Clinically relevant timing of antenatal sildenafil treatment reduces pulmonary vascular remodeling in congenital diaphragmatic hernia

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 311; no. 4; p. L734
• Main Authors: Mous, Daphne S, Kool, Heleen M, Buscop-van Kempen, Marjon J, Koning, Anton H, Dzyubachyk, Oleh, Wijnen, Rene M H, Tibboel, Dick, Rottier, Robbert J
• Format: Journal Article
• Language: English
• Published: United States 01-10-2016
• Subjects: Animals; Drug Evaluation, Preclinical; Female; Hernias, Diaphragmatic, Congenital - chemically induced; Hernias, Diaphragmatic, Congenital - physiopathology; Hernias, Diaphragmatic, Congenital - prevention & control; Lung - blood supply; Lung - pathology; Maternal Exposure; Maternal-Fetal Exchange; Phenyl Ethers; Phosphodiesterase 5 Inhibitors - pharmacology; Phosphodiesterase 5 Inhibitors - therapeutic use; Pregnancy; Rats, Sprague-Dawley; Sildenafil Citrate - pharmacology; Sildenafil Citrate - therapeutic use; Vascular Remodeling - drug effects; lung; development; angiogenesis; pulmonary hypertension
• ISSN: 1522-1504
• DOI: 10.1152/ajplung.00180.2016

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.