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.
Methods and Findings
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-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.
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.
In an autopsy study of human fetuses, Jacques Bourbon and colleagues report that pulmonary surfactant content is not decreased in congenital diaphragmatic hernia.
Congenital diaphragmatic hernia (CDH), a fetal malformation in which the abdominal organs are displaced into the chest cavity, occurs in approximately one out of 3,000 live births and accounts for approximately 8% of major birth defects. The displaced lungs tend to be underdeveloped at birth, and decreased lung function is a major cause of sickness and death in affected babies.
Pulmonary surfactant, a substance naturally produced by cells in the lungs in the weeks before birth, is necessary for normal breathing. Surfactant acts to keep the walls of the lung's airspaces from collapsing onto each other, much as detergent can keep the walls of a moist plastic bag from sticking together.
Why Was This Study Done?
The specific aspects of lung immaturity that cause decreased function in babies with CDH are not fully understood. In particular, it has been unclear whether abnormally low levels of pulmonary surfactant contribute to the lung problems caused by CDH. Some studies in sheep or rat models of CDH have found that surfactant levels are abnormally low, while others have found normal or even increased levels of surfactant. Studies in human CDH have also shown controversial results, and few have investigated surfactant production in lung tissue itself.
Doctors can artificially increase babies' pulmonary surfactant levels if necessary through the instillation of exogenous surfactant material, but doing so involves some risk. This is a routine treatment with demonstrated benefit in premature neonates with normal, although not fully developed, lungs. Pulmonary surfactant is sometimes given also to babies with CDH, but in this particular instance, the benefit of this practice is unclear. The authors of this study wanted to determine whether or not babies with CDH really have low levels of pulmonary surfactant.
What Did the Researchers Do and Find?
The researchers performed autopsies to study lung tissue from human fetuses in pregnancies that ended in fetal death, were terminated for medical reasons, or resulted in death immediately after birth. They compared surfactant production in 16 fetuses with CDH to that in 33 fetuses with conditions not involving the lungs. They found that, taking fetal age into account, surfactant was present at similar levels in lung tissue from both groups, and that production of surfactant components and other factors involved in lung maturation was not delayed in CDH.
The researchers also studied sheep fetuses with surgically induced CDH, a model that has been used in the past to study lung development in CDH. In contrast with the findings in humans, they found that factors stimulating surfactant production were decreased in sheep with surgically induced CDH.
What Do These Findings Mean?
These findings suggest that surfactant deficiency is not a major contributor to lung problems in babies with CDH, and that further clinical research may be appropriate to determine whether administering surfactant to these babies is beneficial. The findings also suggest that commonly used animal models of CDH may be of limited relevance to human CDH.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040237.
Read the related Perspective on this article by Marcus Davey
Information from the MedlinePlus Encyclopedia (US National Library of Medicine) on diaphragmatic hernia
Article from eMedicine on congenital diaphragmatic hernia
Wikipedia entry on pulmonary surfactant (note: Wikipedia is an online encyclopedia that anyone can edit)