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Title: Sorafenib attenuates monocrotaline-induced sinusoidal obstruction syndrome in rats through suppression of JNK and MMP-9.
Authors: Nakamura, Kojiro
Hatano, Etsuro
Narita, Masato
Miyagawa-Hayashino, Aya
Koyama, Yukinori
Nagata, Hiromitsu
Iwaisako, Keiko
Taura, Kojiro  kyouindb  KAKEN_id
Uemoto, Shinji  kyouindb  KAKEN_id
Author's alias: 中村, 公治郎
波多野, 悦朗
Keywords: Sorafenib
Sinusoidal obstruction syndrome
Issue Date: Nov-2012
Publisher: Elsevier Ireland Ltd.
Journal title: Journal of hepatology
Volume: 57
Issue: 5
Start page: 1037
End page: 1043
Abstract: [Background & Aims]: 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 (2 mg/kg) or vehicle, 36 h and 12 h 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 6 h 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.
Rights: © 2012 European Association for the Study of the Liver. Published by Elsevier Ireland Ltd.
This is not the published version. Please cite only the published version.
DOI(Published Version): 10.1016/j.jhep.2012.07.004
PubMed ID: 22796153
Appears in Collections:Journal Articles

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