Congenital Diafragmatic hernia: the frontier between basic and clinical science

Abstract

A newborn with a congenital diaphramatic hernia (CDH) represents one of the challenges of modern medicine. The early herniation of viscera such as the liver before 24 weeks of gestation produces severe pulmonary hypoplasia which is incompatible with life. For this reason we investigated the molecular signals responsible for pulmonary hypoplasia and to develop new intrauterine therapies. The model most used in research is the nitrofen induced CDH rat. This model allows the study of growth factors, nitric oxide mediators, endothelin, surfactant and in utero effects of tracheal occlusion on lung parenchyma and vasculature. FGF is an important growth factor for lung development and VEGF, endothelin-1 and its receptors are important for vascular development in CDH. There are in utero surgery protocols for newborns with a high mortality from CDH. Attempts for a complete in utero correction have failed, but basic research has supported the use of tracheal occlusion techniques in human foetus. In animal and human foetus it has been demonstrated that tracheal occlusion produces a dramatic growth of the lung and that the lung vasculature returns to normal. Currently under investigation are in utero tracheal occlusion techniques using endoscopy in controlled clinical trials, with a mortality risk close to 100% for the foetus. Growth factors like VEGF and FGF could be possible candidates for in utero gene therapy. It is possible in the future that the combination of tracheal occlusion and in utero gene therapy could provide a new approach for treating this devastating disease.