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Modeling mechanisms of susceptibility in vitro: Differential activation of the MAP kinase ERK, but not p38, mediates variability and adaptation in the pro-inflammatory response to ozone
Citation:
Bowers, E., S. McCullough, D. Morgan, L. Dailey, AND D. Diaz-Sanchez. Modeling mechanisms of susceptibility in vitro: Differential activation of the MAP kinase ERK, but not p38, mediates variability and adaptation in the pro-inflammatory response to ozone. Society of Toxicology Annual Meeting, Baltimore, MD, March 12 - 16, 2017.
Impact/Purpose:
The data included in this abstract provide insight into the molecular mechanisms responsible for the inter-individual variability in the response to air pollution exposure.
Description:
Ozone is a ubiquitous ambient air pollutant that causes pulmonary inflammation upon exposure. The ozone-induced inflammatory response varies by orders of magnitude and the range of variation in “healthy” individuals extends beyond that of “susceptible” populations, as defined by conventional risk factors. To investigate the molecular mechanisms responsible for this variability, we used an in vitro ozone exposure model with fully-differentiated primary bronchial epithelial cells collected from the lungs of a panel of healthy human donors. We assessed the inter-individual variability in the induction of the ozone-responsive genes IL-8, IL-6, COX2, and HMOX1 following exposure. Inductions were found to be a reproducible property of replicate exposures in cultures derived from the same donor. We separated donor cultures into “high” and “low” responders based on their induction of IL-8 relative to the group mean. Given that the MAP kinases ERK and p38 are the primary drivers of the ozone-mediated pro-inflammatory response, we sought to determine whether the observed variability in ozone-mediated gene expression was driven by variability in MAP kinase activation. High-responding cells exhibited significantly greater ozone-induced activation of ERK than their low-responding counterparts. While p38 activation was consistent between the two groups, the inhibition of both the ERK and p38 pathways was required to diminish ozone-mediated pro-inflammatory gene induction. Using these findings we explored the role of MAP kinase activation in ozone adaptation, an in vivo phenomenon that occurs during repeated ozone exposure that is long-observed but poorly understood. Upon repeated exposure, high-responding cells exhibited pro-inflammatory suppression that resembled ozone adaptation; however, contrary to previous hypotheses, adaptation did not correlate with increases in antioxidant potential. Instead, we found that activation of ERK, but not p38, is reduced during repeated exposures and correlated with adaptation. Gaining a better understanding the molecular mechanisms underlying variability and adaptation will help refine the prediction and protection of susceptible populations and also lend insight into the health effects of repeated ozone exposures.