Restoring Effects of Vitamin A on Surfactant Synthesis in Nitrofen-induced Congenital Diaphragmatic Hernia in Rats

Abstract

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.

Local Fetal Lung Renin-Angiotensin System as a Target to Treat Congenital Diaphragmatic Hernia

“…No differences between groups were detected in CCSP, SP-C and PAS-stained cells score. Contradictory results about lung maturity and surfactant status in CDH animal models have been published, with studies demonstrating that the CDH lung is surfactant deficient (51)(52)(53) and others indicating no change in alveolar surfactant composition, un- changed or even increased surfactant protein expression (54)(55)(56)(57). However, one of the most recent studies performed with human CDH fetuses demonstrated that surfactant maturation is not delayed (54).…”

Vitamin A Is Systemically Bioavailable After Intratracheal Administration With Surfactant in an Animal Model of Newborn Respiratory Distress

“…The potential advantage of intratracheal administration of vitamin A with surfactant would be to achieve a direct local effect with decreased systemic side effects. This could possibly occur through the effect that vitamin A has on stimulation of surfactant synthesis (20,21). This is, however, unlikely because it happened independently from changes in lung compliance.…”

Spatial and Temporal Expression of Glucocorticoid, Retinoid, and Thyroid Hormone Receptors Is Not Altered in Lungs of Congenital Diaphragmatic Hernia

“…These results are supported by a series of experiments undertaken in the nitrofen rat model for CDH. This study was inspired by the promising results obtained by the administration of glucocorticoids, thyroid hormone or vitamin A to nitrofen-treated rats (13,16,17,(25)(26)(27). In our previous study, we have shown the expression of the nuclear hormone receptors in human lung from 13.5 wk until term with no change in localization throughout development (21).…”

“…Transgenic RAR␣/RXR␣ and RAR␣/␤ double knockout mice were shown to have lung hypoplasia or agenesis (37)(38)(39). Our collaborative studies in the nitrofen rat model for CDH demonstrated that prenatal administration of vitamin A reduces the incidence of CDH and increases the levels of surfactant protein A and C in the offspring (16,17). In …”

“…The incidence of a diaphragmatic defect reduced from 31% to 24% when a single dose of vitamin A administrated to vitamin Adeficient female rats on d 15 of pregnancy (15). Thebaud et al (16,17) have shown that antenatal treatment with vitamin A in the nitrofen-induced CDH model reduces the incidence of CDH at term as well as improving lung growth and maturation. In humans, lower plasma vitamin A levels were found in prematurely born infants, especially in patients with respiratory distress and in a selective number of term newborns with pulmonary hypoplasia associated with congenital diaphragmatic hernia (18,19).…”