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

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• 作者：María de Lourdes Lemus-Varela (1)
  Amed Soliz (2)
  Belinda Claudia Gómez-Meda (3)
  Ana Lourdes Zamora-Perez (3) (4)
  José Manuel Ornelas-Aguirre (5)
  Valery Melnikov (6)
  Blanca Miriam Torres-Mendoza (7)
  Guillermo Moisés Zú?iga-González (8)
  
• 关键词：antenatal treatment ; bosentan ; congenital diaphragmatic hernia ; pulmonary hypoplasia ; sildenafil
• 刊名：World Journal of Pediatrics
• 出版年：2014
• 出版时间：November 2014
• 年：2014
• 卷：10
• 期：4
• 页码：354-359
• 全文大小：596 KB
• 参考文献：1. Reiss I, Schaible T, van den Hout L, Capolupo I, Allegaert K, van Heijst A, et al. Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium consensus. Neonatology 2010;98:354-64. CrossRef
  2. Stevens TP, van Wijngaarden E, Ackerman KG, Lally PA, Lally KP. Congenital Diaphragmatic Hernia Study Group. Timing of delivery and survival rates for infants with prenatal diagnoses of congenital diaphragmatic hernia. Pediatrics 2009;123:494-02. CrossRef
  3. Sluiter I, van de Ven CP, Wijnen RM, Tibboel D. Congenital diaphragmatic hernia: still a moving target. Semin Fetal Neonatal Med 2011;16:139-44. CrossRef
  4. Pober BR. Overview of epidemiology, genetics, birth defects, and chromosome abnormalities associated with CDH. Am J Med Genet C Semin Med Genet 2007;145C:158-71. CrossRef
  5. Lakshminrusimha S. The pulmonary circulation in neonatal respiratory failure. Clin Perinatol 2012;39:655-83. CrossRef
  6. Haroon J, Chamberlain RS. An evidence-based review of the current treatment of congenital diaphragmatic hernia. Clin Pediatr (Phila) 2013;52:115-24. CrossRef
  7. van den Hout L, Sluiter I, Gischler S, De Klein A, Rottier R, Ijsselstijn H, et al. Can we improve outcome of congenital diaphragmatic hernia? Pediatr Surg Int 2009;25:733-43. CrossRef
  8. Safavi A, Lin Y, Skarsgard ED, Canadian Pediatric Surgery Network. Perinatal management of congenital diaphragmatic hernia: when and how should babies be delivered? Results from the Canadian Pediatric Surgery Network. J Pediatr Surg 2010;45:2334-339. CrossRef
  9. Garne E, Haeusler M, Barisic I, Gjergja R, Stoll C, Clementi M, et al. Congenital diaphragmatic hernia: evaluation of prenatal diagnosis in 20 European regions. Ultrasound Obstet Gynecol 2002;19:329-33. CrossRef
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  12. Claus F, Sandaite I, DeKoninck P, Moreno O, Cruz Martinez R, Van Mieghem T, et al. Prenatal anatomical imaging in fetuses with congenital diaphragmatic hernia. Fetal Diagn Ther 2011;29:88-00. CrossRef
  13. Deprest JA, Flemmer AW, Gratacos E, Nicolaides K. Antenatal prediction of lung volume and in-utero treatment by fetal endoscopic tracheal occlusion in severe isolated congenital diaphragmatic hernia. Semin Fetal Neonatal Med 2009;14:8-3. CrossRef
  14. Gallindo RM, Gon?alves FL, Barreto CT, Schmidt AF, Pereira LA, Sbragia L. Evaluation of histological changes after tracheal occlusion at different gestational ages in a fetal rat model. Clinics (Sao Paulo) 2013;68:59-3. CrossRef
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• 作者单位：María de Lourdes Lemus-Varela (1)
  Amed Soliz (2)
  Belinda Claudia Gómez-Meda (3)
  Ana Lourdes Zamora-Perez (3) (4)
  José Manuel Ornelas-Aguirre (5)
  Valery Melnikov (6)
  Blanca Miriam Torres-Mendoza (7)
  Guillermo Moisés Zú?iga-González (8)
  
  1. Division of Neonatology, High Specialty Medical Unit, Pediatric Hospital, Western National Medical Center, Mexican Social Security Institute, Guadalajara, Jalisco, México
  2. Neonatal Intensive Care Unit, Division of Neonatology, Miami Children’s Hospital, Miami, FLD, USA
  3. Molecular Biology in Medicine Institute, Molecular Biology and Genomic Department, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco, México
  4. Odontology Research Institute, Integrated Odontology Clinic Department, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco, México
  5. Pathology Department, High Specialty Medical Unit, North-western National Medical Center, Mexican Social Security Institute, Ciudad Obregón, Sonora, México
  6. School of Medicine, University of Colima, Colima, México
  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
  8. Mutagenesis Laboratory, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco, México
  
• ISSN：1867-0687

文摘

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 16-0; 4) nitrofen+bosentan 30 mg/kg per day, at PCD 16-0, 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-.0278)] in the nitrofen group versus 0.0385 (95% CI 0.0355-.0424) in the control group (P=0.0001). Pulmonary arterial wall thickness was decreased to 3.0 (95% CI 2.8-.7) μm in the nitrofen+sildenafil group versus 5.0 (95% CI 4.1-.9) μm in the nitrofen group (P=0.02). Terminal bronchioles increased to 13.7 (95% CI 10.7-5.2) μm in the nitrofen+bosentan group in contrast to 8.7 (95% CI 7.2-.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 12.5-5.4) μm versus 8.5 (95% CI 7.1-.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.