title: Intrapulmonary instillation of perflurooctylbromide improves lung growth, alveolarization, and lung mechanics in a fetal rabbit model of diaphragmatic hernia.
abstract: OBJECTIVE
  Fetal tracheal occlusion of hypoplastic rabbit lungs results in lung growth and alveolarization although the surfactant protein messenger RNA expression is decreased and the transforming growth factor-β pathway induced. The prenatal filling of healthy rabbit lungs with perfluorooctylbromide augments lung growth without suppression of surfactant protein synthesis. We hypothesizes that Intratracheal perfluorooctylbromide instillation improves lung growth, mechanics, and extracellular matrix synthesis in a fetal rabbit model of lung hypoplasia induced by diaphragmatic hernia.
  
  
  METHODS
  On day 23 of gestation, DH was induced by fetal surgery in healthy rabbit fetuses. Five days later, 0.8ml of perfluorooctylbromide (diaphragmatic hernia-perfluorooctylbromide) or saline (diaphragmatic hernia-saline) was randomly administered into the lungs of previously operated fetuses. After term delivery (day 31), lung mechanics, lung to body weight ratio, messenger RNA levels of target genes, assessment of lung histology, and morphological distribution of elastin and collagen were determined. Nonoperated fetuses served as controls.
  
  
  RESULTS
  Fetal instillation of perfluorooctylbromide in hypoplastic lungs resulted in an improvement of lung-to-body weight ratio (0.016 vs 0.013 g/g; p = 0.05), total lung capacity (23.4 vs 15.4 μL/g; p = 0.03), and compliance (2.4 vs 1.2 mL/cm H2O; p = 0.007) as compared to diaphragmatic hernia-saline. In accordance with the results from lung function analysis, elastin staining of pulmonary tissue revealed a physiological distribution of elastic fiber to the tips of the secondary crests in the diaphragmatic hernia-perfluorooctylbromide group. Likewise, messenger RNA expression was induced in genes associated with extracellular matrix remodeling (matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2). Surfactant protein expression was similar in the diaphragmatic hernia-perfluorooctylbromide and diaphragmatic hernia-saline groups. Distal airway size, mean linear intercept, as well as airspace and tissue fractions were similar in diaphragmatic hernia-perfluorooctylbromide, diaphragmatic hernia-saline, and control groups.
  
  
  CONCLUSIONS
  Fetal perfluorooctylbromide treatment improves lung growth, lung mechanics, and extracellular matrix remodeling in hypoplastic lungs, most probably due to transient pulmonary stretch, preserved fetal breathing movements, and its physical characteristics. Perfluorooctylbromide instillation is a promising approach for prenatal therapy of lung hypoplasia.
authors.affiliation: 1Division of Neonatology, Dr. von Hauner Children's Hospital, Perinatal Center Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany. 2Laboratory of Physiology and Physiopathology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium. 3Comprehensive Pneumology Center, University Hospital, Ludwig-Maximilian-University and Helmholtz Centre, Munich, Germany. 4Department of Obstetrics and Gynecology, University Hospital Brugmann, Brussels, Belgium.
authors.forename: Susanne
authors.initials: S
authors.lastname: Herber-Jonat
authors.forename: Aline
authors.initials: A
authors.lastname: Vuckovic
authors.forename: Rashmi
authors.initials: R
authors.lastname: Mittal
authors.forename: Anne
authors.initials: A
authors.lastname: Hilgendorff
authors.forename: Jacques C
authors.initials: JC
authors.lastname: Jani
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Flemmer
mesh_terms: D000818:Animals; D005333:Fetus; D005466:Fluorocarbons / Q000494:pharmacology*; D065630:Hernias, Diaphragmatic, Congenital / Q000188:drug therapy*; D006842:Hydrocarbons, Brominated; D008168:Lung / Q000254:growth & development / Q000503:physiopathology*; D008170:Lung Compliance / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D011663:Pulmonary Surfactants / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011817:Rabbits; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis
chemical_list: D005466:Fluorocarbons; D006842:Hydrocarbons, Brominated; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; C003072:perflubron