DEFEROXAMINE INTERFERES WITH ADHESIVE FUNCTIONS OF ACTIVATED HUMAN NEUTROPHILS

Deferoxamine is a potent chelator of ferric iron. Past studies have sh own that deferoxamine interferes with acute inflammatory tissue injury in a number of animal models; In cell culture, it inhibits neutrophil -mediated killing of endothelial cells, Both the animal model and cell culture data are thought to reflect the capacity of deferoxamine to i nterfere with the superoxide anion- and and ferric iron-dependent redu ction 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 t hat deferoxamine has the capacity to inhibit neutrophil adhesion to lu ng epithelial cells and vascular endothelial cells. Adhesion of phorbo l ester-stimulated neutrophils to both cell types is reduced by 70-80% . The inhibitory effects are reversible and are overcome when ferric i ron is present along with deferoxamine in a 2:1 molar ratio, Concentra tions of deferoxamine that prevent neutrophil adhesion also prevent ne utrophil-mediated killing of the same target cells. In contrast, defer oxamine does not significantly inhibit activation-induced up-regulatio n of neutrophil surface adhesion structures (CD11b/CD18) and does not prevent binding of a monoclonal antibody that recognizes beta 2 integr ins in the high-affinity state. Release of proteolytic enzymes from ac tivated cells is also not significantly inhibited by deferoxamine. Tak en together, these data indicate that deferoxamine modulates neutrophi l adhesive functions associated with the activated state, The ability of deferoxamine to interfere with neutrophil binding to target cells m ay contribute to its anti-inflammatory activity.