Brain-derived neurotrophic factor (BDNF)-TrkB signaling regulates alveolar epithelial type 2 (AT2) cell survival and is reduced in hyperoxia-induced neonatal lung injury.

<bold>Introduction</bold> Oxygen supplementation causes an arrest of alveolar formation and a loss of alveolar epithelial type 2 (AT2) in preterm infants, features of bronchopulmonary dysplasia (BPD). Since BDNF is a key integrator of cell homeostasis and contributes to chronic lung diseases, we now (i) performed a spatiotemporal profiling of the BDNF-signaling in neonatal mice after hyperoxia and (ii) analyzed the functional role of the BDNF receptor TrkB in AT2. <bold>Methods:</bold> (1) Wild-type mice were exposed to 85% O₂ (HYX) or 21% O₂ from birth to P28. Lungs were examined at P3-P70. (2) MLE12 cells and primary murine AT2 (mAT2) were treated with non-selective Trk inhibitor (K252a) and selective TrkB antagonist (Ana12). <bold>Results:</bold> (i) TrkB expression and phosphorylation were increased during in the alveolar phase (P7-P21), and predominantly expressed in AT2 and ACTA2+ cells. Single cell transcriptomic profiling revealed a strong expression of <italic>Bdnf</italic> in mesenchymal cells. While hyperoxia induced a 40-fold upregulation of lung <italic>Bdnf</italic> and a 3-fold elevation of serum BDNF, TrkB abundance and activation were decreased by 90%. This was related to a lower <italic>Sftpc</italic> and increased of <italic>Acta2</italic> in lungs. (ii) Non-selective and selective blockade of TrkB reduced viability and proliferation of MLE12 and mAT2 with a loss of epithelial AT1 and AT2 markers. <bold>Discussion</bold> Our data identify an important functional role of TrkB signaling in AT2 cell homeostasis, a mechanism that is blocked in neonatal mouse lungs after hyperoxia and may contribute to a lack of regeneration and to the arrest of alveolar growth in infants with BPD, serving as a target for new therapies.