Surfactant maturation is not delayed in human fetuses with diaphragmatic hernia.
BACKGROUND
Pulmonary hypoplasia and persistent pulmonary hypertension account for significant mortality and morbidity in neonates with congenital diaphragmatic hernia (CDH). Global lung immaturity and studies in animal models suggest the presence of surfactant deficiency that may further complicate the pathophysiology of CDH. However, data about surfactant status in human fetuses with CDH at birth are contradictory. The lack of a chronological study of surfactant content in late pregnancy has been a significant limitation. The appropriateness of administering surfactant supplements to neonates with CDH is therefore a debated question.


RESULTS
We investigated surfactant content in human fetuses with CDH compared to age-matched fetuses with nonpulmonary diseases used as controls. Concentrations of disaturated phosphatidylcholine and surfactant proteins were found to be similar at a given stage of pregnancy, with both components showing a similar pattern of increase with progressing pregnancy in fetuses with CDH and in control fetuses. Thyroid transcription factor 1, a critical regulator of surfactant protein transcription, similarly displayed no difference in abundance. Finally, we examined the expression of three glucocorticoid-regulated diffusible mediators involved in lung epithelial maturation, namely: keratinocyte growth factor (KGF), leptin, and neuregulin 1 beta 1 (NRG1-beta1). KGF expression decreased slightly with time in control fetuses, but remained unchanged in fetuses with CDH. Leptin and NRG1-beta1 similarly increased in late pregnancy in control and CDH lungs. These maturation factors were also determined in the sheep fetus with surgical diaphragmatic hernia, in which surfactant deficiency has been reported previously. In contrast to the findings in humans, surgical diaphragmatic hernia in the sheep fetus was associated with decreased KGF and neuregulin expression. Fetoscopic endoluminal tracheal occlusion performed in the sheep model to correct lung hypoplasia increased leptin expression, partially restored KGF expression, and fully restored neuregulin expression.


CONCLUSIONS
Our results indicate that CDH does not impair surfactant storage in human fetuses. CDH lungs exhibited no trend toward a decrease in contents, or a delay in developmental changes for any of the studied surfactant components and surfactant maturation factors. Surfactant amounts are likely to be appropriate to lung size. These findings therefore do not support the use of surfactant therapy for infants with CDH. Moreover, they raise the question of the relevance of CDH animal models to explore lung biochemical maturity.
Institut national de la santé et de la recherche médicale (INSERM), Unité 841-Institut Mondor de Recherche Biomédicale, Créteil, France.
Olivier
O
Boucherat
Alexandra
A
Benachi
Bernadette
B
Chailley-Heu
Marie-Laure
ML
Franco-Montoya
Caroline
C
Elie
Jelena
J
Martinovic
Jacques R
JR
Bourbon
D000818:Animals; D015153:Blotting, Western; D005260:Female; D005333:Fetus / Q000378:metabolism*; D051523:Fibroblast Growth Factor 7 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006548:Hernia, Diaphragmatic / Q000235:genetics / Q000378:metabolism*; D065630:Hernias, Diaphragmatic, Congenital; D006801:Humans; D007231:Infant, Newborn; D020738:Leptin / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000196:embryology / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020890:Neuregulin-1; D011247:Pregnancy; D011663:Pulmonary Surfactants / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012756:Sheep
D020738:Leptin; C094131:NRG1 protein, human; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D011663:Pulmonary Surfactants; D051523:Fibroblast Growth Factor 7