Year of Publication
Doctor of Philosophy (PhD)
Dr. Bernhard Hennig
Within the last few decades, epidemiological evidence has linked exposure to air pollution, both its particles and its organic components, with cardiovascular disease (CVD) progression. CVD is a life long disease with the disruption of the endothelium being the inaugural event in this inflammatory process. The vascular endothelium is extremely susceptible to environmental insults given its tremendous surface area and that it is in constant contact with blood and components circulating within the blood, including xenobiotics. The endothelium is important as a barrier from blood constituents however, dysfunction of this barrier leads to the influx of lymphocytes and granulocytes that lead to the fatty build‐up characteristic of atherosclerosis.
The studies presented in this dissertation tested the hypothesis that two unique environmental contaminants, alumina nanoparticles and benzo[a]pyrene (B[a]P), lead to increased endothelial cell dysfunction, characterized by increased adhesion molecule expression. Alumina nanoparticles induced vascular cell adhesion molecule‐1 (VCAM‐1), intercellular adhesion molecule‐1 (ICAM‐1), and E‐selectin (ELAM‐1), as well as increased monocyte adhesion to activated endothelium. Polystyrene nanoparticles did not elicit this response. B[a]P induced ICAM‐1 expression, but only after toxification by aryl hydrocarbon receptor (AhR) controlled enzymes. Silencing of either AhR or the membrane microdomains called caveolae attenuated the B[a]P‐induced ICAM‐1 response. It was also shown that the induction of ICAM‐1 occurred by signaling through MEK, p‐38 MAPK, and activator protein‐1 (AP‐1). These data provide a novel mechanism by which air pollutants like B[a]P may cause increased atherosclerosis and describe a new toxicant, alumina nanoparticles, as a possible threat for the development of inflammatory diseases, such as atherosclerosis.
Little is known about dietary interventions capable of alleviating xenobiotic‐induced toxicity. Nutrition is an obtainable and inexpensive means of possible preventative therapy. With this in mind, it was also hypothesized that plant polyphenols, such as flavonoids, can down‐regulate B[a]P‐induced ICAM‐1. Selective flavonoids, containing both a 4’ B‐ring hydroxyl substitution and a 2‐3 C‐ring double bond, protected against B[a]P‐induced ICAM‐1 activation, however this protection did not correlate with the flavonoid’s antioxidant capacity.
Oesterling, Elizabeth Grace, "ENDOTHELIAL CELL DYSFUNCTION BY ENVIRONMENTAL CONTAMINANTS" (2008). University of Kentucky Doctoral Dissertations. 642.