DEFECTS IN INTRACELLULAR OXIDATIVE-METABOLISM OF NEUTROPHILS UNDERGOING APOPTOSIS

Apoptosis permits neutrophil recognition by macrophages, thereby not o nly limiting potential cytotoxicity but also promoting resolution of i nflammation. A direct relationship between apoptosis and intracellular hydrogen peroxide (H2O2) production was observed in phorbol 12-myrist ate 13-acetate (PMA)-stimulated neutrophils aged in culture. A signifi cant decrease in intracellular H2O2 production was observed in aging n eutrophils at 12, 24, and 48 h. However, intracellular superoxide anio n production in response to PMA stimulation was preserved up to 24 h, implying retention of intracellular signaling pathways leading to NADP H oxidase stimulation. A significant decrease in the cytoplasmic conte nt and activity of Cu,Zn superoxide dismutase was responsible for the observed decline in intracellular H2O2 production in apoptotic neutrop hils. Intracellular glutathione content also decreased concomitantly w ith H2O2 production. These observations indicate that onset of apoptos is in neutrophils is in part mediated by oxidative stress resulting fr om the down-regulation of key antioxidant defense systems of the cell, namely superoxide dismutase and glutathione.