Free radical-triggered hepatic injury of experimental obstructive jaundiceof rats involves overproduction of proinflammatory cytokines and enhanced activation of nuclear factor kappa B

Excessive production of hydroxyl radicals in blood and liver has previously been demonstrated by us in rats with obstructive jaundice induced by commo n bile duct ligation (CBDL). In this study, we demonstrate overproduction o f superoxide radicals in circulating blood of CBDL rats by the lucigenin-am plified chemiluminescence technique. To pinpoint the molecular agents that mediate these processes, we measured circulating proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin- 1 beta (IL-1 beta), and interleukin-6 (IL-6) in controls and CBDL rats. Concentrations of these cytokines in blood of CBDL rats were markedly elevated when compar ed to the controls (TNF-alpha: 36.7+/-5.0 vs 13.8+/-0.5 pg/mL; IL-6: 2,814/-1,740 vs 0 pg/mL; IL-1 beta: 11.9+/-2.6 vs 0 pg/mL). The overproduction o f free radicals triggered by elevated cytokines in CBDL rats was correlated with the activation of NF-kappaB in hepatic tissue. Using the TdT-mediated dUTP nick-end label staining technique, we showed that hepatic tissue sect ions from CBDL rats had an increase in the apoptotic index (AI). Based on t hese findings, we propose that the severe hepatic injury in CBDL rats is me diated by a cycle that involves the activation of NF-kappaB by combined act ion of proinflammatory cytokines and reactive oxygen species (ROS). NF-kapp aB, in turn, initiates the transcription of cytokine genes (eg, IL-6, IL-8, TNF-alpha), which triggers hepatic injury, at least in part, by a free rad ical-mediated apoptotic mechanism. Elevated ROS may be as a positive feedba ck signal that triggers NF-kappaB reactivation; the severe hepatic injury o f CBDL rats may result from perpetuation of this vicious cycle.