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Annals of Clinical & Laboratory Science 31:383-390 (2001)
© 2001 Association of Clinical Scientists

Free Radical-Triggered Hepatic Injury of Experimental Obstructive Jaundice of Rats Involves Overproduction of Proinflammatory Cytokines and Enhanced Activation of Nuclear Factor {kappa}B

Tsan-Zon Liu1,2, King-Teh Lee3, Chi-Liang Chern1,4, Jiin-Tsuey Cheng4, Arnold Stern5 and Li-Yu Tsai6
1 Department of Medical Research, Yuan’s General Hospital, Kaohsiung, Taiwan
2 Department of Medical Technology, Fooyin Institute of Technology, Ta-Liao, Kaohsiung Hsien, Taiwan
3 Department of Surgery, Kaohsiung Medical University, Kaohsiung, Taiwan
4 Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
5 Department of Pharmacology, New York University Medical Center, New York City, New York, USA
6 Department of Clinical Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.

Address correspondence to Li-Yu Tsai, Ph.D., Department of Clinical Biochemistry, School of Technology for Medical Sciences, Kaohsiung Medical University, Taiwan 807; tel 886 7 312 1101, x7052; fax 886 7 237 0544; e-mail tsliyu{at}cc.kmu.edu.tw.

Excessive production of hydroxyl radicals in blood and liver has previously been demonstrated by us in rats with obstructive jaundice induced by common bile duct ligation (CBDL). In this study, we demonstrate overproduction of superoxide radicals in circulating blood of CBDL rats by the lucigenin-amplified 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-1ß ( IL-1ß), and interleukin-6 (IL-6) in controls and CBDL rats. Concentrations of these cytokines in blood of CBDL rats were markedly elevated when compared to the controlsSTNF-{alpha}: 36.7±5.0 vs 13.8±0.5 pg/mL; IL-6: 2,814±1,740 vs 0 pg/mL; IL-1ß: 11.9±2.6 vs 0 pg/mL). The overproduction of free radicals triggered by elevated cytokines in CBDL rats was correlated with the activation of NF-{kappa}B in hepatic tissue. Using the TdT-mediated dUTP nick-end label staining technique, we showed that hepatic tissue sections from CBDL rats had an increase in the apoptotic index (AI). Based on these findings, we propose that the severe hepatic injury in CBDL rats is mediated by a cycle that involves the activation of NF-{kappa}B by combined action of proinflammatory cytokines and reactive oxygen species (ROS). NF-{kappa}B, 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 radical-mediated apoptotic mechanism. Elevated ROS may be as a positive feedback signal that triggers NF-{kappa}B reactivation; the severe hepatic injury of CBDL rats may result from perpetuation of this vicious cycle.

Keywords: common bile duct ligation, oxidant stress, cytokines, nuclear transcription factor NF-{kappa}B






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