intracellular signaling. These studies improve our understanding of the microvascular effects of CeO2 NP, which is essential for the development of these nanoparticles in commercial and therapeutic applications.

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