Receptor for advanced glycation end-products modulates lung development and lung sensitivity to hyperoxic injury in newborn mice
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The receptor for advanced glycation end-products is mainly expressed in type I alveolar epithelial cells but its importance in lung development and response to neonatal hyperoxia is unclear. Therefore, our study aimed at the analysis of young wildtype and RAGE knockout mice which grew up under normoxic or hyperoxic air conditions for the first 14 days followed by a longer period of normoxic conditions. Lung histology, expression of lung-specific proteins, and respiratory mechanics were analyzed when the mice reached an age of 2 or 4 months. These analyses indicated less but larger and thicker alveoli in RAGE knockout mice, reverse differences in the mRNA and protein amount of pro-surfactant proteins (pro-SP-B, pro-SP-C) and aquaporin-5, and differences in the amount of elastin and CREB, a pro-survival transcription factor, as well as higher lung compliance. Despite this potential disadvantages, RAGE knockout lungs showed less long-term damages mediated by neonatal hyperoxia. In detail, the hyperoxia-mediated reduction in alveoli, enlargement of airspaces, fragmentation of elastic fibers, and increased lung compliance combined with reduced peak airflows was less pronounced in RAGE knockout mice. In conclusion, RAGE supports the alveolarization but makes the lung more susceptible to hyperoxic injury shortly after birth. Blocking RAGE function could still be a helpful tool in reducing hyperoxia-mediated lung pathologies during alveolarization.
KeywordsAntioxidant enzymes Elastic fibers Lung development Lung histology Respiratory biomechanics Superoxide anion
We thank Holger Lehnich and Dieter Barowsky (Centre of Medical Basic Research; Halle, Germany) for constructing the oxygen chamber, Hans-Jürgen Brömme (Centre of Medical Basic Research; Halle, Germany) for help with the ROS detection, and Anika Küttner for general technical assistance.
This project was supported by Wilhelm Roux program at the Medical Faculty of the Martin Luther University Halle-Wittenberg, Halle (Saale) (28/14).
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