Attenuation of MIR-17∼92 cluster in bronchopulmonary dysplasia

Rationale: Bronchopulmonary dysplasia remains a significant cause of neonatal morbidity; however, the identification of novel targets to predict or prevent the development of bronchopulmonary dysplasia remains elusive. Proper microRNA (miR)-17z92 cluster is necessary for normal lung development, and alterations in expression are reported in other pulmonary diseases. The overall hypothesis for our work is that altered miR-17z92 cluster expression contributes to the molecular pathogenesis of bronchopulmonary dysplasia. Objectives: The current studies tested the hypothesis that alterations in miR-17z92 cluster and DNA methyltransferase expression are present in bronchopulmonary dysplasia. Methods: miR-17z92 cluster expression, promoter methylation, and DNA methyltransferase expression were determined in autopsy lung samples obtained from premature infants who died with bronchopulmonary dysplasia, or from term/near-term infants who died from nonrespiratory causes. Expression of miR-17z92 cluster members miR-17 and -19b was measured in plasma samples collected in the first week of life from a separate cohort of preterm infants at a second institution in whom bronchopulmonary dysplasia was diagnosed subsequently. Measurements and Main Results: Autopsy tissue data indicated that miR-17z92 expression is significantly lower in bronchopulmonary dysplasia lungs and is inversely correlated with promoter methylation and DNA methyltransferase expression when compared with that of control subjects without bronchopulmonary dysplasia. Plasma sample analyses indicated that miR-17 and -19b expression was decreased in infants who subsequently developed bronchopulmonary dysplasia. Conclusions:Ourdata are thefirst todemonstrate alteredexpression of the miR-17z92 cluster in bronchopulmonary dysplasia. The consistency between our autopsy and plasma findings further support our working hypothesis that the miR-17z92 cluster contributes to the molecular pathogenesis of bronchopulmonary dysplasia.