title: Disruption of the bone morphogenetic protein receptor 2 pathway in nitrofen-induced congenital diaphragmatic hernia.
abstract: OBJECTIVE
  Congenital diaphragmatic hernia (CDH) remains a major therapeutic challenge despite advances in neonatal resuscitation and intensive care. The high mortality and morbidity in CDH has been attributed to pulmonary hypoplasia and persistent pulmonary hypertension (PH). Bone morphogenetic protein receptor 2 (BMPR2) plays a key role in pulmonary vasculogenesis during the late stages of fetal lung development. BMPR2 is essential for control of endothelial and smooth muscle cell proliferation. Dysfunction of BMPR2 and downstream signaling have been shown to disturb the crucial balance of proliferation of smooth muscle cells contributing to the pathogenesis of human and experimental PH. We designed this study to investigate the hypothesis that BMPR2 signaling is disrupted in nitrofen-induced CDH.
  
  
  METHODS
  Pregnant rats were treated with nitrofen or vehicle on gestational day 9 (D9). Fetuses were sacrificed on D21 and divided into CDH and control. Quantitative real-time polymerase chain reaction, Western blotting, and confocal-immunofluorescence were performed to determine pulmonary gene expression levels and protein expression of BMPR2 and related proteins.
  
  
  RESULTS
  Pulmonary Bmpr2 gene expression levels were significantly decreased in nitrofen-induced CDH compared to controls. Western blotting and confocal microscopy revealed decreased pulmonary BMPR2 protein expression and increased activation of p38(MAPK) in CDH compared to controls.
  
  
  CONCLUSIONS
  The observed disruption of the BMPR2 signaling pathway may lead to extensive vascular remodeling and contribute to PH in the nitrofen-induced CDH model. BMPR2 may therefore represent a potential target for the treatment of PH in CDH.
authors.affiliation: National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland; Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Jan-Hendrik
authors.initials: JH
authors.lastname: Gosemann
authors.forename: Florian
authors.initials: F
authors.lastname: Friedmacher
authors.forename: Naho
authors.initials: N
authors.lastname: Fujiwara
authors.forename: Luis A J
authors.initials: LA
authors.lastname: Alvarez
authors.forename: Nicolae
authors.initials: N
authors.lastname: Corcionivoschi
authors.forename: Prem
authors.initials: P
authors.lastname: Puri
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006548:Hernia, Diaphragmatic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D065630:Hernias, Diaphragmatic, Congenital; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010647:Phenyl Ethers / Q000633:toxicity*; D019000:Phosphotyrosine / Q000378:metabolism; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D052006:Bone Morphogenetic Protein Receptors, Type II; D010647:Phenyl Ethers; D019000:Phosphotyrosine; D012333:RNA, Messenger; D051785:Smad Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C498862:Acta2 protein, rat; C498220:Bmpr2 protein, rat; C007350:nitrofen
keywords: BMPR2; congenital diaphragmatic hernia; nitrofen; pulmonary hypertension