Deferoxamine interferes with adhesive functions of activated human neutrophils.
Deferoxamine is a potent chelator of ferric iron. Past studies have shown that deferoxamine interferes with acute inflammatory tissue injury in a number of animal models. In cell culture, it inhibits neutrophil-medicated killing of endothelial cells. Both the animal model and cell culture data are thought to reflect the capacity of deferoxamine to interfere with the superoxide anion- and and ferric iron-dependent reduction of hydrogen peroxide to the hydroxyl radical (Fenton Reaction). The present study describes a second mechanism by which deferoxamine may interfere with the acute inflammatory response. Here it is shown that deferoxamine has the capacity to inhibit neutrophil adhesion to lung epithelial cells and vascular endothelial cells. Adhesion of phorbol ester-stimulated neutrophils to both cell types is reduced by 70-80%. The inhibitory effects are reversible and are overcome when ferric iron is present along with deferoxamine in a 2:1 molar ratio. Concentrations of deferoxamine that prevent neutrophil adhesion also prevent neutrophil-mediated killing of the same target cells. In contrast, deferoxamine does not significantly inhibit activation-induced up-regulation of neutrophil surface adhesion structures (CD11b/CD18) and does not prevent binding of a monoclonal antibody that recognizes beta 2 integrins in the high-affinity state. Release of proteolytic enzymes from activated cells is also not significantly inhibited by deferoxamine. Taken together, these data indicate that deferoxamine modulates neutrophil adhesive functions associated with the activated state. The ability of deferoxamine to interfere with neutrophil binding to target cells may contribute to its anti-inflammatory activity.
Varani
J
J
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109, USA.
Dame
M K
MK
Diaz
M
M
Stoolman
L
L
D000328:Adult; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology*; D004492:Edetic Acid / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D006895:Hydroxyethyl Starch Derivatives; D066298:In Vitro Techniques; D019272:Leukocyte Elastase / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D018375:Neutrophil Activation; D009504:Neutrophils / Q000187:drug effects*; D010196:Pancreatic Elastase / Q000378:metabolism; D010618:Phenanthrolines / Q000494:pharmacology; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002614:Chelating Agents; D006895:Hydroxyethyl Starch Derivatives; D010618:Phenanthrolines; D004533:Egtazic Acid; D004492:Edetic Acid; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D008666:Metalloendopeptidases; D003676:Deferoxamine; D013755:Tetradecanoylphorbol Acetate; C025205:1,10-phenanthroline