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Antenatal use of bosentan and/or sildenafil attenuates pulmonary features in rats with congenital diaphragmatic hernia
Mar¨ªa de Lourdes Lemus-Varela, Amed Soliz, Belinda Claudia G¨®mez-Meda, Ana Lourdes Zamora-Perez, Jos¨¦ Manuel Ornelas-Aguirre, Valery Melnikov, Blanca Miriam Torres-Mendoza, Guillermo Mois¨¦s Z¨²ñiga-Gonz¨¢lez
Guadalajara, M¨¦xico
Author Affiliations: Division of Neonatology, High Specialty Medical Unit, Pediatric Hospital, Western National Medical Center, Mexican Social Security Institute, Guadalajara, Jalisco, M¨¦xico (Lemus-Varela ML); Neonatal Intensive Care Unit, Division of Neonatology, Miami Children's Hospital, Miami FLD, USA (Soliz A); Molecular Biology in Medicine Institute, Molecular Biology and Genomic Department, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco, M¨¦xico (G¨®mez-Meda BC, Zamora-Perez AL); Odontology Research Institute, Integrated Odontology Clinic Department, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco, M¨¦xico (Zamora-Perez AL); Pathology Department, High Specialty Medical Unit, North-western National Medical Center, Mexican Social Security Institute, Ciudad Obreg¨®n, Sonora, M¨¦xico (Ornelas-Aguirre JM); School of Medicine, University of Colima, Colima, M¨¦xico (Melnikov V); Division of Neurosciences, Western Biomedical Research Center, Mexican Social Security Institute and Department of Clinics, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco, M¨¦xico (Torres-Mendoza BM); Mutagenesis Laboratory, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco, M¨¦xico (Z¨²ñiga-Gonz¨¢lez GM)
Corresponding Author: Guillermo Mois¨¦s Z¨²ñiga-Gonz¨¢lez, PhD, Laboratorio de Mutag¨¦nesis, Centro de Investigaci¨®n Biom¨¦dica de Occidente, Instituto Mexicano del Seguro Social, Sierra Mojada 800, Colonia Independencia, C.P. 44340, Guadalajara, Jalisco, M¨¦xico (Tel: +52(33)36683000 ext 31937, Fax: +52(33)36181756; Email: mutagenesis95@hotmail.com)
doi: 10.1007/s12519-014-0512-y
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 nitrofen-induced 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.
World J Pediatr 2014;10(4):354-359
Key words: antenatal treatment;
bosentan;
congenital diaphragmatic hernia;
pulmonary hypoplasia;
sildenafil
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