title: Caffeine administration modulates TGF-β signaling but does not attenuate blunted alveolarization in a hyperoxia-based mouse model of bronchopulmonary dysplasia.
abstract: BACKGROUND
  Caffeine is widely used to manage apnea of prematurity, and reduces the incidence of bronchopulmonary dysplasia (BPD). Deregulated transforming growth factor (TGF)-β signaling underlies arrested postnatal lung maturation in BPD. It is unclear whether caffeine impacts TGF-β signaling or postnatal lung development in affected lungs.
  
  
  METHODS
  The impact of caffeine on TGF-β signaling in primary mouse lung fibroblasts and alveolar epithelial type II cells was assessed in vitro. The effects of caffeine administration (25 mg/kg/d for the first 14 d of postnatal life) on aberrant lung development and TGF-β signaling in vivo was assessed in a hyperoxia (85% O2)-based model of BPD in C57BL/6 mice.
  
  
  RESULTS
  Caffeine downregulated expression of type I and type III TGF-β receptors, and Smad2; and potentiated TGF-β signaling in vitro. In vivo, caffeine administration normalized body mass under hyperoxic conditions, and normalized Smad2 phosphorylation detected in lung homogenates; however, caffeine administration neither improved nor worsened lung structure in hyperoxia-exposed mice, in which postnatal lung maturation was blunted.
  
  
  CONCLUSIONS
  Caffeine modulated TGF-β signaling in vitro and in vivo. Caffeine administration was well-tolerated by newborn mice, but did not influence the course of blunted postnatal lung maturation in a hyperoxia-based experimental mouse model of BPD.
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.|Institute of Bioprocess Engineering and Pharmaceutical Technology, Technische Hochschule Mittelhessen-University of Applied Sciences, Giessen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Rath
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, 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), 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, 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), Giessen, Germany.
authors.forename: David E
authors.initials: DE
authors.lastname: Surate Solaligue
authors.affiliation: Department of Forensic and Clinical Toxicology, Labor Krone, Bad Salzuflen, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Agius
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, 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), Giessen, Germany.
authors.forename: Ivana
authors.initials: I
authors.lastname: Mižíková
authors.affiliation: Institute of Bioprocess Engineering and Pharmaceutical Technology, Technische Hochschule Mittelhessen-University of Applied Sciences, Giessen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hühn
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), 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), 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), Giessen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.affiliation: Institute of Bioprocess Engineering and Pharmaceutical Technology, Technische Hochschule Mittelhessen-University of Applied Sciences, Giessen, Germany.|Faculty of Biology and Chemistry, Justus Liebig University, Giessen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Runkel
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, 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), 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, 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), Giessen, Germany.
authors.forename: Rory E
authors.initials: RE
authors.lastname: Morty
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D002110:Caffeine / Q000494:pharmacology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018496:Hyperoxia / Q000150:complications*; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta; C071736:betaglycan; D002110:Caffeine; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I