Soluble thrombomodulin attenuates sinusoidal obstruction syndrome in rat through suppression of high mobility group box 1

Abstract

Sinusoidal obstruction syndrome (SOS) is a drug-induced liver injury caused by anticancer treatment such as oxaliplatin-based chemotherapy in patients with hepatic colorectal metastases. SOS is also associated with postoperative morbidity after hepatectomy. The aim of this study was to investigate the effects of recombinant human soluble thrombomodulin (rTM) in a monocrotaline (MCT)-induced SOS model in rats. Rats were administered rTM by intravenous injection (3 mg/kg) and subcutaneous injection (3 mg/kg) concurrently with MCT administration. Other rats received the same volume of normal saline (NS) and MCT. Liver tissue and blood were collected 48 h after MCT administration to evaluate SOS. Survival after 30% partial hepatectomy was also investigated in both groups. Electron microscopy and immunohistochemistry were used to examine sinusoidal endothelial cells (SECs). Serum concentrations of high mobility group box 1 (HMGB1) and neutrophil accumulation were also measured. In the NS group, liver histology showed SOS phenotypes. In the rTM group, these changes were suppressed, total SOS scores were significantly lower, and serum transaminase levels were significantly reduced compared with the NS group. Survival after 30% hepatectomy was significantly higher in the rTM group (57% vs. 22%, P = 0.0070). Electron microscopy and immunohistochemistry showed a protective effect of rTM on SECs. rTM also attenuated the serum HMGB1 level (9.2 vs. 19.6 ng/ml, P = 0.0086), active neutrophil recruitment and myeloperoxidase activity. rTM preserved SECs and attenuated MCT-induced SOS in rats through suppression of circulatory HMGB1 and neutrophil accumulation, resulting in improved survival after hepatectomy.