DOI

10.17077/etd.ds1a-z7ui

Document Type

Dissertation

Date of Degree

Fall 2018

Access Restrictions

Access restricted until 01/31/2020

Degree Name

PhD (Doctor of Philosophy)

Degree In

Chemical and Biochemical Engineering

First Advisor

Fiegel, Jennifer

First Committee Member

Nuxoll, Eric

Second Committee Member

Stanier, Charles

Third Committee Member

Roman, David

Fourth Committee Member

Jessop, Julie

Abstract

Particles that deposit in the respiratory airways can come from many sources, such as environmental pollution, particles created in the workplace, and inhalers that are designed to deliver medicines to the lungs. Once these particles deposit in the respiratory airways, they can interact in a variety of ways. Some particles are toxic and can cause damage to lung tissues, others may have little to no effect on health, and some may provide some benefit or therapy. Once particles land in the respiratory airways, the interactions they have with proteins can impact where they go and how they behave.

This thesis explores how particles that are inhaled may impact health through toxicity to lung cells. Aerosols produced from photooxidation of decamethylcyclopenta-siloxane, an ingredient common in personal care products, were exposed to lung cells using an air-liquid interface exposure system to assess if these aerosols impact lung cell health. No significant impacts on lung cell health were observed. Copper oxide, a component of cigarette smoke, urban particulate matter, and e-cigarette vapor, was assessed for its role in lung disease. Copper oxide nanoparticles were exposed to lung cells, and their viability, expression of a platelet activating factor receptor (PAFR), and susceptibility to infection with a pneumonia-causing bacterium (S. pneumoniae) were measured. Copper oxide nanoparticles were found to be toxic to lung cells. At some doses, increases in PAFR were observed, but no clear differences in susceptibility to bacterial infection were observed. This research improves knowledge of how inhaled materials can impact health, providing insight into how particles from human-derived sources affect the lungs.

This thesis further explores how particles behave in the thin layer of fluid that covers the respiratory epithelium. This fluid contains a complex mixture of proteins, and this work aims to identify some of the ways these proteins interact with particles and influence behavior. This was accomplished by first investigating how individual proteins from this fluid interact with particles. Particle behavior was studied after exposure to these proteins, as well as the lung cell responses to the particles before and after interaction with individual proteins. These lung proteins were found to induce aggregation, significantly alter surface charge, and reduce cell uptake of particles. After studying how individual proteins might specifically affect particle behavior, particles were exposed to bronchoalveolar lavage fluid (BALF), a diluted lung fluid collected by rinsing lungs with saline. Particle responses to proteins in this fluid were compared to those in serum, a protein-rich blood extract. These studies identified differences in how various surface-functionalized polystyrene particles aggregated in BALF compared to serum. When particles were exposed to serum or BALF, they tended to be less likely to associate with lung cells. With some particle types studied, there were significant differences in how much BALF or serum reduced cell attachment and uptake. In addition to demonstrating that lung fluids impact particle behavior in a manner that differs from serum, a method was developed to increase the concentration of the proteins in BALF to partially undo the dilution that occurs during collection. After studying how protein adsorption can cause aggregation, cover up particle surfaces, and reduce attachment and uptake by lung cells, a polymer coating was synthesized to reduce particle interactions with these proteins and assist in stabilizing particles in lung fluids. This coating was tested in both BALF and serum to demonstrate its general utility at reducing undesired interactions with proteins in biological fluids and was found to enhance particle stability in lung fluids as well as saline. This research enhances understanding of how particles behave in the respiratory airways, providing tools to further study how particles behave in lung fluids and demonstrating a polymer coating that is useful in this environment.

Keywords

Drug Delivery, Inhaled Particles, Nanoparticles, Protein Corona, Pulmonary Health, Zwitterionic Polymers

Pages

xxii, 196 pages

Bibliography

Includes bibliographical references (pages 179-196).

Comments

This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: http://www.lib.uiowa.edu/sc/contact/

Copyright

Copyright © 2018 Benjamin Michael King

Available for download on Friday, January 31, 2020

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