High-mobility group box 1 inhibition protects against hepatic ischemia-reperfusion injury

Introduction. Hepatic ischemia followed by reperfusion (I/R) occurs in the settings of trauma, transplantation, and elective liver resections. The mechanisms that account for local organ damage are only partially understood. High-mobility group box 1 (HMGB1) has been identified as a late mediator of lethality in sepsis and is released by damaged tissues where it could also act as a mediator of inflammation and organ injury. We hypothesized that HMGB1 would contribute to organ injury following hepatic I/R. Methods. HMGB1 protein expression and hepatocellular secretion were determined in rat hepatocytes subjected to hypoxia (1% O₂) versus normoxic cells. The role of HMGB1 in mediating hepatic I/R injury was examined in C57Bl/6 mice that underwent 90 min of partial I/R injury. These mice were pretreated with neutralizing HMGB1 antibody (600 μg) or control normal saline 1 h prior to ischemia. Results. Basal HMGB1 expression was observed in normoxic hepatocytes and was dramatically up regulated 12-24 h after hypoxia. This corresponded to increased HMGB1 secretion 18-24 h after hypoxia. In mice undergoing partial warm liver I/R injury, HMGB1 protein expression is increased as early as 1 h after reperfusion and then increases in a time-dependent manner up to 24 h. Inhibition of HMGB1 activity with neutralizing antibody significantly decreased liver damage after warm ischemia compared to control animals.

TABLE—ABSTRACT 81.

Group	ALT-1 h	ALT-6 h	ALT-24h
Sham	67 ± 24	57 ± 8	51 ± 2
Control	3101 ± 1167	8140 ± 1656	905 ± 65
Anti-HMGB1	662 ± 120∗	2382 ± 687∗	265 ± 16∗

Note. Data are mean ± SEM, n = 3-4 per group;

∗

indicates P < 0.05 versus control.

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