title: Clinically relevant timing of antenatal sildenafil treatment reduces pulmonary vascular remodeling in congenital diaphragmatic hernia.
abstract: Patients with congenital diaphragmatic hernia (CDH) suffer from severe pulmonary hypertension attributable to altered development of the pulmonary vasculature, which is often resistant to vasodilator therapy. Present treatment starts postnatally even though significant differences in the pulmonary vasculature are already present early during pregnancy. We examined the effects of prenatal treatment with the phosphodiesterase-5 inhibitor sildenafil on pulmonary vascular development in experimental CDH starting at a clinically relevant time. The well-established, nitrofen-induced CDH rodent model was treated daily with 100 mg/kg sildenafil from day 17.5 until day 20.5 of gestation (E17.5-20.5). Importantly, this timing perfectly corresponds to the developmental stage of the lung at 20 wk of human gestation, when CDH is detectable by 2D-ultrasonography and/or MRI. At E21.5 pups were delivered by caesarean section and euthanized by lethal injection of pentobarbital. The lungs were isolated and subsequently analyzed using immunostaining, real-time PCR, and volume measurements. Prenatal treatment with sildenafil improved lung morphology and attenuated vascular remodeling with reduced muscularization of the smaller vessels. Pulmonary vascular volume was not affected by sildenafil treatment. We show that prenatal treatment with sildenafil within a clinically relevant period improves pulmonary vascular development in an experimental CDH model. This may have important implications for the management of this disease and related pulmonary vascular diseases in human.
authors: Department of Pediatric Surgery, Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: Daphne S
authors: DS
authors: Mous
authors: Department of Pediatric Surgery, Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: Heleen M
authors: HM
authors: Kool
authors: Department of Pediatric Surgery, Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: Marjon J
authors: MJ
authors: Buscop-van Kempen
authors: Department of Bioinformatics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Anton H
authors: AH
authors: Koning
authors: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Oleh
authors: O
authors: Dzyubachyk
authors: Department of Pediatric Surgery, Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: Rene M H
authors: RM
authors: Wijnen
authors: Department of Pediatric Surgery, Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: Dick
authors: D
authors: Tibboel
authors: Department of Pediatric Surgery, Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands; Member of European Cooperation in Science and Technology (COST) action BM1201, "Developmental Origins of Chronic Lung Disease" r.rottier@erasmusmc.nl.
authors: Robbert J
authors: RJ
authors: Rottier
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D005260:Female; D065630:Hernias, Diaphragmatic, Congenital / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D008168:Lung / Q000098:blood supply / Q000473:pathology; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange; D010647:Phenyl Ethers; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011247:Pregnancy; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate / Q000494:pharmacology / Q000627:therapeutic use*; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D010647:Phenyl Ethers; D058986:Phosphodiesterase 5 Inhibitors; D000068677:Sildenafil Citrate; C007350:nitrofen
keywords: angiogenesis; development; lung; pulmonary hypertension