Abstract
Background: Congenital diaphragmatic hernia (CDH) has a high mortality rate mainly due to lung hypoplasia and persistent pulmonary hypertension of the newborn (PPHN). We recently reported that antenatal treatment with sildenafil or simvastatin prevented pulmonary hypoplasia and PPHN in experimental CDH. Objectives. We sought to evaluate the efficacy of antenatal sildenafil-simvastatin combination on pulmonary hypoplasia and PPHN associated to nitrofen-induced CDH.
Methods: On embryonic day (E)9.5, nitrofen or vehicle was administered to pregnant rats. Nitrofen-treated rats were randomly assigned to antenatal sildenafil (100 mg/kg/day) and simvastatin (20 mg/kg/day) combination or placebo administration from E11 to E21. On E21, foetuses were delivered by caesarean section, killed and checked for left-sided CDH.
Results: In nitrofen-induced CDH, simvastatin-sildenafil totally prevented left-sided CDH in the offspring, but failed to increase body weight and lung-to-body weight ratio. Antenatal simvastatin-sildenafil improved lung parenchyma structure, with decreased alveolar septal thickness and increased radial alveolar count. Antenatal simvastatin-sildenafil restored pulmonary vascular density and external diameter, and reduced pulmonary arteriolar remodeling. This was associated with restored epithelial and vascular activation of apoptotic processes in the lungs. Antenatal combination therapy was more efficacious than antenatal therapy with simvastatin or sildenafil alone.
Conclusions: Antenatal simvastatin-sildenafil combination therapy improves pathological features of lung hypoplasia and PPHN in experimental nitrofen-induced CDH.
- Copyright ©the authors 2016