title: Lung injury caused by high tidal volume mechanical ventilation and hyperoxia is dependent on oxidant-mediated c-Jun NH2-terminal kinase activation.
abstract: Both prolonged exposure to hyperoxia and large tidal volume mechanical ventilation can each independently cause lung injury. However, the combined impact of these insults is poorly understood. We recently reported that preexposure to hyperoxia for 12 h, followed by ventilation with large tidal volumes, induced significant lung injury and epithelial cell apoptosis compared with either stimulus alone (Makena et al. Am J Physiol Lung Cell Mol Physiol 299: L711-L719, 2010). The upstream mechanisms of this lung injury and apoptosis have not been clearly elucidated. We hypothesized that lung injury in this model was dependent on oxidative signaling via the c-Jun NH(2)-terminal kinases (JNK). We, therefore, evaluated lung injury and apoptosis in the presence of N-acetyl-cysteine (NAC) in both mouse and cell culture models, and we provide evidence that NAC significantly inhibited lung injury and apoptosis by reducing the production of ROS, activation of JNK, and apoptosis. To confirm JNK involvement in apoptosis, cells treated with a specific JNK inhibitor, SP600125, and subjected to preexposure to hyperoxia, followed by mechanical stretch, exhibited significantly reduced evidence of apoptosis. In conclusion, lung injury and apoptosis caused by preexposure to hyperoxia, followed by high tidal volume mechanical ventilation, induces ROS-mediated activation of JNK and mitochondrial-mediated apoptosis. NAC protects lung injury and apoptosis by inhibiting ROS-mediated activation of JNK and downstream proapoptotic signaling.
authors.affiliation: Dept. of Medicine, Univ. of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Patrudu S
authors.initials: PS
authors.lastname: Makena
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Gorantla
authors.forename: Manik C
authors.initials: MC
authors.lastname: Ghosh
authors.forename: Lavanya
authors.initials: L
authors.lastname: Bezawada
authors.forename: Louisa
authors.initials: L
authors.lastname: Balazs
authors.forename: Charlean
authors.initials: C
authors.lastname: Luellen
authors.forename: Kuashik
authors.initials: K
authors.lastname: Parthasarathi
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Waters
authors.forename: Scott E
authors.initials: SE
authors.lastname: Sinclair
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D002460:Cell Line; D045304:Cytochromes c / Q000037:antagonists & inhibitors / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D018496:Hyperoxia / Q000201:enzymology* / Q000209:etiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055370:Lung Injury / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012121:Respiration, Artificial / Q000009:adverse effects / Q000379:methods; D013990:Tidal Volume
chemical_list: D000873:Anthracenes; D061945:Caspase Inhibitors; D016877:Oxidants; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; C432165:pyrazolanthrone; D045304:Cytochromes c; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D000111:Acetylcysteine