Antenatal use of bosentan and/or sildenafil attenuates pulmonary features in rats with congenital diaphragmatic hernia

María de Lourdes Lemus-Varela, Amed Soliz, Belinda Claudia Gómez-Meda, Ana Lourdes Zamora-Perez, José Manuel Ornelas-Aguirre, Valery Melnikov, Blanca Miriam Torres-Mendoza, Guillermo Moisés Zúñiga-González*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Background: Lung hypoplasia, pulmonary persistent hypertension of the newborn and its morphological changes are the main features in congenital diaphragmatic hernia (CDH). This study was undertaken to investigate if antenatal use of sildenafil and/or bosentan attenuates vascular remodeling, promotes branching, and improves alveolarization in experimental nitrofeninduced CDH.

Methods: Nitrofen (100 mg) was gavage-fed to pregnant rats at post conception day (PCD) 9 to induce CDH. The rats were randomized to 5 groups: 1) control; 2) nitrofen; 3) nitrofen+sildenafil 100 mg/kg per day at PCD 16–20; 4) nitrofen+bosentan 30 mg/kg per day, at PCD 16–20, and 5) nitrofen+bosentan+sildenafil, same doses and administration days. After cesarean delivery, the offsprings were sacrificed. The diaphragmatic defect and pulmonary hypoplasia were identified, and the lungs were dissected. Arterial wall thickness, bronchiolar density and alveolarization were assessed.

Results: The offsprings with CDH were characterized by severe pulmonary hypoplasia (lung weight-to-body weight ratio: 0.0263 [95% confidence interval (CI) 0.0242–0.0278)] in the nitrofen group versus 0.0385 (95% CI 0.0355–0.0424) in the control group (P=0.0001). Pulmonary arterial wall thickness was decreased to 3.0 (95% CI 2.8–3.7) μm in the nitrofen+sildenafil group versus 5.0 (95% CI 4.1–4.9) μm in the nitrofen group (P=0.02). Terminal bronchioles increased to 13.7 (95% CI 10.7–15.2) μm in the nitrofen+bosentan group in contrast to 8.7 (95% CI 7.2–9.4) μm in the nitrofen group (P=0.002). More significant differences (P=0.0001) were seen in terminal bronchioles in the nitrofen+sildenafil+bosentan group than in the nitrofen group [14.0 (95% CI 12.5–15.4) μm versus 8.5 (95% CI 7.1–9.3) μm]. Pulmonary arterial wall thickness was also decreased in the former group.

Conclusions: In this rat model, antenatal treatment with sildenafil attenuates vascular remodeling. Bosentan promotes the development of terminal bronchioles in nitrofen-induced CDH.

Original languageEnglish
Pages (from-to)354-359
Number of pages6
JournalWorld Journal of Pediatrics
Volume10
Issue number4
DOIs
StatePublished - 17 Dec 2014
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2014, Children's Hospital, Zhejiang University School of Medicine and Springer-Verlag Berlin Heidelberg.

Keywords

  • antenatal treatment
  • bosentan
  • congenital diaphragmatic hernia
  • pulmonary hypoplasia
  • sildenafil

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