Restoring effects of vitamin A on surfactant synthesis in nitrofen-induced congenital diaphragmatic hernia in rats.
Congenital diaphragmatic hernia (CDH) is a major cause of refractory respiratory failure in the newborn. Besides pulmonary hypoplasia, the pathophysiology of CDH also includes surfactant deficiency. Vitamin A (vit A) is important for various aspects of lung development. We hypothesized that antenatal treatment with vit A would stimulate lung surfactant synthesis in experimental CDH induced in rats by maternal ingestion of the herbicide nitrofen (2,4-dichloro-phenyl-p-nitrophenyl-ether) on Day 12. Fetuses were assigned to six experimental groups: (1) controls from rats that received olive oil, the vehicle; (2) fetuses from rats that received olive oil on Day 12 and vit A orally (15,000 IU) on Day 14; (3) nitrofen (N)-exposed fetuses without diaphragmatic hernia (N/no DH); (4) N/no DH from rats given vit A on Day 14; (5 ) nitrofen-exposed fetuses with DH (N/+DH); (6) N/+DH from rats given vit A on Day 14. Fetuses were delivered by C-section at Day 21. Lung DNA content was lowered in the nitrofen group as compared with the controls group, but increased by subsequent vit A treatment. Lung surfactant disaturated phosphatidylcholine was reduced in the N/+DH group and restored to control level by vit A. The expression level of surfactant proteins (SP) -A and -C was decreased in vit A-treated control rats and in nitrofen-exposed fetuses with or without DH. Vit A restored SP-A and -C mRNA expression to control levels in N/+DH. SP-B expression was lowered in N/no DH and increased by vit A in this group. The proportion of type II cells assessed by SP-B immunolabeling was lowered in N/+DH and restored by vit A treatment. We conclude that antenatal treatment with vit A restores lung maturation in nitrofen-induced hypoplastic lungs with CDH. These findings point out vit A as a potential therapeutical agent for correcting surfactant deficiency in CDH.
Thébaud
B
B
Réanimation Néonatale-UPRES 2704, Hôpital Antoine Béclère, Université Paris-Sud, Assistance Publique-Hôpitaux de Paris, France. bthebaud@ualberta.ca
Barlier-Mur
A M
AM
Chailley-Heu
B
B
Henrion-Caude
A
A
Tibboel
D
D
Dinh-Xuan
A T
AT
Bourbon
J R
JR
D000704:Analysis of Variance; D000818:Animals; D015152:Blotting, Northern; D002855:Chromatography, Thin Layer; D004247:DNA / Q000032:analysis; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D005865:Gestational Age; D006540:Herbicides / Q000633:toxicity*; D006548:Hernia, Diaphragmatic / Q000517:prevention & control*; D065630:Hernias, Diaphragmatic, Congenital; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008297:Male; D010647:Phenyl Ethers / Q000633:toxicity*; D010713:Phosphatidylcholines / Q000032:analysis; D011247:Pregnancy; D011663:Pulmonary Surfactants / Q000032:analysis / Q000096:biosynthesis* / Q000172:deficiency / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D014801:Vitamin A / Q000494:pharmacology*
D006540:Herbicides; D010647:Phenyl Ethers; D010713:Phosphatidylcholines; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D014801:Vitamin A; D004247:DNA; C007350:nitrofen