Year of Award

2021

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Toxicology

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Andrij Holian

Commitee Members

Christopher T. Migliaccio, Scott Wetzel, J.B. Alexander (Sandy) Ross, John Reiners

Keywords

Engineered nano-material, Lipid order, Lysosome, Model Membrane, Silica

Abstract

Engineered nano-materials (ENM), which have at least one dimension less than 100 nm are an emerging group of materials that are widely used in everyday products and workplaces. Because of the wide variety of ENM and their use in today’s society, there is a concern for the impacts of ENM on human health following exposure. While humans could be exposed to ENM through various routes, there is significant concern for inhalation of ENM due to their size and ease of aerosolization. Studies have reported that ENM can deposit into the lungs, particularly in the alveoli, where resident macrophages can encounter and phagocytose these materials. An event known as phagolysosomal membrane permeability (LMP) caused by ENM in macrophages has been shown to trigger NLRP3 inflammasome formation and inflammatory cytokine release, which could lead to the development of chronic inflammatory diseases. It is predicted that LMP is a key step in this inflammatory response and that a mechanistic understanding of this process is important for the design of safer ENM and potential therapeutics for ENM-exposed individuals. Here, two of the most commonly used ENM, titanium dioxide (TiO2) and zinc oxide (ZnO), were selected for testing their ability to cause changes in membrane properties leading to LMP. Crystalline silica was included because it is well known in its ability to cause LMP and inflammatory diseases. Lipid membrane systems, such as liposomes and human red blood cells (RBC), were used to model lysosomes of macrophages, in order to determine how ENM disrupt lipid membranes and cause permeability. Spectroscopic techniques were used to demonstrate that TiO2, ZnO, and silica interact with lipid membranes and cause changes to membrane order, most notably an increase in lipid order, which lead to membrane permeability of small molecules in these model systems. The ability of these materials to trigger LMP and NLRP3 inflammasome formation in macrophage-like THP-1 cells was also investigated. Increased cell death and inflammasome formation was observed upon treatment with these materials, indicating that LMP is occurring, which precedes NLRP3 inflammasome formation and cytokine release. Together, these data indicate that the ENM and silica tested can interact with and change the order of lipid membranes. This change to order influences membrane permeability and could be a mechanism of LMP in macrophages.

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© Copyright 2021 Matthew Josiah Sydor