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.
abstract: 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+/-, 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.
authors.affiliation: 1 Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Angara
authors.initials: A
authors.lastname: Sureshbabu
authors.affiliation: 1 Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.|2 Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Mansoor
authors.initials: M
authors.lastname: Syed
authors.affiliation: 2 Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Pragnya
authors.initials: P
authors.lastname: Das
authors.affiliation: 3 Children's Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Janér
authors.affiliation: 4 Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York; and.
authors.forename: Gloria
authors.initials: G
authors.lastname: Pryhuber
authors.affiliation: 4 Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York; and.
authors.forename: Arshad
authors.initials: A
authors.lastname: Rahman
authors.affiliation: 3 Children's Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Sture
authors.initials: S
authors.lastname: Andersson
authors.affiliation: 5 Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Homer
authors.affiliation: 1 Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.|2 Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Vineet
authors.initials: V
authors.lastname: Bhandari
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D056809:Alveolar Epithelial Cells / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001997:Bronchopulmonary Dysplasia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D005260:Female; D006801:Humans; D018496:Hyperoxia / Q000150:complications* / Q000378:metabolism / Q000473:pathology*; D006976:Hypertension, Pulmonary / Q000150:complications / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000150:complications / Q000473:pathology; D007231:Infant, Newborn; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009287:Naphthyridines / Q000494:pharmacology; D010641:Phenotype; D000076223:Regulatory-Associated Protein of mTOR; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C558529:9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one; D048868:Adaptor Proteins, Signal Transducing; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D009287:Naphthyridines; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D016159:Tumor Suppressor Protein p53
keywords: bronchopulmonary dysplasia; cell death; newborn; oxygen; pulmonary