Year of Award

2020

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 Migliaccio, Mark Pershouse, Yoon Hee Cho, James Pestka

Keywords

crystalline silica, docosahexaenoic acid, macrophage phenotype, multi-walled carbon nanotube, phagolysosomal membrane damage, pulmonary inflammation

Publisher

University of Montana

Abstract

Acute and chronic inflammation are vital contributing factors to pulmonary diseases which can be triggered by the exposure to airborne toxicants such as crystalline silica (SiO2) and nanomaterials. There has been an increasing trend in the use of nanomaterials; specifically multi-walled carbon nanotubes (MWCNT), in various consumer products that in turn will increase the risk of pulmonary diseases. Unfortunately, there is a lack of preventative and therapeutic treatments for these diseases. A potential treatment that has been shown to have anti-inflammatory effects is the common dietary supplement docosahexaenoic acid (DHA); an omega-3 polyunsaturated fatty acid most commonly found in fish oil. However, the anti-inflammatory mechanisms of DHA are unclear in regard to particle-induced inflammation. Macrophages are important regulators in an immune response to inhaled foreign materials, such as SiO2 and MWCNT, in order to maintain homeostasis. Exposure to various particles can cause phagolysosomal membrane permeability (LMP) within macrophages which activates the NLRP3 inflammasome resulting in inflammation. Macrophage functions are dependent upon various signaling factors which generate different macrophage phenotypes described broadly as classically activated, “pro-inflammatory” M1 and alternatively activated, “anti- inflammatory” M2 as well as the additional M2 subsets. Signaling factors determine which macrophage phenotype is dominant to regulate the overall response to foreign particles. This research investigated DHA as both a prophylactic and a therapeutic treatment for particle-induced inflammation. The mechanisms by which DHA functions as an anti- inflammatory dietary supplement in regard to particle-induced inflammation were assessed by characterizing the impact of DHA on macrophage phenotypes and LMP.

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© Copyright 2020 Paige Lynn Fletcher