Recombinant human soluble thrombomodulin ameliorates acetaminophen-induced liver toxicity in mice.

Recombinant human soluble thrombomodulin alpha (rhTM) has been developed as an anticoagulant with anti-inflammatory activity. Notably, acetaminophen (APAP) -induced liver disease (AILI) is caused by direct metabolite-induced hepatotoxicity as well as hepatic hyper-coagulation. To evaluate the utility of anticoagulant for the treatment of AILI, rhTM was administered in a mouse AILI model and liver damage was analyzed. AILI was induced in 8-week-old mice by intraperitoneal injection of APAP. rhTM (20 mg/kg) or placebo was injected at the same time as APAP administration. Serum alanine aminotransferase, fibrin degradation products and high-mobility group box 1 levels were significantly decreased in the rhTM-treated group compared with the control group. Furthermore, rhTM reduced the necrotic area and fibrin deposition in liver sections. rhTM suppressed the mRNA expression of heme oxygenase-1, plasminogen activator inhibitor type-1, tissue factors, and inflammatory cytokines compared with the control group. rhTM did not change the hepatic GSH content at 2 h after APAP injection, but restored them at 4 h after the insult. rhTM ameliorated liver damage in mice with AILI, probably via the improvement in liver perfusion induced by it's anticoagulant acitivity, which can lead to the suppression of secondary liver damage.