Abstract
BackgroundMicroRNA (miR) are small conserved RNA that regulate gene expression post-transcription. Previous genome-wide analysis studies in preterm infants indicate that pathways of miR 219-5p are important in infants with Bronchopulmonary Dysplasia (BPD).MethodsHere we report a prospective cohort study of extremely preterm neonates wherein infants diagnosed with severe BPD expressed increased airway miR-219-5p and decreased platelet derived growth factor receptor alpha (PDGFR-α), a target of mir-219-5p and a key regulator of alveolarization, compared to post-conception age-matched term infants.ResultsmiR-219-5p was highly expressed in the pulmonary epithelial lining in lungs of infants with BPD by in situ hybridization of human infant lungs. In both in vitro and in vivo (mouse) models of BPD, miR-219-5p was increased on exposure to hyperoxia compared with the normoxia control, with a complementary decrease of PDGFR-α. To further confirm the target relationship between miR‐219 and PDGFR-α, pulmonary epithelial cells (MLE12) and lung primary fibroblasts were treated with a mimic of miR-219-5p and a locked nucleic acid (LNA) based inhibitor of miR-219-5p. In comparison with the control group, the level of miR‐219 increased significantly after miR‐219 mimic treatment, while the level of PDGFR-α declined markedly. LNA exposure increased PDGFR-α. Moreover, in BPD mouse model, over-expression of miR-219-5p inhibited alveolar development, indicated by larger alveolar spaces accompanied by reduced septation.ConclusionsTaken together, our results demonstrate that increased miR-219-5p contributes to the pathogenesis of BPD by targeting and reducing PDGFR-α. The use of specific miRNA antagonists may be a therapeutic strategy for preventing the development of BPD.
Highlights
MicroRNA are small conserved RNA that regulate gene expression post-transcription
Tracheal aspirate (TA) samples were collected from preterm infants with established severe Bronchopulmonary Dysplasia (BPD) at 36 week’s postmenstrual age (PMA) and from full term infants who were 37–38 week’s gestation
Results miR‐219‐5p is increased whereas PDGFR‐α is decreased in airways of preterm infants with severe BPD when compared with gestation matched controls We collected 30 tracheal aspirate samples from infants with established severe BPD and 30 tracheal aspirate samples from term controls (Total 60, n = 30 each group)
Summary
MicroRNA (miR) are small conserved RNA that regulate gene expression post-transcription. Bronchopulmonary dysplasia (BPD) is a chronic lung disease with a high mortality rate that primarily affects premature infants receiving prolonged oxygen supplementation or mechanical ventilation [1]. The pathogenesis of this disease involves impaired alveolar septation accompanied by abnormal vascular remodeling, lung inflammation, and fibrosis [2]. Our group has identified dynamic microRNA-regulated interaction networks involved in normal lung development [5]. MicroRNAs (miRNAs) are a large conserved class of short noncoding RNA that usually function at the post-transcriptional level in diverse biological pathways [6]. The aberrant expression of different miRNA has been recognized in several lung diseases including BPD and has been reported extensively by our group [7,8,9,10] and others [11]
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