Prenatal hormonal therapy improves pulmonary morphology in rats with congenital diaphragmatic hernia

The high mortality of congenital diaphragmatic hernia (CDH) is due to associated pulmonary hypoplasia, which resembles that seen in premature newborns with respiratory distress syndrome (RDS). By use of successful therapies extrapolated from RDS, quantitative stereologic morphometry techniques were applied to evaluate pulmonary development following prenatal hormonal therapy in rats with nitrofen-induced CDH. Antenatal hormonal therapy was administered on Days 18.5 and 19.5 prior to delivery on Day 21.5 (term = Day 22), using dexamethasone (Dex), thyrotropin-releasing hormone (TRH), Dex-TRH, or normal saline (NS) as vehicle control. Lungs from CDH rats (n = 5) and non-nitrofen-fed controls (n = 5) were studied, and 10 morphometric airspace parameters were determined by point counting 18-30 fields/lung/animal. Indices of maturation, including total internal surface area (SA), airspace volume fractions (V(Valv)), duct fractions (V(Vducts)), and radial alveolar count (RAC), were improved by Dex and Dex-TRH compared with NS-CDH controls (P = 0.0001), as were five other morphometric airspace parameters (P < 0.05). Strikingly, Dex and Dex-TRH treatment corrected average airspace volume (AAV) and the volume fraction of air-conducting elements (V(Vducts)) toward normal values seen in non-nitrofen-fed control animals. TRH therapy alone had minimal beneficial effects. Prenatal steroid +/- TRH thus improved multiple morphometric parameters of lung maturity in CDH rats, supporting the potential use of in utero hormonal therapy to treat humans with antenatally diagnosed CDH.