The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion

High-mobility group box 1 (HMGB1) is a nuclear factor that is released extracellularly as a late mediator of lethality in sepsis as well as after necrotic, but not apoptotic, death. Here we demonstrate that in contrast to the delayed role of HMGB1 in the systemic inflammation of sepsis, HMGB1 acts as an early mediator of inflammation and organ damage in hepatic ischemia reperfusion (I/R) injury. HMGB1 levels were increased during liver I/R as early as 1 h after reperfusion and then increased in a time-dependent manner up to 24 h. Inhibition of HMGB1 activity with neutralizing antibody significantly decreased liver damage after I/R, whereas administration of recombinant HMGB1 worsened I/R injury. Treatment with neutralizing antibody was associated with less phosphorylation of c-Jun NH2-terminal kinase and higher nuclear factor–κB DNA binding in the liver after I/R. Toll-like receptor 4 (TLR4)-defective (C3H/Hej) mice exhibited less damage in the hepatic I/R model than did wild-type (C3H/HeOuj) mice. Anti-HMGB1 antibody failed to provide protection in C3H/Hej mice, but successfully reduced damage in C3H/Ouj mice. Together, these results demonstrate that HMGB1 is an early mediator of injury and inflammation in liver I/R and implicates TLR4 as one of the receptors that is involved in the process.

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Effect of heat shock preconditioning on NF-κB/I-κB pathway during I/R injury of the rat liver

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00466.2001 ◽

2002 ◽

Vol 282 (6) ◽

pp. G962-G971 ◽

Cited By ~ 38

Author(s):

Hiroshi Uchinami ◽

Yuzo Yamamoto ◽

Makoto Kume ◽

Kei Yonezawa ◽

Yasuhide Ishikawa ◽

...

Keyword(s):

Heat Shock ◽

Messenger Rna ◽

Ischemia Reperfusion ◽

Nuclear Factor Κb ◽

Control Group ◽

Nuclear Factor ◽

Fatal Complication ◽

Hepatic Ischemia ◽

Proinflammatory Mediators ◽

Hepatic Ischemia Reperfusion

Hepatic ischemia-reperfusion (I/R) injury continues to be a fatal complication after liver surgery. Heat shock (HS) preconditioning is an effective strategy for protecting the liver from I/R injury, but its exact mechanism is still unclear. Because the activation of nuclear factor-κB (NF-κB) is an important event in the hepatic I/R-induced inflammatory response, the effect of HS preconditioning on the pathway for NF-κB activation was investigated. In the control group, NF-κB was activated 60 min after reperfusion, but this activation was suppressed in the HS group. Messenger RNA expressions of proinflammatory mediators during reperfusion were also reduced with HS preconditioning. Concomitant with NF-κB activation, NF-κB inhibitor I-κB proteins were degraded in the control group, but this degradation was suppressed in the HS group. This study shows that HS preconditioning protected the liver from I/R injury by suppressing the activation of NF-κB and the subsequent expression of proinflammatory mediators through the stabilization of I-κB proteins.

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