Author ORCID Identifier

https://orcid.org/0000-0002-2012-8189

Semester

Fall

Date of Graduation

2023

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Salik Hussain

Committee Member

Eric Kelley

Committee Member

Michael Gunther

Committee Member

Scott Weed

Committee Member

Timothy Nurkiewicz

Abstract

Inhalation of nano-TiO2 is linked to adverse clinical outcomes that affect people worldwide, particularly those who work in manufacturing. For example, cardiovascular consequences and changes in microvascular responses are, in part, associated with exposure to engineered nanomaterials such as nano-TiO2; however, the mechanism(s) driving this process is unknown. Nano-TiO2 is an engineered nanomaterial (ENM) that is reported to, upon inhalation, impair endothelium-dependent vasodilation in several vascular beds via enhanced local oxidant generation and diminished nitric oxide bioavailability. This dissertation aims to address the health concerns generated by occupational exposure to nano-TiO2 and identify a link between the oxidant producing enzyme, xanthine oxidoreductase (XOR) and nano-TiO2-mediated vascular dysfunction. The overarching hypothesis is that XOR plays a critical role in nano-TiO2-mediated vascular dysfunction and that altering XOR product identity from oxidants to NO can provide a novel treatment strategy. This hypothesis was tested using two aims: 1) define XOR-mediated contributions to vascular dysfunction allied to inhalation of nano-TiO2 and establish the liver as the source of amplified circulating XOR and 2) Assess the impact of manipulating XOR product identity from oxidants to nitric oxide on nano-TiO2-mediated vascular dysfunction. The results demonstrate that inhalation of nano-TiO2 mediates systemic vascular dysfunction as assessed in the mesenteric system concomitant with an elevation of circulating XO which is likely released by hepatocytes. In addition, treatment with nitrite can serve to switch XOR-derived products from oxidants to NO and thus protect vasculature, the results in this dissertation have helped to gain an insight to the mechanisms driving nano-TiO2-mediated vascular dysfunction and potential clinical intervention via nitrite supplementation.

Embargo Reason

Publication Pending

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Available for download on Tuesday, August 13, 2024

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