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

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

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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.
Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.
Department of Forensic and Clinical Toxicology, Labor Krone, Bad Salzuflen, Germany.
Faculty of Biology and Chemistry, Justus Liebig University, Giessen, Germany.



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.


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.


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.


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.

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