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microRNA Profiling Reveals Differential Response to Ozone between Asthmatic and Healthy Donors
Citation:
JARDIM, M. J., L. A. DAILEY, H. REN, AND D. DIAZ SANCHEZ. microRNA Profiling Reveals Differential Response to Ozone between Asthmatic and Healthy Donors. Presented at American Thoracic Society Conference, New Orleans, CA, May 14 - 19, 2010.
Impact/Purpose:
We hypothesized that observed bronchial hyperresponsiveness of asthmatics could be due to differences in molecular responses to pollutants, specifically in the regulation ofmiRNA expression.
Description:
Introduction: Morbidity and mortality attributable to air pollution continue to be growing problems worldwide. People with underlying pulmonary diseases, such as asthma, are susceptible to the negative health effects of air pollutant exposure. Asthma is characterized by an increase in airway hyperresponsiveness and chronic inflammation, which are exacerbated when individuals are exposed to oxidant pollutants, such as ozone. Despite several studies on the health effects of ambient air pollution, underlying molecular mechanisms of susceptibility and disease remain elusive. MicroRNAs are small noncoding RNAs that have been quickly established as key regulators ofgene expression. We hypothesized that observed bronchial hyperresponsiveness of asthmatics could be due to differences in molecular responses to pollutants, specifically in the regulation ofmiRNA expression. Methods: Bronchial epithelial cells (BECs) from healthy and mild/moderate asthmatic donors were exposed to O.4ppm ozone for 4 hours. TotalRNA was isolated and analyzed for miRNA using microarray profile analysis and quantitative real-time PCR. Putative targets for significantly changed miRNAs were identified using miRBase and miRDB databases. Molecular network analyses were generated with Ingenuity Pathway Analysis. Results: We show here that BECs from mild/moderate asthmatics differentially.respond to ozone exposure than do cells from healthy individuals as seen by the up-or down-regulation ofmiRNAs. The expression of 89 and 74 miRNAs significantly changed (~1.5 fold.p-valuesu.Oo) in healthy and asthmatic groups, respectively, out ofapproximately 312 detectable miRNAs. 23 miRNAs changed similarly in both groups whereas 50 changed specifically in the asthmatic group and 65 were unique to healthy donors. Molecular network analysis of putative targets for significantly changed common miRNAs revealed that these miRNAs may regulate cell processes such as DNA damage and cell cycle progression (p-valuegl O' 4). Putative targets of miRNAs unique to healthy donors seemed to regulate anti-oxidant responses (p-valuexlO") whereas those specific to asthmatic donors seemed to modulate the inflammatory response (p-valuexl O"). Conclusions: Exposure to ozone rapidly alters miRNA expression profiles in BECs from both, asthmatic and healthy donors. Additionally, these data suggest that cellular responses to air pollutants may be different in susceptible populations, which may explain exacerbation ofthe negative health effects observed in these groups. Overall, these results not only suggest that underlying epigenetic mechanisms may be influenced by environmental pollutants but thatdifferences in these mechanisms may contribute to the susceptibility of certain groups to the negative impact of pollutant exposure. THIS ABSTRACT OF A PROPOSED PRESENTATION DOES NOT NECESSARILY REFLECT EPA POLICY.