Interactions among Ozone, Oxysterols, and Adverse Health Effects in the Human Lung Public Deposited

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Last Modified
  • March 22, 2019
Creator
  • Speen, Adam
    • Affiliation: School of Medicine, Curriculum in Toxicology
Abstract
  • Despite the wealth of studies examining the adverse health effects of ozone exposure and its association with increased airway inflammation, the mechanisms behind it have yet to be fully described. Ours and previous studies have shown that exposure to O3 results in the formation of electrophilic lipid peroxidation products, notably through the oxidation of cholesterol in the airway lining fluid. These electrophilic oxysterols are capable of forming covalent linkages with nucleophilic centers of proteins, particularly lysine residues, thus altering cellular signaling pathways. Much remains to be learned about the identity of the reactive species and the range of potential proteins modified by the oxysterols in the lung and the biological consequences. Using 2D LC-MS/MS shotgun proteomics and “click” chemistry, we have generated a database of oxysterol-adducted proteins in airway epithelial cells treated with purified oxysterol Secosterol A as well as O3-derived oxysterols. Among those oxysterol-adducted proteins were LXR and NLRP2. O3-derived oxysterol adduction of LXR inhibits transcription of cholesterol transport and binding proteins and increases NF-κB activation and inflammatory cytokine signaling. NLRP2 is the most abundantly expressed member of the NLR family of proteins in human airway epithelial cells. Further, we show that exposure of epithelial cells to O3 increases NLRP2 expression, active caspase-1 levels, and markers of inflammasome assembly, suggesting that NLRP2 inflammasome complexes play important roles in airway epithelial cells and more specifically in the context of O3 exposure and oxysterol formation. Finally, we identify that the widely prescribed anti-psychotic drug Aripiprazole (APZ) has the potential to increase inflammatory response in human airway epithelial cells. We determine that APZ acts as an inhibitor of dehydrocholestrol reductase 7, resulting in an increased cellular concentration of the cholesterol precursor 7-dehydrocholesterol (7DHC). Ozonization of 7-DHC produces highly reactive oxysterol species in comparison to cholesterol ozonization products and our data shows that ozonization of 7-DHC compared to cholesterol results in increased inflammatory cytokine expression. Potentiation of the O3 inflammatory response by APZ reveals a new paradigm of study and highlights the need for further drug-x-environment interaction research.
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Advisor
  • Jaspers, Ilona
  • Hernandez, Michelle
  • Fessler, Michael
  • Samet, James
  • Kelada, Samir
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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