Adrenomedullin is up-regulated in nitrofen-induced fetal pulmonary hypoplasia.
OBJECTIVE
Pulmonary hypoplasia associated with congenital diaphragmatic hernia remains a major therapeutic problem. Adrenomedullin (AM), a multifunctional regulatory peptide, has been suggested to play a role in the mechanisms of fetal lung differentiation and maturation. The aim of this study was to investigate the pulmonary expression of AM in nitrofen-induced fetal pulmonary hypoplasia.


METHODS
Pulmonary hypoplasia was induced in timed-pregnant Sprague-Dawley rats after administration of 100 mg nitrofen on day 9.5 of gestation. Fetal and neonatal lungs were excised on gestational days 16.5, 19, and 21 and 1 hour after birth and divided into the following 3 groups: nitrofen with diaphragmatic defect, nitrofen without diaphragmatic defect, and control (without nitrofen). Pulmonary levels of AM and AM messenger RNA expression were measured by radioimmunoassay and real time quantitative reverse transcriptase polymerase chain reaction, respectively. Localization of pulmonary AM was identified by immunohistochemical staining.


RESULTS
There was a significant increase in pulmonary level of AM in the nitrofen-treated groups on gestational days 19 and 21. Real time quantitative reverse transcriptase polymerase chain reaction on gestational day 19 confirmed an increase of AM gene expression in the nitrofen-treated groups. Adrenomedullin immunoreactivity was more strongly expressed in airway epithelial cells in the nitrofen-treated groups than in the control.


CONCLUSIONS
Nitrofen up-regulates expression of AM in the fetal lung, which suggests that AM has some pathophysiological role in the differentiation and/or maturation processes of pulmonary hypoplasia in congenital diaphragmatic hernia.
Kamiyama
Masafumi
M
Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. kamiyama@pedsurg.med.osaka-u.ac.jp
Usui
Noriaki
N
Kamata
Shinkichi
S
Fukuzawa
Masahiro
M
Nagaya
Noritoshi
N
Kangawa
Kenji
K
D000014:Abnormalities, Drug-Induced / Q000378:metabolism; D053607:Adrenomedullin; D000818:Animals; D005260:Female; D008168:Lung / Q000002:abnormalities* / Q000378:metabolism; D010455:Peptides / Q000502:physiology*; D010647:Phenyl Ethers / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
D010455:Peptides; D010647:Phenyl Ethers; D053607:Adrenomedullin; C007350:nitrofen