Protection of Phagocytic Leukocytes by Endogenous Glutathione: Studies in a Family With Glutathione Reductase Deficiency

• Published in: Blood 1979-05, Vol.53 (5), p.851-866
• Main Authors: Roos, Dirk, Weening, Ron S., Voetman, Alwin A., van Schaik, Margriet L.J., Bot, Annet A.M., Meerhof, Louis J., Loos, Johannes A.
• Format: Article
• Language: English
• Subjects: Adult; Chemotaxis, Leukocyte; Female; Glutathione - pharmacology; Glutathione Reductase - deficiency; Hexosephosphates - metabolism; Humans; Leukocytes - enzymology; Male; Methylene Blue - pharmacology; Oxidation-Reduction; Oxygen Consumption; Phagocytes - enzymology; Phagocytosis; Time Factors; Zymosan - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V53.5.851.851

The significance of the glutathione redox system in phagocytic leukocytes was studied in a family with glutathione reductase deficiency. The polymorphonuclear leukocytes and monocytes of all 3 children in this family contained 10 % -15 % of normal glutathione reductase activity; the parents' cells showed about half the normal activity. Chemotaxis toward casein, phagocytosis of Staphylococcus aureus, DNA-anti-DNA complexes, and zymosan particles, as well as release of lysosomal enzymes during phagocytosis, were normal in the glutathione-reductase-deficient cells. At high ratios of S. aureus to glutathione-reductase-deficient neutrophils the killing in vitro of these bacteria was slightly depressed. The metabolic response of the glutathione-reductase-deficient neutrophils during phagocytosis showed characteristic abnormalities. During the first 5-10 min normal oxygen consumption, hydrogen peroxide generation, and zymosan iodination were observed; thereafter these reactions stopped completely. The production of 14CO2 from glucose-1-14C took place at a half-normal rate from the start of phagocytosis and stopped after about 10 min. The same aberration in H2O2 formation as found in the neutrophils was also observed in the homozygous-deficient monocytes. The heterozygous neutrophils did not show this abnormality. The level of reduced glutathione in the homozygous-deficient granulocytes decreased faster during phagocytosis and reached a lower level than in normal cells. This effect was particularly pronounced when catalase and myeloperoxidase were inhibited by azide. The respiration of glutathione-reductase-deficient cells was no longer activated during phagocytosis after incubation of the cells with an H2O2-generating system. From these and the previously mentioned results it appears that these cells are easily damaged by oxidative stress, either from outside or during phagocytosis. Exogenous cytochrome c, which acts as an oxygen radical scavenger, protected the cells against this damage; in its presence normal stimulation of superoxide generation during phagocytosis was found. We conclude that the glutathione redox system is not involved in the generation of bactericidal oxygen products. Our data support the view that this system is of vital importance in the protection of phagocytic leukocytes against oxidative injury during phagocytosis.