Lipopolysaccharide, Dexamethasone, 및 N-Nitro-L-Arginine Methyl Ester가 흰쥐 간 조직의 프리라디칼 발생과 제거에 미치는 영향

Abstract

Lipopolysaccharide (LPS) stimulates various immune and inflammatory reactions to induces the generation of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI). ROI and RNI are free radicals with very high reactivity, oxidize cellular constituents including proteins and lipid membranes, and thus play important roles in the pathogenesis of tissue damages in LPS-induced septic shock. The present study examined effects of dexamethasone (DexM), and N-nitro-L-arginine methyl ester (L-NAME) on the generation of ROI and RNI, and on the activities of enzymes removing ROI in the liver of rat model of septic shock. DexM has widely been used as an immunosuppressant. L-NAME has known to block synthesis of nitric oxide (NO), the main RNI, by inhibiting NO synthase (NOS). LPS (10 mg/kg body weight) markedly enhanced NO generation in serum and liver. The increased NO generation was completely blocked by pretreatment with DexM (10 mg/kg) and effectively inhibited by L-NAME (10 mg/kg). Induction of NOS protein expression by LPS was demonstrated by a Western analysis. The NOS expression was completely blocked by DexM pre-treatment, and markedly inhibited by L-NAME. However, the generation of superoxide radical, an important ROI, was not enhance in rat liver by LPS, rather it was decreased a little. Superoxide radical production was increased by L-NAME treatment or combined treatment of DexM and LPS. The level of lipid peroxidation, an index for free radical-induced cell damage, was increased by either LPS or DexM. The enhancement of lipid peroxidation by DexM was abolished by adding LPS. DexM markedly enhanced the activities of ROI removing enzymes, superoxide dismutase, glutathione peroxidase and catalase. However, rats were treated with LPS in addition to DexM, the elevated activities of superoxide dismutase, glutathione peroxidase and catalase were abolished. These results provide information on the generation and removal of ROI and RNI by LPS, DexM and L-NAME in rat liver, and on development of drugs to inhibit free radical-induced liver damage in sepsis.