title: Transplacental sildenafil rescues lung abnormalities in the rabbit model of diaphragmatic hernia.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Cluster Organ Systems, Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Russo
authors.affiliation: Cluster Organ Systems, Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Jaan
authors.initials: J
authors.lastname: Toelen
authors.affiliation: Cluster Organ Systems, Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium.
authors.forename: M Patrice
authors.initials: MP
authors.lastname: Eastwood
authors.affiliation: Cluster Organ Systems, Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium Department of Obstetrics and Gynecology, Clinica Alemana, Santiago, Chile.
authors.forename: Julio
authors.initials: J
authors.lastname: Jimenez
authors.affiliation: Cluster Organ Systems, Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium.
authors.forename: Andre Hadyme
authors.initials: AH
authors.lastname: Miyague
authors.affiliation: Department of Imaging and Pathology, Biomedical MRI/MoSAIC, KU Leuven, Leuven, Belgium.
authors.forename: Greetje
authors.initials: G
authors.lastname: Vande Velde
authors.affiliation: Cluster Organ Systems, Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium.
authors.forename: Philip
authors.initials: P
authors.lastname: DeKoninck
authors.affiliation: Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Uwe
authors.initials: U
authors.lastname: Himmelreich
authors.affiliation: Department of Obstetrics and Gynecology, University of Milano-Bicocca, Monza, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Vergani
authors.affiliation: Cluster Organ Systems, Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium Department of Neonatalogy, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: Allegaert
authors.affiliation: 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.
authors.forename: Jan
authors.initials: J
authors.lastname: Deprest
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D065630:Hernias, Diaphragmatic, Congenital / Q000150:complications* / Q000188:drug therapy*; D008168:Lung / Q000002:abnormalities* / Q000098:blood supply / Q000000981:diagnostic imaging; D011247:Pregnancy; D011817:Rabbits; D011897:Random Allocation; D015656:Respiratory Mechanics; D000068677:Sildenafil Citrate / Q000493:pharmacokinetics / Q000494:pharmacology*; D018608:Ultrasonography, Doppler; D014655:Vascular Resistance / Q000187:drug effects; D055114:X-Ray Microtomography
chemical_list: D000068677:Sildenafil Citrate
keywords: Paediatric Lung Disaese; Rare lung diseases