Airway Epithelial Resilience to Environmental/Oxidative Threats: Intersection with Type-2 Biology and Racial Inequity

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Project Summary/Abstract Although asthma is common, the morbidity/mortality rates for Black Americans are unacceptably high. Gene-by-environment interactions likely play important roles, such that greater exposures to exogenous oxidative stressors, especially unhealthy air in many US Black communities could adversely affect outcomes. These exposures also intersect with various non-biologic factors, including institutional racism. “Redlining,” or discriminatory mortgage lending and form of institutional racism, provides historic/geographically validated regions of interest across the US to study the intersection of airway biology with racial and environmental inequity. Endogenously, epithelial cells can resist exogenous oxidative stress, like air pollutants, but at the expense of reduced glutathione (GSH). In preliminary data, our lab showed that reduced GSH is depleted in epithelial cells of Type-2 Hi asthma, secondary to activation of the 15-lipoxygenase 1 (15LO1) pathway which leads to higher endogenous oxidative stress. 15LO1-Hi conditions also promote autophagy, potentially modulating the release of extracellular vesicles (EVs), including exosomes, while decreasing the release of free/’toxic” mitochondrial DNA. Unfortunately, factors that further stress epithelial cells overcome these programmed resiliency factors to induce ferroptosis, a recently identified form of cell death that promotes the release of “free” mtDNA associated with further reductions in EVs. We hypothesize that environmental hazards that increase exogenous oxidative stress, such as higher levels of exposure to air pollution as associated with racism, intersect with T2 asthma-associated, 15LO1-dependent endogenous oxidative stress in airway epithelial cells. This convergence depletes resiliency factors (GSH, “healthy” mtDNA, EVs) and increases inflammation and susceptibility to ferroptotic death, which worsens asthma outcomes. To address this hypothesis, we propose 2 aims: 1) determine the effect of increasingly toxic environments on intracellular and intercellular resiliency factors, with emphasis on the intersection with asthma biology ex vivo and 2) determine the singular and combinatorial effect of endogenous and exogenous oxidative stress on intracellular and intercellular resiliency factors in vitro. My goal is to gain cell biology, epidemiology, and bioinformatics training, facilitating my transition to an independent scientist with the necessary skill set to address the environmental health effects of racism on asthma through cutting-edge translational science. Through this fellowship, I will also receive clinical asthma, research ethics, and public health training, which will pave my path to success. The data obtained here will help me in my next career stages and also form the foundation for asthma interventions targeting communities damaged by racism.