Abstract:
Inhalation of particulate matter (PM) has long been implicated to influence health. Historically, emphasis has been placed on adverse effects to the lung, but advances in ambient PM monitoring and use of modern epidemiological techniques have revealed strong associations with the progression of cardiovascular disease and cardiovascular mortality. The aerodynamic diameter of particles determines deposition location within the lung, and fine particles (PM2.5) can reach deep into the lung and have been highlighted as having the most significant effect on cardiovascular health. The biological mechanism of PM2.5- mediated effect remains unclear, but many investigations point to the generation of oxygen radicals and subsequent oxidative stress as a principle driver of these observations. Glutathione (GSH) is a tripeptide thiol antioxidant and it is the principle determinant of the reductive potential within a cell. Common human polymorphisms within GSH synthesis genes have been shown to impair GSH synthesis, increase risk of myocardial infarction and lead to vasomotor dysfunction. As GSH is an important antioxidant and can prevent oxidative stress, we hypothesize that GSH and its de novo synthesis plays an important role in mediating the adverse pulmonary and cardiovascular effects of DE inhalation. To investigate this hypothesis we, 1) employed in vitro modeling using collected diesel exhaust particulate (DEP), 2) used a mouse model of compromised GSH synthesis to determine susceptibility to DEP-induced lung inflammation, 3) investigated the role of GSH and GSH synthesis in normal vascular function, and 4) investigated the effect of compromised GSH synthesis in mediating adverse pulmonary and vascular effects following acute DE inhalation. Together, this dissertation provides data to support the hypothesis that GSH and its de novo synthesis plays a role in mediating the adverse effects of DE inhalation, has provided valuable contributions to our understanding of biological mechanisms of DE-effects, and has provided sufficient evidence to warrant further investigations into the potential Gene X Environment interaction between GSH synthesis genes and PM2.5.