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

Creagh Breuner, Christopher Migliaccio, K. Michael Pollard, Kevan Roberts, Scott Wetzel

Abstract

The majority of lung diseases occur with a sex-bias is prevalence and/or severity. However, due to the historical disregard for sex as a biological variable in basic and clinical research, there is a fundamental lack of understanding on when and why respiratory inflammation preferentially affects males or females. The inhalation of engineered nanomaterials (ENM; intentionally produced by anthropogenic means and defined as having one dimension as < 100 nm) are of particular concern when considering emerging threats to lung health. Due to their extremely small size, these respirable particles are capable of reaching the functional gas exchange region of the lungs, where they cannot be easily cleared and subsequently lead to persistent inflammation, decreased lung function, and susceptibility to the development of other respiratory diseases. Multi-walled carbon nanotubes (MWCNT) are an ENM of interest due to their widespread use in industrial, consumer, and medical applications, making them a potential hazard in both occupational and environmental settings. Alveolar macrophages (AMs) are the resident immune cells within the lungs that are responsible for phagocytosing and clearing inhaled xenobiotics, including ENM. However, typical AM clearance mechanisms are ineffective at removing persistent and pathogenic ENM such as MWCNTs, leading to the production of inflammatory mediators and the recruitment of other inflammatory immune cells. AMs have the ability to adopt a wide spectrum of functional phenotypes dependent upon endogenous and exogenous signals; these phenotypes ensure that the appropriate immune response is initiated in response to a given xenobiotic. However, when dysregulated, these phenotypes are also associated with different disease states. Interestingly, there is emerging data that sex steroid hormones (estrogen, specifically) impact AM phenotype development and inflammatory signaling, which may be, in part, responsible for the reported sex-biases observed in human lung diseases. The present research identifies sex-differences in MWCNT-induced lung inflammation, AM phenotype development, and one mechanism by which sex hormones impact AM function and subsequent inflammation.

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© Copyright 2021 Jessica Lynn Ray