An oxygen-dependent mechanism of neutrophil-mediated cytotoxicity

Abstract

Human neutophils stimulated with phorbol myristate acetate were able to rapidly destroy autologous red blood cell targets. Neutrophil-mediated cytotoxicity was related to phorbol myristate acetate concentration and neutrophil number. The ability of stimulated neutrophils to lyse red blood cell targets was markedly impaired by catalase or superoxide dismutase but not by heat-inactivated enzymes or albumin. Despite a simultaneous requirement for O2.- and H2O2 in the cytotoxic event, a variety of OH. and 1O2 did not effect cytolysis. The myeloperoxidase inhibitor cyanide did not reduce red blood destruction, while azide consistently impaired cytolysis. The inability of cyanide to reduce cytotoxicity coupled with the protective effect of superoxide dismutase suggests that cytotoxicity is independent of the classic myeloperoxidase-H2O2-halide system. We propose that neutrophils, stimulated with phorbol myristate acetate, generate O2.- and H2O2, which play an integral role in a novel cytotoxic mechanism.

Appearance of WBC-Platelet Complex in Acute Ischemic Stroke, Predominantly in Atherothrombotic Infarction

“…A BD FACS Calibur (Becton Dickinson Biosciences) was used to analyze white blood cells, which were identified based on CD45 fluorescence, forward leading to endothelial cell damage 3,4) . Granulocyte elastase, a protease released from activated granulocytes, especially damages endothelial cells, because it is most active at neutral pH and has broad substrate specificity 5) .…”

The Anti-Inflammatory Properties of Antithrombin III: New Therapeutic Implications

“…25 One of the various mechanisms postulated for the I/R-induced hepatic damage includes activated leukocytes, 26 which release various inflammatory mediators, including cytokines, neutrophil proteases, and reactive oxygen species, any of which can damage the adjacent endothe lial cells and tissues. 27 As a consequence of the release of such inflammatory mediators, the microcirculatory dis turbances resulting from the injury to endothelial cells may cause hepatic injury. Since AT III promotes the en dothelial release of PGI 2 that inhibits leukocyte activa tion and dilates the blood vessels, it is possible that AT III may prevent the I/R-induced liver injury by promot ing the release of PGI 2 from the endothelial cells and maintaining the hepatic tissue blood flow.…”

Injury to endothelial cells by phagocytosing polymorphonuclear leukocytes and modulatory role of lipoxygenase products

“…All of these products have been implicated in tissue injury. Lysosomal enzymes have been implicated for their effect on extracellular matrices and for their nonlytic damage to cultured cellular monolayers (7,16,33,43); oxygen-derived products have been cited for their cytotoxic effects (9,26,27,29,39,42,44); and inflammatory mediators, such as leukotrienes and prostaglandins, have been implicated for their effects on vascular permeability and for their vasomotor and chemotactic effects (for a review, see reference 32). Evidence for a role for these products from PMN in tissue damage, however, has been obtained in studies in which PMN were stimulated with soluble agents or with opsonized zymosan, a large phagocytosable particle, or in studies in which more or less purified products were used.…”

“…The phenomenon of regurgitation during phagocytosis of microorganisms is well known. Yet, in most studies on the cytotoxic effects of PMN, the phagocytes are stimulated with soluble products, such as phorbol myristate acetate (PMA), N-formylmethionyl-leucyl-phenylalanine, or complement component C5a (27,29,42,44). Activation by these compounds leads to a direct extracellular release of toxic PMN products and not to inadvertent leakage, as might occur during phagocytosis of microorganisms.…”