Lipopolysaccharide‐induced oxidative stress is not potentiated by knockout of GPX1 and SOD1 in mice

Abstract

Our lab has previously found that knockout of cellular glutathione peroxidase (GPX1) and copper, zinc-superoxide dismutase (SOD1) attenuated protein nitration mediated by peroxynitrite. Because bacterial endotoxin lipopolysaccharide (LPS) triggers inflammatory responses involving the release of cytokines, nitric oxide (NO) and superoxide in targeted organs such as liver, we used GPX1 knockout (GPX1−/−), SOD1 knockout (SOD1−/−), GPX1 and SOD1 double-knockout (DKO) and their wild-type (WT) mice to investigate the role of these two antioxidant enzymes in LPS-induced oxidative injury in liver. Mice of the four genotypes (2-month old, Se-adequate) were killed at 0, 3, 6 or 12 h after an ip injection of saline or 5 mg LPS/kg body weight. The LPS injection caused similar increase in plasma alanine aminotransferase (P < 0.05) among the four genotypes. Hepatic total glutathione (GSH) was decreased (P < 0.05) compared with the initial values by the LPS injection at all time points in the WT mice, but only at 6 and 12 h in the other three genotypes. The GSH level in the DKO mice was higher (P < 0.05) than in the WT at 6 h. Although the LPS injection resulted in substantial increases in plasma NO in a time-dependent manner in all genotypes, the NO level in the DKO mice was lower (P < 0.05) at 3, 6, and 12 h than in the WT. The level in the GPX1−/− and SOD1−/− mice was also lower (P < 0.05) than in the WT at 3 h. The LPS-mediated hepatic protein nitration was detected in the WT, GPX1−/− and DKO mice at 3, 6 or 12 h, but not in the SOD1−/−. In conclusion, knockout of GPX1 and (or) SOD1 did not potentiate the LPS-induced liver injury, but delayed the induced hepatic GSH depletion and plasma NO production. [NIH DK53108 to XGL]