Year of Award

2017

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Toxicology

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Kevan Roberts

Commitee Members

Andrij Holian, Stephen Lodmell, Christopher Migliaccio, Mark Pershouse

Keywords

Airborne Particulate Matter, Eosinophils, Inflammatory Effects, Lung, Nanoparticle, Woodsmoke

Abstract

Asthma, defined as a complex, chronic inflammatory disease of the airways, affects approximately 300 million individuals worldwide and is the single most common chronic disease among children. Airway inflammation is the defining characteristic of asthmatic pathophysiology; and as asthma increases in severity, the airways become more susceptible to environmental insults, including air pollutants. Wildfires and prescribed burns are significant sources of airborne particles, as well as gaseous pollution, which can temporarily increase the overall levels of air pollution over hundreds or thousands of square miles. Multi-walled carbon nanotubes (MWCNT) are increasingly used in a broad range of applications, including medical treatments, construction in the aerospace industry, and electronics manufacture. Accordingly, the following studies were conducted to narrow the gaps in existing knowledge of the health hazards posed by wood smoke (WS) and inhaled MWCNT. To model allergic asthma, the most common form of the disease, we introduced house dust mite (HDM) allergen, an allergy trigger for almost 85% of asthmatics. We found that adult C57BL/6 mice previously sensitized to HDM displayed significantly exacerbated lung inflammation following oropharyngeal MWCNT instillation. This was characterized by elevated levels of EPO and correspondingly increased eosinophil populations, measured by flow cytometry, in the BALF. Th2-associated cytokines traditionally implicated in allergic asthma, such as IL-13 and IL-22, were notably lacking; likewise, no clear alteration in CD4+ or CD8+ T cells was found. Instead, a significant increase in levels of cysteinyl leukotrienes (cys-LT) was detected, which correlated to increases in eosinophilia. This coincidence of augmented eosinophil recruitment and increased cys-LT production was again observed in our study of WS exposure. Adult female mice exposed to WS while pregnant displayed markedly increased eosinophilia when later sensitized to HDM, as evidenced by EPO levels and quantification via flow cytometry, as well as elevated cys- LT levels. Interestingly, the offspring of those WS-exposed mice, when sensitized to HDM in adulthood, responded with dramatically exacerbated inflammation in the same mode. H&E and PAS staining revealed mucus deposition and marked cellular infiltration in the lungs of prenatally exposed offspring following HDM challenge. Pups displayed highly significant differences in EPO levels between WS/HDM and Air/HDM groups at 8 weeks of age; eosinophilia decreased over time, with these differences remaining significant at 16 weeks and being lost by 24 weeks. The numbers of CD4+ and CD8+ T cells were also affected: in dams, WS inflated these populations and HDM decreased them; in pups, the opposite was true. These findings indicate a direct relationship between the biosynthesis of cys-LT and the recruitment of eosinophils in response to MWCNT inhalation, and suggest that a similar mechanism—likely with a greater T cell component—may be responsible for the inflammation arising from exposure to WS.

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© Copyright 2017 Sophia Tracy Carvalho