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Hyperoxia Impairs Antibacterial Function of Macrophages Through Effects on Actin

Department of Medicine, Division of Pulmonary and Critical Care Medicine; Department of Anesthesiology; Department of Genomics and Pathobiology; and Department of Physiology and Biophysics, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama

Address correspondence to: Dr. Sadis Matalon, Dept. of Anesthesiology, University of Alabama at Birmingham, 901 19th Street South, BMR II, Rm. 224, Birmingham AL 35205-3703. E-mail: Sadis.Matalon{at}ccc.uab.edu

Oxidative stress may impair alveolar macrophage function in patients with inflammatory lung diseases or those exposed to high concentrations of oxygen. We investigated putative mechanisms of injury to macrophages by oxidative stress, using RAW 264.7 cells exposed to 95% oxygen for 48 h. Hyperoxia-exposed macrophages were less able to phagocytose and kill Klebsiella pneumoniae than normoxic controls, despite increased production of nitric oxide, a free radical important in pathogen killing. Exposure of macrophages to hyperoxia had marked effects on the actin cytoskeleton, including increased actin polymerization, loss of cortical actin, formation of stress fibers, de novo synthesis of actin, and actin oxidation. Hyperoxia induced changes in cell morphology, with increased cell size and pseudopod formation. Exposure of macrophages to jasplakinolide, an agent that increases actin polymerization, also impaired their ability to phagocytose Klebsiella. Alveolar macrophages isolated from mice exposed to 100% oxygen for 84 h also demonstrated impaired phagocytic function, as well as similar effects on the actin cytoskeleton and cell morphology to macrophages exposed to hyperoxia in vitro. We conclude that oxidative stress in vitro and in vivo impairs macrophage antibacterial function through effects on actin.

Abbreviations: alveolar macrophages, AM • acute respiratory distress syndrome, ARDS • adenosine triphosphate, ATP • Dulbecco's modified Eagle's medium, DMEM • 2,4-dinitrophenylhydrazine, DNPH • interferon-, IFN- • jasplakinolide, JP • lipopolysaccharide, LPS • mitogen-activated protein kinase, MAPK • nitric oxide, NO • polyacrylamide gel electrophoresis, PAGE • phosphate-buffered saline, PBS • reactive oxygen species, ROS • sodium dodecyl sulfate, SDS • trifluoroacetic acid, TFA • tris (hydroxymethyl) aminomethane, TRIS

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