Harnessing Inter-Individual Variability to Identify Molecular Mechanisms Shaping Airway Epithelial Cell Transcriptional Responses to Ozone Exposure
Public Deposited- Last Modified
- March 19, 2019
- Creator
-
Bowers, Emma
- Affiliation: School of Medicine, Curriculum in Toxicology
- Abstract
- Millions of people are exposed to levels of the ambient air pollutant ozone that are known to produce pulmonary inflammation; however, inflammatory responses exhibit extensive inter-individual variability. Moreover, during multi-day exposures acute inflammatory responses are attenuated, resulting in a phenomenon known as “ozone adaptation.” The mechanisms governing these phenomena are not understood, but their identification is essential in understanding the health impacts of air pollutant exposure. The ozone-mediated induction of pro-inflammatory genes is a key step in the release of cytokines and chemokines in the airway. Thus, differences in the regulation of transcription may be a potential source of ozone inflammatory response inter-individual variability and may explain ozone adaptation. To model ozone associated transcriptional inter-individual variability, primary human bronchial epithelial cells (phBECs) were collected from different individuals, cultured at air-liquid-interface, and exposed to ozone in vitro. I then examined the expression of the chemokine IL-8, a central mediator of pulmonary inflammation, in addition to other ozone-responsive genes. I found that ozone inductions exhibited inter-individual variability and were reproducible within donors even when phBECs were collected, cultured, and exposed at different times. This suggests that ozone-responsive gene induction adheres to a set of biological rules that remain to be defined. Recent findings suggest that the MAPKs p38 and ERK1/2 mediate ozone response in phBECs, thus I investigated whether these kinases also controlled gene induction inter-individual variability. I found that phBECs with higher inductions of IL-8 are distinguished by elevated activation of ERK1/2, but not p38, following ozone exposure. Upon repeated ozone exposure, ozone-responsive gene expression was suppressed and was paralleled by decreases in ERK1/2 activation, suggesting that this may be an important adaptive mechanism. In collaboration with other scientists, I also found that epigenetic modifications at pro-inflammatory gene promoters were strongly associated with ozone-associated gene expression, suggesting that the epigenome is critical part of epithelial cell response ‘programming.’ In summary, this work identifies novel molecular mechanisms that dictate responsiveness to ozone exposure. This information can be used to refine definitions of susceptible populations and better predict health outcomes associated with air pollutant exposures.
- Date of publication
- May 2017
- Keyword
- DOI
- Resource type
- Rights statement
- In Copyright
- Advisor
- Diaz-Sanchez, David
- Jaspers, Ilona
- Fry, Rebecca
- Emanuele, Michael
- Weissman, Bernard
- Degree
- Doctor of Philosophy
- Degree granting institution
- University of North Carolina at Chapel Hill Graduate School
- Graduation year
- 2017
- Language
Relations
- Parents:
This work has no parents.
Items
| Thumbnail | Title | Date Uploaded | Visibility | Actions |
|---|---|---|---|---|
|
|
Bowers_unc_0153D_17181.pdf | 2019-04-09 | Public | Download |