title: Standardisation of oxygen exposure in the development of mouse models for bronchopulmonary dysplasia.
abstract: Progress in developing new therapies for bronchopulmonary dysplasia (BPD) is sometimes complicated by the lack of a standardised animal model. Our objective was to develop a robust hyperoxia-based mouse model of BPD that recapitulated the pathological perturbations to lung structure noted in infants with BPD. Newborn mouse pups were exposed to a varying fraction of oxygen in the inspired air (FiO2) and a varying window of hyperoxia exposure, after which lung structure was assessed by design-based stereology with systemic uniform random sampling. The efficacy of a candidate therapeutic intervention using parenteral nutrition was evaluated to demonstrate the utility of the standardised BPD model for drug discovery. An FiO2of 0.85 for the first 14 days of life decreased total alveoli number and concomitantly increased alveolar septal wall thickness, which are two key histopathological characteristics of BPD. A reduction in FiO2to 0.60 or 0.40 also caused a decrease in the total alveoli number, but the septal wall thickness was not impacted. Neither a decreasing oxygen gradient (from FiO20.85 to 0.21 over the first 14 days of life) nor an oscillation in FiO2(between 0.85 and 0.40 on a 24 h:24 h cycle) had an appreciable impact on lung development. The risk of missing beneficial effects of therapeutic interventions at FiO20.85, using parenteral nutrition as an intervention in the model, was also noted, highlighting the utility of lower FiO2in selected studies, and underscoring the need to tailor the model employed to the experimental intervention. Thus, a state-of-the-art BPD animal model that recapitulates the two histopathological hallmark perturbations to lung architecture associated with BPD is described. The model presented here, where injurious stimuli have been systematically evaluated, provides a most promising approach for the development of new strategies to drive postnatal lung maturation in affected infants.
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.|Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), 35392 Giessen, Germany.
authors.forename: Claudio
authors.initials: C
authors.lastname: Nardiello
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.|Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), 35392 Giessen, Germany.
authors.forename: Ivana
authors.initials: I
authors.lastname: Mižíková
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.|Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), 35392 Giessen, Germany.
authors.forename: Diogo M
authors.initials: DM
authors.lastname: Silva
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.|Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), 35392 Giessen, Germany.
authors.forename: Jordi
authors.initials: J
authors.lastname: Ruiz-Camp
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), 35392 Giessen, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Mayer
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), 35392 Giessen, Germany.
authors.forename: István
authors.initials: I
authors.lastname: Vadász
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), 35392 Giessen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.|Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), 35392 Giessen, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany rory.morty@mpi-bn.mpg.de.|Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), 35392 Giessen, Germany.
authors.forename: Rory E
authors.identifier: 0000-0003-0833-9749
authors.initials: RE
authors.lastname: Morty
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000150:complications / Q000473:pathology*; D004195:Disease Models, Animal; D018496:Hyperoxia / Q000150:complications / Q000473:pathology; D008168:Lung / Q000473:pathology; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000008:administration & dosage*; D012015:Reference Standards
chemical_list: D010100:Oxygen
keywords: Alveolarisation; Animal model; BPD; Hyperoxia; Structure