Rationale: We previously demonstrated that decreased miR-17~92 cluster expression was: 1) present in lungs from human infants who died with bronchopulmonary dysplasia (BPD); 2) inversely correlated with DNA methyltransferase (DNMT) expression and promoter methylation; 3) correlated with a subsequent diagnosis of BPD at 36 weeks' gestational age. Objectives: We tested the hypothesis that plasma miR-17 levels would be lowest in infants who ultimately develop severe BPD. Secondly, we utilized our well-characterized murine model of severe BPD which combines perinatal inflammation with postnatal hyperoxia to test the hypothesis that alterations in lung miR-17~92, DNMT, and promoter methylation in our model would mirror our findings in tissues from premature human infants. Methods: Plasma was obtained during the first 5 days of life from premature infants born ≤32 weeks gestation. Lung tissues were harvested from mice exposed to maternal inflammation and neonatal hyperoxia for 14 days after birth. miR-17~92 cluster expression and DNA methyltransferase expression were measured by qRT-PCR, and promoter methylation was assessed by Methyl-Profiler Assay. Measurements and Main Results: Plasma miR-17 levels are significantly lower in the first week of life in human infants who develop severe BPD compared to mild or moderate BPD. Data from our severe BPD murine model reveal that lung miR-17~92 cluster expression is significantly attenuated, and levels inversely correlated with DNMT expression and miR-17~92 cluster promoter methylation. Conclusion: Collectively, our data support a plausible role for epigenetically altered miR-17~92 cluster in the pathogenesis of severe BPD.
- Bronchopulmonary Dysplasia (BPD)
- Copyright © 2016, American Journal of Physiology-Lung Cellular and Molecular Physiology