Amelia Freeman1, Luhua Qiao1, Nelida Olave1, Gabriel Rezonzew1, Samuel Gentle1, Brian Halloran1, Gloria S Pryhuber2, Amit Gaggar3, Trent E Tipple4, Namasivayam Ambalavanan1, Charitharth Vivek Lal5,6. 1. Division of Neonatology, Department of Pediatrics, Women and Infants Center, University of Alabama At Birmingham, 176F Suite 9380619 South 19th Street, Birmingham, AL, 35249-7335, USA. 2. Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA. 3. Program in Matrix and Pulmonary Biology, Department of Medicine, University of Alabama, Birmingham, AL, USA. 4. Center for Pregnancy and Newborn Research, Section of Neonatal-Perinatal Medicine, University of Oklahoma College of Medicine, Oklahoma, OK, USA. 5. Division of Neonatology, Department of Pediatrics, Women and Infants Center, University of Alabama At Birmingham, 176F Suite 9380619 South 19th Street, Birmingham, AL, 35249-7335, USA. clal@peds.uab.edu. 6. Program in Matrix and Pulmonary Biology, Department of Medicine, University of Alabama, Birmingham, AL, USA. clal@peds.uab.edu.
Abstract
BACKGROUND: MicroRNA (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). METHODS: Here 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. RESULTS: miR-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. CONCLUSIONS: Taken 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.
BACKGROUND: MicroRNA (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). METHODS: Here 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. RESULTS:miR-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. CONCLUSIONS: Taken 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.
Authors: Marcel H Schulz; Kusum V Pandit; Christian L Lino Cardenas; Namasivayam Ambalavanan; Naftali Kaminski; Ziv Bar-Joseph Journal: Proc Natl Acad Sci U S A Date: 2013-08-28 Impact factor: 11.205
Authors: Lynette K Rogers; Mary Robbins; Duaa Dakhlallah; Zhaogang Yang; L James Lee; Madison Mikhail; Gerard Nuovo; Gloria S Pryhuber; Gerald McGwin; Clay B Marsh; Trent E Tipple Journal: Ann Am Thorac Soc Date: 2015-10
Authors: Namasivayam Ambalavanan; C Michael Cotten; Grier P Page; Waldemar A Carlo; Jeffrey C Murray; Soumyaroop Bhattacharya; Thomas J Mariani; Alain C Cuna; Ona M Faye-Petersen; David Kelly; Rosemary D Higgins Journal: J Pediatr Date: 2014-11-06 Impact factor: 4.406
Authors: P Lindahl; L Karlsson; M Hellström; S Gebre-Medhin; K Willetts; J K Heath; C Betsholtz Journal: Development Date: 1997-10 Impact factor: 6.868