We found that nonlethal lysosomal enzyme release from human peripheral blood leukocytes during phagocytosis of opsonized zymosan in vitro was modified by the oxygen tension under which the cells were incubated ; with decreasing PoZ, zymosan-induced release of lysosomal enzymes was potentiated. The effect on enzyme release could not be attributed secondarily to an effect on phagocytosis, because, as others have reported, PoZ had little effect on that response . Metabolic responses that accompany phagocytosis were also modified by oxygen tension . Stimulation of oxidation by way of the pentose cycle was further enhanced by increasing PoZ. Conversely, anaerobic glycolysis was promoted by decreasing oxygen tension . ATP levels fell as a function of time and concentration of phagocytic stimulus, mirroring lysosomal enzyme release as modified by PoZ . Cyclic AMP levels fell during phagocytosis and lysosomal enzyme release, a change that could act to facilitate lysosomal enzyme release. However, the fall in nucleotide level was greatest with highest PoZ (i .e ., when lysosomal enzyme release was least) . The inverse relationship between oxidative metabolism and enzyme release suggested that a product of oxidative metabolism might adversely influence enzyme release. Sulfhydryl antioxidants (cysteine, glutathione) and scavengers of oxygen-derived reactants (superoxide dismutase, catalase, benzoate, hypoxanthine, xanthine, histidine, azide) all potentiated zymosan-stimulated enzyme release. These findings are consistent with the interpretation that one or more factors (e .g ., superoxide anion, hydrogen peroxide, hydroxyl radical, singlet oxygen), generated in association with the burst of oxidative metabolism which accompanies phagocytosis, acts to inhibit lysosomal enzyme release.Neutrophils play an essential role in the pathogenesis of inflammation (1). Lysosomal enzymes released from neutrophils stimulated at sites of inflammation are capable of degrading tissue (2). Toxic by-products of oxidative metabolism may also damage cells and extracellular tissue components (3). Phagocytosis and release of lysosomal enzymes by neutrophils are associated with enhanced glucose oxidation by way of the pentose cycle and enhanced lactate production that results from anaerobic glycolysis (4). Results of experiments in which anaerobic glycolysis was suppressed by metabolic inhibitors have been interpreted as indicating that this pathway must be intact to support both phagocytosis (4) and release of lysosomal enzymes (5). To elucidate further the interrelationships between neutrophil function and metabolism, we have altered cell metabolism by incubating cells in media with varying oxygen tension (PoZ),' a technique that does not depend on the use of drugs or metabolic inhibitors . With this method, we 'Abbreviations used in this paper: H202, hydrogen peroxide; KRP, Krebs-Ringer phosphate buffer; LDH, lactate dehydrogenase; Oz , superoxide anion; OH ., hydroxyl radical; '02, singlet oxygen; Poz, partial pressure of oxygen ; SO...