TNF-α suppression by glutathione preconditioning attenuates hepatic ischemia reperfusion injury in young and aged rats.

Background And Aim: Hepatic ischemia reperfusion (I/R) stimulates Kupffer cells and initiates injury through tumor necrosis factor-α (TNF-α) upregulation. Aim of this study was to compare the variable effects of reduced glutathione (GSH) pre-treatment on I/R liver injury in young and aged rats.

Methods: Wistar male rats were sorted into young (groups I-III) and aged (groups IV-VI). All groups except sham (groups I and IV) were subjected to 90-min ischemia and 2-h reperfusion. The treatment groups received 200 mg/kg bwt (groups III and VI) of GSH, 30 min prior to I/R. Variable effects of GSH were studied by transaminase activities, thiobarbituric acid-reactive substances (TBARS), GSH level, GSH/oxidized GSH (GSSG) ratio, TNF-α level, apoptotic markers and confirmed by histopathological observations.

Results: Our findings revealed that I/R inflicted more liver damage in aged rats than young rats. The GSH treatment prior to surgery significantly lowered the serum transaminase activities, hepatic TBARS level and effectively restored the GSH/GSSG ratio in both young and aged rats more remarkably in the mitochondria. Western analysis depicted that the GSH treatment effectively suppressed TNF-α expression and apoptotic markers in both young and aged rats. These findings were further confirmed by terminal deoxynucleotide transferase dUTP nick end labeling assay and histopathological observations of liver sections of young and aged rats.

Conclusion: Restoration of GSH/GSSG ratio through GSH pre-conditioning inhibits TNF-α and apoptosis in hepatic I/R injury. Hence, GSH pre-conditioning may be utilized in both young and aged individuals during liver transplantation/surgery for better post-operative outcomes.