Defects in intracellular oxidative metabolism of neutrophils undergoing apoptosis

Apoptosis permits neutrophil recognition by macrophages, thereby not only limiting potential cytotoxicity but also promoting resolution of inflammation. A direct relationship between apoptosis and intracellular hydrogen peroxide (H2O2) production was observed in phorbol 12-myristate 13-acetate (PMA)-stimulated neutrophils aged in culture. A significant decrease in intracellular H2O2 production was observed in aging neutrophils at 12, 24, and 48 h. However, intracellular superoxide anion production in response to PMA stimulation was preserved up to 24 h, implying retention of intracellular signaling pathways leading to NADPH oxidase stimulation. A significant decrease in the cytoplasmic content and activity of Cu,Zn superoxide dismutase was responsible for the observed decline in intracellular H2O2 production in apoptotic neutrophils. Intracellular glutathione content also decreased concomitantly with H2O2 production. These observations indicate that onset of apoptosis in neutrophils is in part mediated by oxidative stress resulting from the down-regulation of key antioxidant defense systems of the cell, namely superoxide dismutase and glutathione.