Myeloperoxidase-Mediated Platelet Release Reaction

Abstract

A B S T R A C T The ability of the neutrophil myeloperoxidase-hydrogen peroxide-halide system to induce the release of human platelet constituents was examined. Both resulted in a small, although significant, release ofboth serotonin and adenine, suggesting some platelet lysis. Substantial release of these markers was observed only with increased H202 concentrations (>0.1 mM) or prolonged incubation (1-2 h).Serotonin release by H202 was markedly enhanced by the addition ofmyeloperoxidase and a halide. Under these conditions, there was a predominance of release of serotonin (50%) vs. adenine (13%), suggesting, in part, a nonlytic mechanism. Serotonin release by the complete peroxidase system was rapid, reaching maximal levels in 2-5 min, and was active at H202 concentrations as low as 10 ,uM. It was blocked by agents which inhibit peroxidase (azide, cyanide), degrade H202 (catalase), chelate Mg2+ (EDTA, but not EGTA), or inhibit platelet metabolic activity (dinitrophenol, deoxyglucose).These results suggest that the myeloperoxidase system initiates the release of platelet constituents primarily by a nonlytic process analogous to the platelet release reaction. Because components of the peroxidase system (myeloperoxidase, H202) are secreted by activated neutrophils, the reactions described here may have implications for neutrophilplatelet interaction in sites of thrombus formation.Portions of this work have appeared in abstract form: Clin.

Chemotactic Factor Inactivation by the Myeloperoxidase-Hydrogen Peroxide-Halide System

“…These observations raise the interesting possibility that chemoattractants could initiate their own inactivation by triggering the release of either MPO and H202 or neutral proteases. The MPO system may, in addition, manifest other biological activities, including the lysis of mammalian cells (27,(31)(32)(33)(34)(35)(36)(37)(38) and the inactivation of other humoral mediators such as the slow-reacting substance of anaphylaxis (55) and serum antiproteases (56)..…”

“…although its activity in microbicidal and cytotoxic systems is markedly enhanced by the addition of MPO and a halide (20,(32)(33)(34) (44). The rank order observed for chemoattractant inactivation was similar with respect to chloride, although iodide and bromide were reversed (Fig.…”

“…The stimulated PMN also undergoes a burst of oxidative metabolism (2,20,21) which results in the extracellular release of various activated oxygen species, including H202 (28)(29)(30). These components of the MPO system might be expected to react with extracellular halides to exert effects on host tissues present in the vicinity of the inflammatory response because the cell-free peroxidase system has been shown to affect a number of mammalian cells, including spermatozoa (31), erythrocytes (32), leukocytes (33), platelets (34), and tumor cells (35,36). Furthermore, the effects of activated PMN on adjacent tumor cells (27,37) and platelets (38) have been shown to be mediated in part by the MPO-H202-halide system.…”

Thrombin stimulates the adherence of neutrophils to human endothelial cells in vitro.

“…Mediators released from platelets during coagulation or after contact with injured vascular intima, such as platelet-derived growth factor and platelet factor IV, have proinflammatory effects (10). Neutrophils also release substances that can activate coagulation and initiate fibrinolysis (1,1 1), and cause platelet activation and the release of platelet products (1,12,13).…”

Functions of interleukin‐8 are mediated through thiol group(s) of IL‐8 receptor in human polymorphonuclear neutrophils

“…Two forms of the IL-8 receptor are known. One form has high affinity for IL-8 itself and two agonists, namely MGSA (GROcr) The PMNs were separated from fresh human peripheral venous blood of a normal healthy donor by dextran sedimentation followed by the Ficoll-Paque centrifugation method [12]. The preparation contained 90-95% PMNs of which 98% were viable.…”