Rogers Lynette K, Robbins Mary, Dakhlallah Duaa, Yang Zhaogang, Lee L James, Mikhail Madison, Nuovo Gerard, Pryhuber Gloria S, McGwin Gerald, Marsh Clay B, Tipple Trent E
1 Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
2 Division of Neonatology and.
Ann Am Thorac Soc. 2015 Oct;12(10):1506-13. doi: 10.1513/AnnalsATS.201501-058OC.
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)-17∼92 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-17∼92 cluster expression contributes to the molecular pathogenesis of bronchopulmonary dysplasia.
The current studies tested the hypothesis that alterations in miR-17∼92 cluster and DNA methyltransferase expression are present in bronchopulmonary dysplasia.
miR-17∼92 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-17∼92 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.
Autopsy tissue data indicated that miR-17∼92 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.
Our data are the first to demonstrate altered expression of the miR-17∼92 cluster in bronchopulmonary dysplasia. The consistency between our autopsy and plasma findings further support our working hypothesis that the miR-17∼92 cluster contributes to the molecular pathogenesis of bronchopulmonary dysplasia.
支气管肺发育不良仍然是新生儿发病的一个重要原因；然而，尚未找到预测或预防支气管肺发育不良发生的新靶点。正常的微小RNA（miR）-17∼92簇对于正常肺发育是必需的，并且在其他肺部疾病中也有表达改变的报道。我们研究的总体假设是，miR-17∼92簇表达的改变促成了支气管肺发育不良的分子发病机制。
当前研究检验了miR-17∼92簇和DNA甲基转移酶表达改变存在于支气管肺发育不良中的假设。
在因支气管肺发育不良死亡的早产儿或因非呼吸原因死亡的足月儿/近足月儿的尸检肺组织样本中，测定miR-17∼92簇表达、启动子甲基化和DNA甲基转移酶表达。在另一家机构从一组早产婴儿出生后第一周采集的血浆样本中，检测miR-17∼92簇成员miR-17和-19b的表达，这些婴儿随后被诊断为支气管肺发育不良。
尸检组织数据表明，与无支气管肺发育不良的对照受试者相比，支气管肺发育不良肺组织中miR-17∼92的表达显著降低，且与启动子甲基化和DNA甲基转移酶表达呈负相关。血浆样本分析表明，随后发生支气管肺发育不良的婴儿中miR-17和-19b表达降低。
我们的数据首次证明了支气管肺发育不良中miR-17∼92簇表达改变。尸检和血浆研究结果的一致性进一步支持了我们的工作假设，即miR-17∼92簇促成了支气管肺发育不良的分子发病机制。
