title: Cumulative effects of neonatal hyperoxia on murine alveolar structure and function.
abstract: Bronchopulmonary dysplasia (BPD) results from alveolar simplification and abnormal development of alveolar and capillary structure. Survivors of BPD display persistent deficits in airflow and membrane and vascular components of alveolar gas diffusion. Despite being the defining feature of BPD, various neonatal hyperoxia models of BPD have not routinely assessed pulmonary gas diffusion.
  
  
  
  To simulate the most commonly-utilized neonatal hyperoxia models, we exposed neonatal mice to room air or ≥90% hyperoxia during key stages of distal lung development: through the first 4 (saccular), 7 (early alveolar), or 14 (bulk alveolar) postnatal days, followed by a period of recovery in room air until 8 weeks of age when alveolar septation is essentially complete. We systematically assessed and correlated the effects of neonatal hyperoxia on the degree of alveolar-capillary structural and functional impairment. We hypothesized that the degree of alveolar-capillary simplification would correlate strongly with worsening diffusion impairment.
  
  
  
  Neonatal hyperoxia exposure, of any duration, resulted in alveolar simplification and impaired pulmonary gas diffusion. Mean Linear Intercept increased in proportion to the length of hyperoxia exposure while alveolar and total lung volume increased markedly only with prolonged exposure. Surprisingly, despite having a similar effect on alveolar surface area, only prolonged hyperoxia for 14 days resulted in reduced pulmonary microvascular volume. Estimates of alveolar and capillary structure, in general, correlated poorly with assessment of gas diffusion.
  
  
  
  Our results help define the physiological and structural consequences of commonly-employed neonatal hyperoxia models of BPD and inform their clinical utility. Pediatr Pulmonol. 2017;52:616-624. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Program in Developmental Biology and Neonatal Medicine, Herman B Wells Center for Pediatric Research, Indianapolis, Indiana.|Division of Neonatology, James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Cox
authors.affiliation: Program in Developmental Biology and Neonatal Medicine, Herman B Wells Center for Pediatric Research, Indianapolis, Indiana.|Program in Pulmonary Inflammation, Asthma and Allergic Diseases, Herman B Wells Center for Pediatric Research, Indianapolis, Indiana.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.|Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Anne-Karina T
authors.initials: AT
authors.lastname: Perl
authors.affiliation: Program in Pulmonary Inflammation, Asthma and Allergic Diseases, Herman B Wells Center for Pediatric Research, Indianapolis, Indiana.|Division of Pulmonary Medicine, Department of Pediatrics, James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Tepper
authors.affiliation: Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.|Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Shawn K
authors.initials: SK
authors.lastname: Ahlfeld
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000473:pathology / Q000503:physiopathology*; D002196:Capillaries / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D018496:Hyperoxia / Q000473:pathology / Q000503:physiopathology*; D007231:Infant, Newborn; D008168:Lung / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D011650:Pulmonary Alveoli / Q000473:pathology / Q000503:physiopathology*
keywords: bronchopulmonary dysplasia; hyperoxia; lung function; neonatal; pulmonary diffusion capacity