Kristen E. Cosselman

Submitted by tranc4 on Mon, 08/13/2018 - 11:16

Project title: Mechanisms and Markers of the Cardiovascular Response to Traffic-Related Air Pollution in Humans

Degree: PhD | Program: Environmental and Occupational Hygiene (EOHY) | Project type: Thesis/Dissertation
Completed in: 2018 | Faculty advisor: Joel D. Kaufman


Exposure to traffic-related air pollution, a problem in city centers worldwide, is associated with an increased risk of cardiovascular morbidity and mortality. Though adverse health effects associated with these inhaled pollutants are well substantiated, the mechanisms between exposure and outcome remain unclear. Identification of molecular and physiological processes is critical in distinguishing susceptible populations and advancing prevention efforts. The studies in this dissertation integrate basic science with clinical measures to examine aspects of the vascular response in humans exposed to diesel exhaust (DE), a model traffic-related pollutant. This work combines three unique opportunities: an on-going genotype-stratified controlled human exposure study, a novel particle deposition device for in vitro modeling at the air liquid interface (ALI), and an inhalation facility designed to generate combustion-based pollutants. The studies examine multiple clinical and cellular responses to DE in humans under highly controlled conditions. Studies were designed based on the hypothesis that inhaled particles interact with nociceptive receptors within the airway epithelium, leading to the release of circulating vasoactive and inflammatory mediators; this in turn induces vasoconstriction and oxidative stress, raising the risk of cardiovascular events. Aims include investigation of 1) the effect and mechanism of DE inhalation on blood pressure and transcriptional outcomes in human subjects, and whether this effect is modified by genotype for the nociceptor TRPV1; 2) the primary response to DE exposure in human bronchial epithelial cells, using a state-of-the-art electrostatic deposition chamber; 3) the secondary response using human coronary artery endothelial cells cultured with DE conditioned media and human serum; and 4) the effect of DE on the ratio of reduced to oxidized glutathione (GSH/GSSG) in healthy adults, and whether pre-exposure antioxidant supplementation modified this response. This dissertation provides data to support the hypothesis that the acute hemodynamic effects of DE act via alpha adrenergic system, and evidence for the involvement of TRPV1; provides evidence that the lung epithelium may play an initial role in inflammatory processes and barrier dysfunction in coronary artery cells; and demonstrates that an acute exposure to DE is associated with a reduction in the GSH/GSSG ratio, consistent with shift in balance toward an oxidized state. Combining in vitro biomarkers with clinically-observed findings may provide key insights into understanding how exposure to traffic-related air pollution can promote or exacerbate the development of disease. URI