Francesca M Russo1, Jaan Toelen2, M Patrice Eastwood3, Julio Jimenez4, Andre Hadyme Miyague3, Greetje Vande Velde5, Philip DeKoninck3, Uwe Himmelreich6, Patrizia Vergani7, Karel Allegaert8, Jan Deprest9. 1. Cluster Organ Systems, Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium. 2. Cluster Organ Systems, Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium. 3. Cluster Organ Systems, Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium. 4. Cluster Organ Systems, Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium Department of Obstetrics and Gynecology, Clinica Alemana, Santiago, Chile. 5. Department of Imaging and Pathology, Biomedical MRI/MoSAIC, KU Leuven, Leuven, Belgium. 6. Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium. 7. Department of Obstetrics and Gynecology, University of Milano-Bicocca, Monza, Italy. 8. Cluster Organ Systems, Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium Department of Neonatalogy, University Hospitals Leuven, Leuven, Belgium. 9. Cluster Organ Systems, Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium Department of Obstetrics and Gynecology, Institute of Women's Health, University College London, London, UK.
Abstract
INTRODUCTION: The management of congenital diaphragmatic hernia (DH) would benefit from an antenatal medical therapy, which addresses both lung hypoplasia and persistent pulmonary hypertension. We aimed at evaluating the pulmonary effects of sildenafil in the fetal rabbit model for DH. METHODS: We performed a dose-finding study to achieve therapeutic fetal plasmatic concentrations without toxicity following maternal sildenafil administration. Subsequently, DH fetuses were randomly exposed to transplacental placebo or sildenafil 10 mg/kg/day from gestational day 24 until examination at term (day 30). Efficacy measures were ipsilateral pulmonary vascular and airway morphometry, micro-CT-based branching analysis, Doppler flow in the main pulmonary artery and postnatal lung mechanics. RESULTS: Fetal sildenafil plasmatic concentration was above the minimal therapeutic level for at least 22 h/day without maternal and fetal side effects. The placebo-exposed DH fetuses had increased wall thickness in peripheral pulmonary vessels and significantly less fifth-order vessels compared with controls (CTR). Sildenafil-exposed DH fetuses, instead, had a medial and adventitial thickness in peripheral pulmonary vessels in the normal range and normal vascular branching. Fetal pulmonary artery Doppler showed a reduction of pulmonary vascular resistances both in DH and in CTR fetuses treated by sildenafil compared with the placebo-treated ones. Sildenafil also reversed the mean terminal bronchiolar density to normal and improved lung mechanics, yet without measurable impact on lung-to-bodyweight ratio. CONCLUSIONS: In the rabbit model for DH, antenatal sildenafil rescues vascular branching and architecture, reduces pulmonary vascular resistances and also improves airway morphometry and respiratory mechanics. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
INTRODUCTION: The management of congenital diaphragmatic hernia (DH) would benefit from an antenatal medical therapy, which addresses both lung hypoplasia and persistent pulmonary hypertension. We aimed at evaluating the pulmonary effects of sildenafil in the fetal rabbit model for DH. METHODS: We performed a dose-finding study to achieve therapeutic fetal plasmatic concentrations without toxicity following maternal sildenafil administration. Subsequently, DH fetuses were randomly exposed to transplacental placebo or sildenafil 10 mg/kg/day from gestational day 24 until examination at term (day 30). Efficacy measures were ipsilateral pulmonary vascular and airway morphometry, micro-CT-based branching analysis, Doppler flow in the main pulmonary artery and postnatal lung mechanics. RESULTS: Fetal sildenafil plasmatic concentration was above the minimal therapeutic level for at least 22 h/day without maternal and fetal side effects. The placebo-exposed DH fetuses had increased wall thickness in peripheral pulmonary vessels and significantly less fifth-order vessels compared with controls (CTR). Sildenafil-exposed DH fetuses, instead, had a medial and adventitial thickness in peripheral pulmonary vessels in the normal range and normal vascular branching. Fetal pulmonary artery Doppler showed a reduction of pulmonary vascular resistances both in DH and in CTR fetuses treated by sildenafil compared with the placebo-treated ones. Sildenafil also reversed the mean terminal bronchiolar density to normal and improved lung mechanics, yet without measurable impact on lung-to-bodyweight ratio. CONCLUSIONS: In the rabbit model for DH, antenatal sildenafil rescues vascular branching and architecture, reduces pulmonary vascular resistances and also improves airway morphometry and respiratory mechanics. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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