Recombinant human soluble thrombomodulin decreases the plasma high-mobility group box-1 protein levels, whereas improving the acute liver injury and survival rates in experimental endotoxemia

Objective: In addition to the hyperactivation of the inflammatory cytokines, high-mobility group box-1 protein (HMGB1), recently identified as a lethal late-phase mediator is suspected to be closely correlated with the development of sepsis. Therefore, the therapeutic efficacy of recombinant human soluble thrombomodulin (ART-123) administration on the production of inflammatory cytokines and the plasma level of HMGB1 was investigated in experimental endotoxemia. Design: Prospective, comparative, experimental study. Setting., Laboratory animal research center at a university. Subjects: Male Sprague-Dawley rats (250-300 g). Interventions: Endotoxemia was induced in rats by a bolus intravenous injection of lipopolysaccharide (LPS) at a dosage of 4 mg/kg (LPS group). ART-123 (11 mg/kg) was administered as a bolus injection 30 minutes before or 4 hours after injection of LPS (ART-123 pretreated/treated group). As a control, an equal volume of physiologic saline was administered instead of LPS and ART-123 (control group). Measurements and Main Results, Rats were randomly divided into ART-123 pretreated group, ART-123 treated group, and LPS group, respectively. After the injection of LPS, the levels of inflammatory cytokines and thrombin-antithrombin III complex, plasma HMGB1 concentrations, liver immunohistochemical and histopathologic characteristics, liver dysfunction, and survival rate were examined. The increased levels of inflammatory cytokines and plasma HMGB1 induced by LPS in this rat model were improved by the administration of ART-123; additionally, reduced liver dysfunction and increased survival rate were observed. Conclusions. This study demonstrated that ART-123 inhibits the expression of inflammatory cytokines and decreases the plasma HMGB1 levels in experimental endotoxemia. In addition, ART-123 administration markedly reduced liver dysfunction and mortality even with delayed treatment of ART-123. The use of ART-123 may therefore be a beneficial treatment for septic patients. (Crit Care Med 2009; 37:2181-2186)