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


OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
rTM preserved SECs and attenuated MCT-induced SOS in rats through suppression of circulatory HMGB1 and neutrophil accumulation, resulting in improved survival after hepatectomy.
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kojiro
K
Nakamura
Etsuro
E
Hatano
Aya
A
Miyagawa-Hayashino
Masayuki
M
Okuno
Yukinori
Y
Koyama
Masato
M
Narita
Satoru
S
Seo
Kojiro
K
Taura
Shinji
S
Uemoto
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D042783:Endothelial Cells / Q000648:ultrastructure; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006498:Hepatectomy; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced / Q000188:drug therapy*; D006801:Humans; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D053208:Kaplan-Meier Estimate; D008297:Male; D008854:Microscopy, Electron; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D018180:Thrombomodulin / Q000008:administration & dosage / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D011994:Recombinant Proteins; D018180:Thrombomodulin
high mobility group box 1; intracellular adhesion molecule-1; neutrophil; receptor for advanced glycation end products; recombinant human soluble thrombomodulin; sinusoidal obstruction syndrome