title: MAPK pathways mediate hyperoxia-induced oncotic cell death in lung epithelial cells.
abstract: Cell injury and cell death of pulmonary epithelium plays an important role in the pathogenesis of acute lung injury in animals exposed to prolonged hyperoxia. The aim of this study was to decipher the molecular mechanisms modulating cell death induced by hyperoxia in lung epithelium. Cell death is thought to be either apoptotic, with shrinking phenotypes and activated caspases, or oncotic, with swelling organelles. Exposure to 95% O2 (hyperoxia) induced cell death of MLE-12 cells with cellular as well as nuclear swelling, cytosolic vacuolation, and loss of mitochondrial structure and enzyme function. Neither elevated caspase-3 activity nor phosphatidylserine translocation were detected, suggesting that in hyperoxia, MLE-12 cells die via oncosis rather than apoptosis. In addition, hyperoxia triggered a sustained activation of the transcription factor AP-1, as well as mitogen-activated protein kinase (MAPK) family members p38 and JNK. Importantly, survival of MLE-12 cells in hyperoxia was significantly enhanced when either AP-1, p38, or JNK activation was inhibited by either specific inhibitors or dominant negative DNA constructs, indicating that in lung epithelial cells hyperoxia induces a program-driven oncosis, involving AP-1, JNK, and p38 MAPK. Interestingly, hydrogen peroxide-induced oxidative apoptosis of MLE-12 cells, with a shrinking nuclear morphology and activated caspase-3 activity, is also mediated by AP-1, JNK, and p38. Therefore, our data indicate that although they have divergent downstream events, oxidative oncosis and apoptosis share upstream JNK/p38 and AP-1 pathways, which could be used as potential targets for reducing hyperoxic inflammatory lung injury.
authors.affiliation: Department of Surgery, North Shore University Hospital, New York University School of Medicine, Manhasset, NY, USA.
authors.forename: John
authors.initials: J
authors.lastname: Romashko
authors.forename: Stuart
authors.initials: S
authors.lastname: Horowitz
authors.forename: William R
authors.initials: WR
authors.lastname: Franek
authors.forename: Tom
authors.initials: T
authors.lastname: Palaia
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Miller
authors.forename: Anning
authors.initials: A
authors.lastname: Lin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.forename: William
authors.initials: W
authors.lastname: Scott
authors.forename: Lin L
authors.initials: LL
authors.lastname: Mantell
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005799:Genes, Dominant; D006861:Hydrogen Peroxide / Q000494:pharmacology; D018496:Hyperoxia / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D010718:Phosphatidylserines / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D016877:Oxidants; D010718:Phosphatidylserines; D018808:Transcription Factor AP-1; D006861:Hydrogen Peroxide; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases