Date Published: July 31, 2007
Publisher: Public Library of Science
Author(s): Olivier Boucherat, Alexandra Benachi, Bernadette Chailley-Heu, Marie-Laure Franco-Montoya, Caroline Elie, Jelena Martinovic, Jacques R Bourbon, Peter J Barnes
Abstract: BackgroundPulmonary 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.Methods and FindingsWe 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-β1). KGF expression decreased slightly with time in control fetuses, but remained unchanged in fetuses with CDH. Leptin and NRG1-β1 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.ConclusionsOur 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.
Partial Text: Congenital diaphragmatic hernia (CDH) is a developmental abnormality that affects one in 2,500–5,000 live births, depending on the studies, and accounts for 8% of all major congenital anomalies. CDH restricts fetal lung development. The resulting lung hypoplasia and hypertension have dramatic consequences at birth, and the disease continues to cause high rates of mortality and morbidity despite recent progress in neonatal care [1,2]. Data from human fetuses with CDH, as well as data from animal models, indicate global lung immaturity with respect to fetal age, including reduced bronchial branching, decreased acinar complexity, thickened septa, and reduced vascularization . Although this concept is debated, lung immaturity in CDH has also been suggested to involve the surfactant system.
A persistent question regarding the care of neonates with CDH is whether these infants are effectively surfactant deficient. The question of whether to administer surfactant to infants born with CDH is not trivial, as this therapy can transiently compromise gas exchange. Information about surfactant status in humans is limited, has been obtained by indirect approaches, and has remained controversial. We reappraised the question through the ontogenetic study of surfactant directly in CDH lung tissue samples. We showed that, contrary to current opinion, surfactant accumulation occurs in CDH lungs at the normal time and rate.