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

被引:943
作者
Tsung, A
Sahai, R
Tanaka, H
Nakao, A
Fink, MP
Lotze, MT
Yang, H
Li, JH
Tracey, KJ
Geller, DA
Billiar, TR
机构
[1] Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15213 USA
[2] Univ Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15213 USA
[3] NYU, Sch Med, N Shore Univ Hosp, Lab Biomed Sci, Manhasset, NY 11030 USA
关键词
D O I
10.1084/jem.20042614
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-kappa B 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.
引用
收藏
页码:1135 / 1143
页数:9
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