Role of myeloperoxidase in the respiratory burst of human neutrophils

Abstract

Myeloperoxidase (MPO), a heme enzyme present in the primary granules of polymorphonuclear leukocytes (PMNs), has been demonstrated to participate in the oxygen-dependent microbicidal activity of these cells. Evidence for the importance of MPO in this role comes in part from studies of normal PMNs treated with the heme enzyme inhibitor, sodium azide. MPO has also been suggested to regulate the respiratory activity of PMNs during phagocytosis. The role of MPO in PMN oxygen metabolism was examined by studying parameters of the respiratory burst of PMNs from a number of unrelated MPO-deficient subjects; in addition, the ability of heme enzyme inhibitors to duplicate the MPO-deficient state was studied by treating normal and MPO-deficient cells with these compounds. MPO-deficient PMNs were found to have a time-dependent hypermetabolic response as assessed by measurement of oxygen consumption, superoxide generation, hydrogen peroxide release, and hexose monophosphate shunt activity. Catabolic pathways for hydrogen peroxide were normal, suggesting the increased recovery of oxygen metabolites reflects increased production rather than decreased catabolism of H2O2. These observations support the concept that MPO may play an important role in terminating the respiratory burst of normal PMNs. The three heme enzyme inhibitors studied--sodium azide, potassium cyanide, and 3-aminotriazole--differed greatly in the degree to which they inhibited various enzymatic systems in the PMN. Nonetheless, as a group, they exerted qualitatively similar effects on oxygen metabolism of normal and of MPO-deficient PMNs. This indicates that many of the mechanisms by which heme enzyme inhibitors influence PMN metabolism are independent of the inhibition of MPO. Conclusions from studies using such treatment of PMNs should be interpreted with caution.

Effects of Diethyldithiocarbamate on Activating Mechanisms of Neutrophils

“…This inhibition of the H,O,-myeloperoxidase system by diethyldithiocarbamate was consistent with previous findings (Bottu 1989). It has been reported that the superoxide-and H,O,-generating capacities of human neutrophils are potentiated by myeloperoxidase-deficiency or by inhibitors of myeloperoxidase (Jandal et al 1978;Nauseef et al 1983). Therefore, the inhibitory effect of diethyldithiocarbamate on myeloperoxidase activity may induce 0,and H,Oz generation from neutrophils.…”

Myeloperoxidase in human neutrophil host defence

“…Furthermore, the ambient H2O2 concentration in phagosomes lacking MPO will be higher than that in normal neutrophils for two reasons. MPO terminates activity of the NADPH oxidase (Jandl et al, 1978) and MPO-deficient neutrophils have prolonged oxidase activity and generate more H2O2 than do normal neutrophils (Klebanoff and Pincus, 1971;Klebanoff and Hamon, 1972;Rosen and Klebanoff, 1976;Nauseef et al, 1983). In addition, the absence of MPO, which normally rapidly consumes H2O2 to generate HOCl, will further increase the concentration of H2O2 (Winterbourn et al, 2006).…”

How neutrophils kill fungi

“…MPO derived from the azurophilic granules converts H 2 O 2 into the highly toxic and longer-lived antimicrobial HOCl 100. Neutrophils from MPO-deficient patients are impaired in the intracellular killing of Candida conidia, which may contribute to their susceptibility to fungal infections 101.…”