Biomedical Sciences ETDs

Publication Date

Spring 5-13-2023

Abstract

Wildfire smoke is a global issue affecting nearly all humans on the surface of this Earth. Smoke dispersion from wildfires can span continents and cross oceans with amazing ease. Furthermore, total acres of land burned per year in the United States has roughly doubled since 1980, meaning this issue will persist for an indeterminate amount of time. Exposure to wildfire smoke is hazardous and promotes aging-associated events in the cardiopulmonary systems. Yet long- and short-term effects on the brain remain relatively unknown. From these, it is critically important to understand the neurological impacts from wildfire smoke exposure; to compare these effects to a more replicable woodsmoke exposure systems in a lab setting; and to endeavor mitigation strategies.

In our first study, we serendipitously exposed mice to wildfire smoke at a distance >1,000 km from the fire source (California, 2020). The exposure quantification revealed an ebb and flow of PM2.5 (particulate matter 2.5 µM diameter)concentration intensities, and variations in the levoglucosan abundance (measure of woodsmoke content). Upon sacrifice, we found markers of blood brain barrier (BBB) permeability, neuronal damage, inflammation, peripheral immune infiltration, and markers that indicated an acceleration of brain aging.

Initial follow-up studies utilized an in-lab woodchip smoldering exposure system to determine the neuroinflammatory temporal dynamics and metabolomic effects of inhaled wildfire smoke. We attempted to model our exposure paradigm based on a lower concentration than millions of Americans receive during yearly wildfires. Our results revealed that vascular inflammation resolved before our experimental cutoff timepoint of 28 days. However, peripheral immune infiltration increased 14 days post exposure, and inflammation persisted in the brain until our final timepoint of 28 days. Slightly more alarming, markers of brain aging and damage were observed at the 28-day timepoint as well. From these, we were unable to determine exactly when neurological inflammation and accelerated aging were fully mitigated, as they appeared to extend past the 28 days we measured.

In our final study, we attempted to reverse the effects seen in studies (1) and (2). Utilizing aged, 18-month-old mice, exposures were performed as in study (2) and therapeutic longevity-promoting drugs were administered for 10 weeks following a 2-week woodsmoke exposure (end age of 21 months). Therapeutic dosing included the combination of a sirtuin 1 activator – Resveratrol – and a nicotinamide adenine dinucleotide (NAD+) booster – nicotinamide mononucleotide (NMN) – and/or the combination of senolytic drugs – Dasatinib and Quercetin. When comparing to filtered air controls, the overt inflammatory effects of wildfire smoke observed in study (2) were naturally resolved within 10 weeks. However, woodsmoke diminished cardiac function, and serotonin levels were decreased in the prefrontal cortex of woodsmoke-exposed animals over the 10-week period. These results reveal long-term effects from a modest exposure paradigm with implications in heart disease and depression, and warrant follow-up studies to determine the most effective mitigation strategies.

Keywords

Willdfire, wood smoke, aging, neuroinflammation, metabolomic, NMN resveratrol Dasatinib and Quercetin

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Alicia Bolt

Second Committee Member

Matthew Campen

Third Committee Member

Mark McCormick

Fourth Committee Member

Jonathan Brigman

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