title: Prenatal treatment with retinoic acid activates parathyroid hormone-related protein signaling in the nitrofen-induced hypoplastic lung.
abstract: OBJECTIVE
  Prenatal treatment with retinoic acid (RA) has been reported to stimulate alveologenesis in hypoplastic lungs (HL) in the nitrofen model of congenital diaphragmatic hernia (CDH). Parathyroid hormone-related protein (PTHrP) promotes alveolar maturation by stimulating surfactant production, regulated by PTHrP receptor (PTHrP-R). PTHrP knockout and PTHrP-R null mice both exhibit pulmonary hypoplasia. We have recently reported that nitrofen inhibits PTHrP signaling in the nitrofen-induced HL. Because both PTHrP and PTHrP-R genes have RA-inducible element, we hypothesized that prenatal administration of RA upregulates pulmonary gene expression of PTHrP and PTHrP-R in the nitrofen-induced HL.
  
  
  METHODS
  Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). RA was given on days D18, D19 and D20. Fetal lungs were obtained on D21 and divided into four groups: control, control + RA, nitrofen, nitrofen + RA. RT-PCR and Immunohistochemistry were performed to investigate the pulmonary PTHrP and PTHrP-R gene and protein expression in each group, respectively.
  
  
  RESULTS
  The pulmonary gene expression levels of PTHrP and PTHrP-R were significantly increased in nitrofen + RA group compared to nitrofen group (p < 0.05). Immunoreactivity of PTHrP and PTHrP-R was also remarkably increased in nitrofen + RA group compared to nitrofen group.
  
  
  CONCLUSIONS
  Upregulation of PTHrP and PTHrP-R genes after prenatal treatment with RA in the nitrofen-induced HL suggests that RA may have a therapeutic potential in reverting lung hypoplasia in CDH, by stimulating surfactant production and alveolar maturation.
authors.affiliation: The Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland.
authors.forename: Takashi
authors.initials: T
authors.lastname: Doi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Elke
authors.initials: E
authors.lastname: Ruttenstock
authors.forename: Jens
authors.initials: J
authors.lastname: Dingemann
authors.forename: Prem
authors.initials: P
authors.lastname: Puri
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D008168:Lung / Q000002:abnormalities* / Q000187:drug effects / Q000196:embryology*; D008171:Lung Diseases / Q000139:chemically induced / Q000196:embryology* / Q000378:metabolism; D000069463:Olive Oil; D044162:Parathyroid Hormone-Related Protein / Q000187:drug effects / Q000378:metabolism*; D010647:Phenyl Ethers; D010938:Plant Oils; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000069463:Olive Oil; D044162:Parathyroid Hormone-Related Protein; D010647:Phenyl Ethers; D010938:Plant Oils; D014212:Tretinoin; C007350:nitrofen