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

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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.

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Author information

Authors and Affiliations

  1. Division of Neonatology, High Specialty Medical Unit, Pediatric Hospital, Western National Medical Center, Mexican Social Security Institute, Guadalajara, Jalisco, México

    María de Lourdes Lemus-Varela

  2. Neonatal Intensive Care Unit, Division of Neonatology, Miami Children’s Hospital, Miami, FLD, USA

    Amed Soliz

  3. Molecular Biology in Medicine Institute, Molecular Biology and Genomic Department, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco, México

    Belinda Claudia Gómez-Meda & Ana Lourdes Zamora-Perez

  4. Odontology Research Institute, Integrated Odontology Clinic Department, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco, México

    Ana Lourdes Zamora-Perez

  5. Pathology Department, High Specialty Medical Unit, North-western National Medical Center, Mexican Social Security Institute, Ciudad Obregón, Sonora, México

    José Manuel Ornelas-Aguirre

  6. School of Medicine, University of Colima, Colima, México

    Valery Melnikov

  7. Division of Neurosciences, Western Biomedical Research Center, Mexican Social Security Institute and Department of Clinics, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco, México

    Blanca Miriam Torres-Mendoza

  8. Mutagenesis Laboratory, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco, México

    Guillermo Moisés Zúñiga-González

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  1. María de Lourdes Lemus-Varela
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  2. Amed Soliz
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  8. Guillermo Moisés Zúñiga-González
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Correspondence to Guillermo Moisés Zúñiga-González.

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Lemus-Varela, M.d.L., Soliz, A., Gómez-Meda, B.C. et al. Antenatal use of bosentan and/or sildenafil attenuates pulmonary features in rats with congenital diaphragmatic hernia. World J Pediatr 10, 354–359 (2014). https://doi.org/10.1007/s12519-014-0512-y

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  • DOI: https://doi.org/10.1007/s12519-014-0512-y

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