{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T15:07:15Z","timestamp":1784128035955,"version":"3.55.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2016,11,1]],"date-time":"2016-11-01T00:00:00Z","timestamp":1477958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Administration of supplemental oxygen remains a critical clinical intervention for survival of preterm infants with respiratory failure. However, prolonged exposure to hyperoxia can augment pulmonary damage, resulting in developmental lung diseases embodied as hyperoxia-induced acute lung injury and bronchopulmonary dysplasia (BPD). We sought to investigate the role of autophagy in hyperoxia-induced apoptotic cell death in developing lungs. We identified increased autophagy signaling in hyperoxia-exposed mouse lung epithelial-12 cells, freshly isolated fetal type II alveolar epithelial cells, lungs of newborn wild-type mice, and human newborns with respiratory distress syndrome and evolving and established BPD. We found that hyperoxia exposure induces autophagy in a Trp53-dependent manner in mouse lung epithelial-12 cells and in neonatal mouse lungs. Using pharmacological inhibitors and gene silencing techniques, we found that the activation of autophagy, upon hyperoxia exposure, demonstrated a protective role with an antiapoptotic response. Specifically, inhibiting regulatory-associated protein of mechanistic target of rapamycin (RPTOR) in hyperoxia settings, as evidenced by wild-type mice treated with torin2 or mice administered (Rptor) silencing RNA via intranasal delivery or Rptor+\/\u2212, limited lung injury by increased autophagy, decreased apoptosis, improved lung architecture, and increased survival. Furthermore, we identified increased protein expression of phospho-beclin1, light chain-3-II and lysosomal-associated membrane protein 1, suggesting altered autophagic flux in the lungs of human neonates with established BPD. Collectively, our study unveils a novel demonstration of enhancing autophagy and antiapoptotic effects, specifically through the inhibition of RPTOR as a potentially useful therapeutic target for the treatment of hyperoxia-induced acute lung injury and BPD in developing lungs.<\/jats:p>","DOI":"10.1165\/rcmb.2015-0349oc","type":"journal-article","created":{"date-parts":[[2016,7,2]],"date-time":"2016-07-02T21:26:16Z","timestamp":1467494776000},"page":"722-735","source":"Crossref","is-referenced-by-count":76,"title":["Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice"],"prefix":"10.1093","volume":"55","author":[{"given":"Angara","family":"Sureshbabu","sequence":"first","affiliation":[{"name":"Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mansoor","family":"Syed","sequence":"additional","affiliation":[{"name":"Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut"},{"name":"Section of Neonatal\u2013Perinatal Medicine, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pragnya","family":"Das","sequence":"additional","affiliation":[{"name":"Section of Neonatal\u2013Perinatal Medicine, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Jan\u00e9r","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Pryhuber","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arshad","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sture","family":"Andersson","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Homer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale University School of Medicine, New Haven, 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