The condition of CDH occurs when the diaphragmatic muscle, which separates the chest from the abdomen, falls to form completely in the developing fetus. The intestines, no longer confined to the abdomen, herniate into the thorax. The defect is often associated with immaturity of the lungs; it is not a rare condition, affecting nearly one in 2,000 pregnancies. Despite many major advances in the surgery and intensive care of infants with CDH, the mortality from the malformation remains as high as 60%. The infants die from inadequate lung function, which is a combination of 1) pulmonary hypoplasia and 2) persistent pulmonary hypertension of the newborn. Lungs of full term infants with CDH are similar to lungs of premature infants. We have used the nitrofen-induced model of CDH in the fetal rat to demonstrate that the lungs are immature by biochemical, morphometric, physiologic, and molecular biologic criteria. We have shown further that the lethally immature lungs of the full term CDH rats can be improved by treating the mothers with parenteral glucocorticoids at doses extrapolated from the current therapy used to accelerate lung development of premature human babies. Addition of thyroid hormone augments this effect. We will search for more potent pulmonary growth enhancers at the gene level, evaluate expression of developmentally regulated genes in CDH, and investigate the role of apoptosis in CDH. We have developed an in vitro organ culture system of nitrofen-induced pulmonary hypoplasia using quantitative mathematical and fractal techniques to screen new agents; we will test their efficacy and optimize dosing in the rat model, then extend these experiments to fetal sheep in whom CDH has been surgically, rather than pharmacologically, created. Combination of these systems will allow us to pretest and develop appropriate therapies for CDH that can be used in future clinical trials for prenatal treatment of humans in whom CDH has been detected in utero by ultrasound.
