Caffeine administration modulates TGF-β signaling but does not attenuate blunted alveolarization in a hyperoxia-based mouse model of bronchopulmonary dysplasia

Pediatr Res. 2017 May;81(5):795-805. doi: 10.1038/pr.2017.21. Epub 2017 Jan 31.


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.

Conclusion: 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.

MeSH terms

  • Animals
  • Animals, Newborn
  • Bronchopulmonary Dysplasia / drug therapy*
  • Bronchopulmonary Dysplasia / etiology
  • Bronchopulmonary Dysplasia / metabolism
  • Bronchopulmonary Dysplasia / physiopathology
  • Caffeine / pharmacology*
  • Cells, Cultured
  • Disease Models, Animal
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Hyperoxia / complications*
  • Mice, Inbred C57BL
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteoglycans / metabolism
  • Pulmonary Alveoli / drug effects*
  • Pulmonary Alveoli / growth & development
  • Pulmonary Alveoli / metabolism
  • Pulmonary Alveoli / pathology
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / drug effects
  • Smad2 Protein / metabolism
  • Time Factors
  • Transforming Growth Factor beta / metabolism*


  • Proteoglycans
  • Receptors, Transforming Growth Factor beta
  • Smad2 Protein
  • Smad2 protein, mouse
  • Transforming Growth Factor beta
  • betaglycan
  • Caffeine
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I