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BDNF (brain-derived neurotrophic factor) is a key integrator of cell homeostasis and contributes to chronic lung diseases. In this study, 1) 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\u2013P70; and 2) 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 Bdnf in mesenchymal cells but no changes during postnatal development. In contrast, immunofluorescent staining showed a predominant localization of TrkB in AT2 and ACTA2+\u2009cells; its expression and phosphorylation were increased at P7\u2013P21. Although hyperoxia induced a 40-fold upregulation of lung Bdnf and a 3-fold elevation of serum BDNF, TrkB abundance and activation decreased by 90%. This was related to a lower Sftpc and increased Acta2 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.<\/jats:p>","DOI":"10.1165\/rcmb.2024-0198oc","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T14:58:38Z","timestamp":1744124318000},"page":"517-529","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":5,"title":["BDNF-TrkB Signaling Maintains Alveolar Epithelial Type 2 Cell Survival and Is Blocked in Hyperoxia-induced Neonatal Lung Injury"],"prefix":"10.1093","volume":"73","author":[{"given":"Celien","family":"Kuiper-Makris","sequence":"first","affiliation":[{"name":"Faculty of Medicine and University Hospital Cologne, Department of Pediatric and Adolescent Medicine"},{"name":"Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics, Department of Pediatric and Adolescent Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luise","family":"Fahle","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and University Hospital Cologne, Department of Pediatric and Adolescent Medicine"},{"name":"Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics, Department of Pediatric and Adolescent Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Zeitouny","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and University Hospital Cologne, Department of Pediatric and Adolescent Medicine"},{"name":"Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics, Department of Pediatric and Adolescent Medicine"},{"name":"Faculty of Medicine and University Hospital Cologne, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Vohlen","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and University Hospital Cologne, Department of Pediatric and Adolescent Medicine"},{"name":"Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics, Department of Pediatric and Adolescent Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleksiy","family":"Klymenko","sequence":"additional","affiliation":[{"name":"Institute for Lung Health (ILH), University of Giessen and Marburg Lung Center (UGMLC) and Cardiopulmonary Institute (CPI), Member of the German Center for Lung Research (DZL)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Stephan","sequence":"additional","affiliation":[{"name":"Institute for Lung Health (ILH), University of Giessen and Marburg Lung Center (UGMLC) and Cardiopulmonary Institute (CPI), Member of the German Center for Lung Research (DZL)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Mi\u017eik","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and University Hospital Cologne, Department of Pediatric and Adolescent Medicine"},{"name":"Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics, Department of Pediatric and Adolescent Medicine"},{"name":"Department of Translational Pulmonology and Translational Lung Research Center Heidelberg, University Hospital Heidelberg, Member of the German Center for Lung Research (DZL), Heidelberg, Germany; 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