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Vitamin E Reduces Transendothelial Migration of Neutrophils and Prevents Lung Injury in Endotoxin-Induced Airway Inflammation

Department of Medical Countermeasures, Divison of NBC Defence, Swedish Defence Research Agency, Umeå; Department of Respiratory Medicine and Allergy, University Hospital Umeå, Sweden; and Department of Medicine, Karolinska Institute, Stockholm, Sweden

Address correspondence to: David Rocksén, M.Sc., Dept. of Medical Countermeasures, FOI NBC Defence, SE-901 82, Umeå, Sweden. E-mail: david.rocksen{at}foi.se

We investigated the pharmacologic effects of the antioxidant Vitamin E (-tocopherol [-toc]) in airway inflammation induced by inhaled endotoxin. A preparation of -toc incorporated in liposomes was administered intraperitoneally in mice 1 h after exposure of aerosolized endotoxin. Injection of 50 mg -toc/kg significantly decreased the number of neutrophils in airspaces and prevented lung injury, monitored both as decreased lactate dehydrogenase activity in airways and reduced lung edema when compared with animals treated with plain liposomes. Immunofluorescence staining of lung tissue revealed that treatment with -toc decreased the number of neutrophils in lung interstitium, whereas the number in lung blood vessels and peripheral blood did not differ between mice treated with -toc and control mice. Our results indicate that -toc downmodulates the migration of neutrophils across the endothelial barrier, but in contrast to strong anti-inflammatory drugs such as corticosteroids, without inhibition of transcription factors involved in the early inflammatory response (nuclear factor-B/activator protein-1). Neither was the endotoxin-induced expression of proinflammatory cytokines in lung tissue downregulated. Treatment with a combination of -toc and a suboptimal dose of 0.5 mg/kg dexamethasone enhanced the effect, suggesting that -toc, in combination with low doses of corticosteroids, might be effective for therapeutic treatment of acute lung injury.

Abbreviations: activator protein-1, AP-1 • -tocopherol, -toc • bronchoalveolar lavage fluid, BALF • electrophoretic mobility shift assay, EMSA • glyceraldehydes-3'-phosphate dehydrogenase, GAPDH • Hanks' balanced salt solution, HBSS • interleukin, IL • lactate dehydrogenase, LDH • lipopolysaccharide, LPS • macrophage inflammatory protein, MIP • nuclear factor-B, NF-B • reactive oxygen species, ROS • tumor necrosis factor-, TNF-

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