Antenatal use of bosentan and/or sildenafil attenuates pulmonary features in rats with congenital diaphragmatic hernia

Background:Lung hypoplasia,pulmonary persistent hypertension of the newborn and its morphological changes are the main features in congenital diaphragmatic hernia(CDH).This study was undertaken to investigate if antenatal use of sildenafil and/or bosentan attenuates vascular remodeling,promotes branching,and improves alveolarization in experimental nitrofeninduced CDH.Methods:Nitrofen(100 mg)was gavage-fed to pregnant rats at post conception day(PCD)9 to induce CDH.The rats were randomized to 5 groups:1)control;2)nitrofen;3)nitrofen+sildenafil 100 mg/kg per day at PCD 16-20;4)nitrofen+bosentan 30 mg/kg per day,at PCD 16-20,and 5)nitrofen+bosentan+sildenafil,same doses and administration days.After cesarean delivery,the offsprings were sacrifi ced.The diaphragmatic defect and pulmonary hypoplasia were identified,and the lungs were dissected.Arterial wall thickness,bronchiolar density and alveolarization were assessed.Results:The offsprings with CDH were characterized by severe pulmonary hypoplasia(lung weight-to-body weight ratio:0.0263[95%confidence interval(CI)0.0242-0.0278)]in the nitrofen group versus 0.0385(95%CI 0.0355-0.0424)in the control group(P=0.0001).Pulmonary arterial wall thickness was decreased to 3.0(95%CI 2.8-3.7)μm in the nitrofen+sildenafil group versus 5.0(95%CI 4.1-4.9)μm in the nitrofen group(P=0.02).Terminal bronchioles increased to 13.7(95%CI 10.7-15.2)μm in the nitrofen+bosentan group in contrast to 8.7(95%CI 7.2-9.4)μm in the nitrofen group(P=0.002).More significant differences(P=0.0001)were seen in terminal bronchioles in the nitrofen+sildenafil+bosentan group than in the nitrofen group[14.0(95%CI 12.5-15.4)μm versus 8.5(95%CI 7.1-9.3)μm].Pulmonary arterial wall thickness was also decreased in the former group.Conclusions:In this rat model,antenatal treatment with sildenafil attenuates vascular remodeling.Bosentan promotes the development of terminal bronchioles in nitrofen-induced CDH.