Human exposure to ambient air pollution is a pervasive global public health problem. Ambient levels of air pollutants, such as particulate matter and ozone, are associated with multiple adverse health effects, including increases in the incidence of morbidity and mortality. The underlying mechanism(s) responsible for the adverse effects of most air pollutants is not well understood. However, oxidative stress has been implicated as being a major contributor to the mechanism of toxic action of numerous gaseous and particulate air pollutants. The lungs serve as the primary route of exposure for air pollutants, making cells of the respiratory epithelia principal targets for many of the toxicological outcomes of air pollution exposure. The concentrations of gaseous and particulate matter (PM) air pollutants are primary determinants of the pulmonary toxicity resultant from air pollutant exposure. The study of oxidative responses to air pollutant exposure requires that a number of methodological challenges be overcome. The studies of this dissertation purposely address these challenges in the following manner: 1) Development and implementation of imaging methodologies for the investigation of effects resulting from particulate and gaseous air pollutant exposure to Human Airway Epithelial Cells (HAEC); 2) Examination of the cellular mechanisms that underlie oxidative stress responses to air pollution exposures in HAEC using live cell imaging methodologies; and 3) Examination of factors that mediate air pollution-induced changes in intracellular redox status. The major features of this body of work were able to validate and establish significant methodologies for examining the interaction of nano-scaled particulates with cellular environments, and observe oxidative alterations in the intracellular redox environment of oxidant-exposed cells in real-time. Moreover, these findings reveal that exposure to oxidative air pollutants, such as ozone, induces a profound increase in the intracellular glutathione redox potential of human airway epithelial cells that is indicative of an oxidant-dependent impairment of redox homeostasis in the cell. Cumulatively, this work advances current toxicological knowledge regarding the spatiotemporal interaction of gaseous and particulate air pollutants with cellular environments, while producing effective methodologies for the assessment of implications resulting from air pollutant exposure. Furthermore, the methodologies described herein can be used in broader toxicological applications assessing similar endpoints from other types of xenobiotic exposures.Doctor of Philosoph
