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p38^mapk and MEK1/2 inhibition contribute to cellular oxidant injury after hypoxia

Birmingham Department of Veterans Affairs Medical Center, Birmingham 35233; and University of Alabama at Birmingham, Birmingham, Alabama 35294

Submitted 16 April 2003 ; accepted in final form 25 November 2003

Lung epithelial cells produce increased reactive oxygen species (ROS) after hypoxia exposure, and they are more susceptible after hypoxia to injury by agents that generate superoxide [; e.g., 2,3-dimethoxy-1,4-naphthoquinone (DMNQ)]. Cellular GSH and MnSOD both decrease in hypoxic lung epithelial cells, altering the redox state. Because ROS participate in signaling pathways involved in cell death or survival, we tested the hypothesis that mitogen-activated protein kinases (MAPK) were involved in a protective response against cellular injury during reoxygenation. Human lung epithelial A549 cells were incubated in hypoxia (<1% O₂ for 24 h) and then reoxygenated by return to air. p38^mapk and MKK3 phosphorylation both decreased after hypoxia. During reoxygenation, cells were incubated with DMNQ (0–50 µM), a redox cycling quinone that produces . Hypoxia preexposure significantly increased epithelial cell lysis resulting from DMNQ. Addition of the p38^mapk inhibitors SB-202190 or SB-203580 markedly increased cytotoxicity, as did the mitogen/extracellular signal-regulated kinase (MEK) 1/2 inhibitor PD-98059 (all 10 µM), suggesting a protective effect of downstream molecules activated by the kinases. Transfection of A549 cells with a dominant active MKK3 plasmid (MKK3[Glu]) partially inhibited cytolysis resulting from DMNQ, whereas the inactive MKK3 plasmid (MKK3[Ala]) had less evident protective effects. Stress-related signaling pathways in epithelial cells are modulated by hypoxia and confer protection from reoxygenation, since hypoxia and chemical inhibition of p38^mapk and MEK1/2 similarly increase cytolysis resulting from .

alveolar epithelium; hypoxia; reoxygenation; mitogen-activated protein kinase; mitogen/extracellular signal-regulated kinase