Published ahead of print on August 12, 2004, doi:10.1165/rcmb.2004-0141OC
© 2004 American Thoracic Society DOI: 10.1165/rcmb.2004-0141OC Extracellular Signal–Regulated Kinase Activation Delays Hyperoxia-Induced Epithelial Cell Death in Conditions of Akt DownregulationRoy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Veterans Administration Medical Center, Iowa City, Iowa Address correspondence to: Martha M. Monick, Division of Pulmonary, Critical Care, and Occupational Medicine; 100 EMRB, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242. E-mail: martha-monick{at}uiowa.edu Hyperoxia (fraction of inspired oxygen = 95%) induces death of lung epithelial cells. The duration of cell survival in the setting of hyperoxia depends on hyperoxia-induced activation of intracellular survival pathways. Two survival pathways with known effects on lung epithelial cells are the propidium iodide 3–kinase/Akt and extracellular signal–regulated kinase (ERK)/mitogen-activated protein (MAP) kinase pathways. We investigated the effect of hyperoxia on activity of both the Akt and ERK pathways in the A549 lung epithelial cell line. Hyperoxia-exposed cells show progressive loss of Akt activation and total Akt protein. Hyperoxia decreases Akt mRNA, consistent with the loss of total Akt. In addition, hyperoxia induces ERK activation. Inhibition of ERK with the MAP kinase kinase 1/2 inhibitor, U0126, shortens the survival time of cells in hyperoxia, suggesting that increased ERK activity partially compensates for the hyperoxia-induced Akt downregulation. Our findings show, for the first time, that hyperoxia has divergent effects on two survival pathways (Akt and ERK), and that ERK activity compensates for the loss of the Akt survival effects, delaying the death of hyperoxia-exposed lung epithelial cells.
Abbreviations: threshold cycle, Ct • extended chemiluminescence, ECL • extracellular signal–regulated kinase, ERK • ethidium homodimer, EthD-1 • fraction of inspired oxygen, FiO2 • hypoxanthine phosphoribosyltransferase, HPRT • mitogen-activated protein, MAP • MAP kinase kinase, MEK • nicotinamide adenine dinucleotide, NAD • poly(ADP-ribose) polymerase, PARP • propidium iodide, PI • phosphatidylinositol 3-kinase, PI3-K • reverse transcriptase–polymerase chain reaction, RT-PCR • tumor necrosis factor, TNF • This article has been cited by other articles:
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