Diesel Exhaust Induces Glucocorticoid Resistance

1. Purpose Inhalation of air pollutants leads to both airway inflammation, with increased cytokine expression and inflammatory cell recruitment to the airways, and to airway hyperresponsiveness, which together contribute to airway resistance and breathing difficulties. Correlational data indicate that exposure to air pollution increases inhaled corticosteroids (ICS) use in asthmatics, suggesting that steroidal anti-inflammatory medications are suboptimally effective under these conditions. However, a major issue is that no study has yet been performed specifically to determine the effects of controlled diesel exhaust (DE) exposure on responses to ICS. Furthermore, investigators need better insight into mechanisms, including the effects of epigenetic modifications and polymorphisms in oxidative stress response genes, which remain under explored. Investigators anticipate that an improved understanding of air pollution-induced ICS hyporesponsiveness (reduced effectiveness) could underpin preventative guidelines, guide ICS usage in response to environmental exposures, and inform rational pharmaceutical development. Ultimately this could lead to fewer exacerbations in asthmatic and other susceptible populations.

Hypothesis:

Acute exposure to DE reduces ICS-inducible gene expression in vivo in asthmatics, in part through effects on epigenetic processes.

Justification:

Air pollution exposure correlates with increased use of ICS inhalers in asthmatics, suggesting that ICS offer less control during periods of higher air pollution. As genes induced by ICS are critical in reducing inflammatory messenger ribonucleic acid (mRNA) and protein expression, the investigators have chosen to focus on the effects of DE on ICS-inducible gene expression as our primary endpoint.