Doctor of Philosophy (PhD)
Epidemiological data associates high levels of combustion-derived particulate matter (PM) with deleterious respiratory outcomes, but the mechanism underlying those outcomes remains elusive. It has been acknowledged by the World Health Organization that PM exposure contributes to more than 4.2 million all-cause mortalities worldwide each year. Current literature demonstrates that PM exacerbates respiratory diseases, impairs lung function, results in chronic respiratory illnesses, and is associated with increased mortality. The proposed mechanisms revolve around oxidative stress and inflammation promoting pulmonary physiological remodeling. Our data demonstrate that environmentally persistent free radicals (EPFRs) stabilized on the surface of PM are capable of inducing oxidative stress and initiating inflammation. I also found that they are capable of inducing T helper cell 17 (Th17) immune responses via aryl hydrocarbon receptor activation. This was associated with neutrophilic invasion characteristic of steroid insensitive asthma. Using single-cell RNA sequencing analysis on adult mice lungs exposed to PM for four hours, I observed that epithelial cells showed upregulation of genes relating to pathogenic Th17 cells (eTh17), as well as upregulation in the AHR induction pathway. Dendritic cells demonstrated a T-helper 17 cell (Th17) specific T-cell activation while T-cells showed upregulation of TNF-alpha, NF-κB, TGF-β, and PI3K-Akt signaling pathways – indicative of a large pro-inflammatory response. I show in this dissertation that PM initiates a eTh17 specific inflammatory response causing neutrophilic asthma that can be rescued by inhibiting AhR or uptake of PM and the specific pathways in epithelial, dendritic, and T cells that promote eTh17 differentiation during initial PM exposure.
Harding, Jeffrey, "The Effects of Radical Containing Combustion Derived Particulate Matter in Adult Mouse Respiratory System" (2020). LSU Doctoral Dissertations. 5362.