BDNF-TrkB Signaling Maintains Alveolar Epithelial Type 2 Cell Survival and Is Blocked in Hyperoxia-induced Neonatal Lung Injury

Oxygen supplementation causes an arrest of alveolar formation and a depletion of alveolar epithelial type 2 (AT2) cells in preterm infants, both characteristics of bronchopulmonary dysplasia. BDNF (brain-derived neurotrophic factor) is a key integrator of cell homeostasis and contributes to chronic lung diseases. In this study, <i>1</i>) wild-type mice were exposed to 85% O₂ or 21% O₂ from birth to postnatal day (P)28, followed by spatiotemporal profiling of pulmonary BDNF signaling on P3-P70; and <i>2</i>) lung epithelial cells (MLE12), primary murine AT2, and precision-cut lung slices were treated with nonselective Trk inhibitor (K252a), selective TrkB antagonist (Ana12), and TrkB agonist (7,8-dihydroxyflavone). Single-cell transcriptomic profiling revealed an expression of <i>Bdnf</i> in mesenchymal cells but no changes during postnatal development. In contrast, immunofluorescent staining showed a predominant localization of TrkB in AT2 and ACTA2⁺ cells; its expression and phosphorylation were increased at P7-P21. Although hyperoxia induced a 40-fold upregulation of lung <i>Bdnf</i> and a 3-fold elevation of serum BDNF, TrkB abundance and activation decreased by 90%. This was related to a lower <i>Sftpc</i> and increased <i>Acta2</i> in lungs. Blockade of Trk(B) reduced survival of MLE12 and murine AT2 with a loss of epithelial AT1 and AT2 markers, whereas the TrkB agonist increased survival and regulated AT2 maintenance in precision-cut lung slices after hyperoxia. Our data identified an important functional role of TrkB signaling in AT2 cells, a mechanism that is blocked in neonatal mouse lungs after hyperoxia and may contribute to a lack of regeneration and to arrest of alveolar growth in infants with bronchopulmonary dysplasia.