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Reactive Oxygen Species and Extracellular Signal-Regulated Kinase 1/2 Mitogen-Activated Protein Kinase Mediate Hyperoxia-Induced Cell Death in Lung Epithelium

Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut; Eastern New Mexico Medical Center, Roswell, New Mexico; Department of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, Connecticut; and Division of Pulmonary, Allergy, and Critical Care, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Address correspondence to: Patty J. Lee, M.D., Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 333 Cedar Street, LCI 105, New Haven, CT 06520. E-mail: patty.lee{at}yale.edu

Therapy with high oxygen concentrations (hyperoxia) is often necessary to treat patients with respiratory failure. However, hyperoxia may exacerbate the development of acute lung injury, perhaps by increasing lung epithelial cell death. Therefore, interrupting lung epithelial cell death is an important protective and therapeutic strategy. In the present study, hyperoxia (95% O₂) results in murine lung epithelium cell death by DNA-laddering, terminal deoxynucleotidyltransferase dUTP nick end labeling, and Annexin V–fluorescein isothiocyanate flow cytometry assay. We show that hyperoxia increases superoxide production, as assessed by nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase activity and flow cytometric assay, and increases phospho–extracellular signal-regulated kinase (ERK)1/2 by Western blot analysis. These processes are inhibited by a reactive oxygen species inhibitor, diphenylene iodonium (DPI), and by an inhibitor of the mitogen-activated protein (MAP) or ERK kinase (MEK)/ERK1/2 pathway, PD98059. ERK1/2 activation in hyperoxia is also inhibited by DPI. Hyperoxia-induced cell death is associated with cytochrome c release, subsequent caspase 9 and 3 activation, and poly (ADP-ribosyl) polymerase cleavage, which can all be suppressed by DPI and PD98059. However, the broad caspase inhibitor z-VAD-FMK protects cells from death without affecting superoxide generation and ERK1/2 activation. Taken together, our data suggest that hyperoxia, by virtue of activating NADPH oxidase, generates reactive oxygen species (ROS), which mediates cell death of lung epithelium via ERK1/2 MAPK activation, and functions upstream of caspase activation in lung epithelial cells.

Abbreviations: 2',7'-dichlorofluroescein, DCF • diphenylene iodonium, DPI • extracellular signal-regulated kinase, ERK • c-Jun NH2-terminal kinase, JNK1/2 • mitogen-activated protein kinase, MAPK • MAP or ERK kinase, MEK • murine lung epithelium, MLE12 • nicotinamide adenine dinucleotide phosphate reduced, NADPH • protein 38, p38 • poly (ADP-ribosyl) polymerase, PARP • phosphate-buffered saline, PBS • reactive oxygen species, ROS • terminal deoxynucleotidyltransferase dUTP nick end labeling, TUNEL

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