Intra-Amniotic Sildenafil Treatment Promotes Lung Growth and Attenuates Vascular Remodeling in an Experimental Model of Congenital Diaphragmatic Hernia

Abstract

Background: Defective lung development resulting in lung hypoplasia and an attenuated and hypermuscularized pulmonary vasculature contributes to significant postnatal mortality in congenital diaphragmatic hernia (CDH). We hypothesize that deficient embryonic pulmonary blood flow contributes to defective lung development in CDH, which may therefore be ameliorated via enhancement of embryonic pulmonary blood flow. Methods: The mouse nitrofen model of CDH was utilized to measure embryonic pulmonary blood flow by in utero intracardiac injection of FITClabeled tomato lectin and color-flow Doppler ultrasound. The effect of prenatal intra-amniotic treatment with sildenafil on survival, lung growth, and vascular morphology in the nitrofen model was determined. Results: Nitrofen-treated embryos exhibited decreased blood flow in the lung periphery compared to controls, and intra-amniotic sildenafil significantly improved embryonic pulmonary blood flow. Similar to nitrofen alone, pups delivered after nitrofen treatment and intra-amniotic injection of dextrose control exhibited respiratory distress and never survived beyond 6 h. Intra-amniotic sildenafil ameliorated respiratory distress in nitrofen-treated pups and improved postnatal survival to 82%. Following intra-amniotic sildenafil treatment at embryonic day (E)10.5, nitrofen-treated P0 lungs were larger with increased left lobe weight, reduced small pulmonary arterial wall muscularization, and increased airway branching complexity compared to controls. Intra-amniotic sildenafil treatment later at E15.5 also resulted in improved survival, lung growth, and attenuation of vascular remodeling in nitrofen-treated embryos. Conclusions: Defective embryonic pulmonary blood flow may contribute to lung maldevelopment in CDH. Enhancement of embryonic pulmonary blood flow via intra-amniotic sildenafil results in lung growth and attenuation of pulmonary vascular remodeling and may have therapeutic potential for CDH.

Rescuing lung development through embryonic inhibition of histone acetylation

“…Identifying fetal interventions that improve the outcome of patients with structural malformations is a major objective, especially for CDH (125)(126)(127)(128)(129). Although genomic analysis, including fetal exome or genome sequencing, could be a useful method to identify patients likely to respond to fetal interventions, CDH-associated sequence and copy number variants continue to be identified, and therefore, at this time, exome and whole-genome sequencing are more likely to yield a genetic diagnosis than a CDH-specific gene panel.…”

Intra-amniotic sildenafil treatment improves lung blood flow and pulmonary hypertension in congenital diaphragmatic hernia rats

“…We have proposed direct sildenafil administration to CDH fetuses via an intra-amniotic (IA) injection. Our prior study using a single intra-amniotic injection of sildenafil in the nitrofen-induced CDH mouse model demonstrated an enhancement of embryonic pulmonary blood flow, improvements in the morphology of pulmonary vasculature, and astonishing survival improvements ( Okolo et al, 2020 ). Since intra-amniotic sildenafil is absorbed by the fetus directly, without first crossing the maternal placenta, we believe that intra-amniotic sildenafil treatment may show a much better therapeutic potential for the fetuses and less burden for the mothers than maternal treatment as a prenatal therapy for CDH.…”