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Pediatric Surgery International

, Volume 27, Issue 1, pp 47–52 | Cite as

Prenatal treatment with retinoic acid activates parathyroid hormone-related protein signaling in the nitrofen-induced hypoplastic lung

  • Takashi Doi
  • Kaoru Sugimoto
  • Elke Ruttenstock
  • Jens Dingemann
  • Prem Puri
Original Article

Abstract

Purpose

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.

Keywords

Nitrofen Parathyroid hormone-related protein Congenital diaphragmatic hernia Retinoic acid Pulmonary hypoplasia 

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Takashi Doi
    • 1
    • 2
  • Kaoru Sugimoto
    • 1
  • Elke Ruttenstock
    • 1
  • Jens Dingemann
    • 1
  • Prem Puri
    • 1
    • 2
  1. 1.The Children’s Research CentreOur Lady’s Children’s HospitalDublin 12Ireland
  2. 2.School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical ResearchUniversity College DublinDublinIreland

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