Sorafenib attenuates monocrotaline-induced sinusoidal obstruction syndrome in rats through suppression of JNK and MMP-9.
OBJECTIVE
Sinusoidal obstruction syndrome (SOS) is a drug-induced liver injury that occurs with oxaliplatin treatment and is associated with postoperative morbidity after hepatectomy. The aim of this study was to investigate the effects of sorafenib in a monocrotaline (MCT)-induced model of SOS in rats.


METHODS
Rats were divided into groups treated with sorafenib (2mg/kg) or vehicle, 36 h and 12h before MCT (90 mg/kg) administration by gavage. Liver tissues and blood were sampled 48 h after MCT administration to evaluate SOS. Survival after hepatectomy was examined and immunohistochemistry and electron microscopy were performed to assess sinusoidal injury.


RESULTS
In the vehicle group, liver histology showed sinusoidal dilatation, coagulative necrosis of hepatocytes, endothelial damage of the central vein, and sinusoidal hemorrhage. In the sorafenib group, these changes were significantly suppressed, total SOS scores were significantly decreased, and the elevation of serum transaminase levels observed in the vehicle group was significantly reduced. Survival after hepatectomy was significantly higher in the sorafenib group compared to the vehicle group (45% vs. 20%, p=0.0137). Immunohistochemistry and electron microscopy revealed a protective effect of sorafenib on sinusoidal endothelial cells at 6h after MCT treatment. Sorafenib also attenuated the activity of metallopeptidase-9 (MMP-9) and phosphorylation of c-Jun N-terminal kinase (JNK).


CONCLUSIONS
Sorafenib reduced the severity of MCT-induced SOS in rats through suppression of MMP-9 and JNK activity, resulting in improvement of survival after hepatectomy.
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kojiro
K
Nakamura
Etsuro
E
Hatano
Masato
M
Narita
Aya
A
Miyagawa-Hayashino
Yukinori
Y
Koyama
Hiromitsu
H
Nagata
Keiko
K
Iwaisako
Kojiro
K
Taura
Shinji
S
Uemoto
D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D006498:Hepatectomy; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D016686:Monocrotaline / Q000009:adverse effects*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077157:Sorafenib
D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D016686:Monocrotaline; D000077157:Sorafenib; D048670:MAP Kinase Kinase 4; D020780:Matrix Metalloproteinase 9