Prenatal treatment with retinoic acid activates parathyroid hormone-related protein signaling in the nitrofen-induced hypoplastic lung.
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.
Doi
Takashi
T
The Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland.
Sugimoto
Kaoru
K
Ruttenstock
Elke
E
Dingemann
Jens
J
Puri
Prem
P
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
D000069463:Olive Oil; D044162:Parathyroid Hormone-Related Protein; D010647:Phenyl Ethers; D010938:Plant Oils; D014212:Tretinoin; C007350:nitrofen