Sorafenib attenuates monocrotaline-induced sinusoidal obstruction syndrome in rats through suppression of JNK and MMP-9

Nakamura, Kojiro; Hatano, Etsuro; Narita, Michiko; Miyagawa‐Hayashino, Aya; Koyama, Yukinori; Nagata, Hiromitsu; Iwaisako, Keiko; Taura, Kojiro; Üemoto, Shinji

doi:10.1016/j.jhep.2012.07.004

Cited by 55 publications

(59 citation statements)

References 40 publications

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“…Rats were thereafter allowed free access to water and standard laboratory chow ad libitum. Because histopathological changes 48 h after MCT administration are similar to those in patients with SOS, (16,18) the rats were anesthetized by inhalation of diethyl ether and sacrificed. Blood was collected from the inferior vena cava, and liver tissues were obtained.…”

Section: Methodsmentioning

confidence: 99%

“…Slides were stained with hematoxylin and eosin (H&E), and ten randomly selected high-power fields (magnification, x200) were examined. The degree of SOS was assessed by examining histological changes in sinusoidal dilatation, coagulative necrosis of hepatocytes, endothelial damage to the central vein, and sinusoidal hemorrhage (16,18,19). Each of these four features was graded on a 4-point scale, with 0, absent; 1, mild (1-30%); 2, moderate (31-60%); and 3, severe (61-100%).…”

Section: Methodsmentioning

confidence: 99%

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Extravasated platelet aggregation in the livers of rats with drug-induced hepatic sinusoidal obstruction syndrome

Hirata

Tajima

Miyashita

et al. 2017

Molecular Medicine Reports

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Abstract. Oxaliplatin-based chemotherapy plays an important role in the treatment of colorectal liver metastases. Oxaliplatin, however, causes sinusoidal obstruction syndrome (SOS), which is characterized by portal hypertension, splenomegaly, thrombocytopenia, and liver dysfunction. SOS is diagnosed histopathologically by disruption of the sinusoidal endothelium, collagen deposition, fibrosis especially around zone 3, dilatation of the sinusoidal space and congestion. This study assessed the characteristics of a rat model of SOS. SOS was induced in rats by administration of monocrotaline (MCT). Blood chemistries and macroscopic and microscopic findings were compared in rats administered MCT and vehicle (control group). Levels of expression in the liver of CD41, P-selectin, rat endothelial cell antigen-1, CD34, and cleaved caspase-3 were analyzed immunohistochemically. Moreover, livers of these rats were analyzed by electron microscopy. Macroscopically, MCT-treated rats showed accumulation of bloody ascites and blue liver and were diagnosed with SOS histologically. Serum concentrations of aspartate aminotransferase (P=0.003), alanine aminotransferase (P=0.008), total-bilirubin (P=0.012), direct-bilirubin (P=0.007), indirect-bilirubin (P=0.003), lactate dehydrogenase (P<0.001) and hyaluronic acid (P=0.016) were significantly higher, and platelet counts significantly lower (P=0.004), in MCT-treated than in control rats. The livers of MCT-treated rats were immunohistochemically positive for CD41 and P-selectin, suggesting platelet aggregates; for rat endothelial cell antigen-1 and CD34, suggesting sinusoidal endothelial disorder; and for cleaved caspase-3, suggesting hepatocyte apoptosis. Electron microscopic findings revealed platelet aggregation in the space of Disse in the MCT group. Extravasated platelet aggregation in Disse's space may be involved in the development of SOS.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Extravasated platelet aggregation in the livers of rats with drug-induced hepatic sinusoidal obstruction syndrome

Hirata

Tajima

Miyashita

et al. 2017

Molecular Medicine Reports

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“…42,43 Nakamura treated rats with sorafenib before induction of SOS by monocrotaline prior to partial hepatectomy, and demonstrated significant suppression of the morphological features of SOS, with significant improvement in post-hepatectomy survival. 41 While loss of endothelial cells was not completely blocked, it did suppress degradation of extracellular matrix in the space of Disse and uplift of the endothelial cells. Hence, although the link to VEGF is not proven owing to the broad inhibitory action of sorafenib on tyrosine kinases, remodeling of the extracellular matrix in the space of Disse is demonstrated to be a contributing factor to the dehiscence of sinusoidal endothelial cells in the development of SOS.…”

Section: Experimental Investigation In Animalsmentioning

confidence: 97%

“…Iguchi et al observed increased serum levels of VEGF during development of SOS in human patients, 40 leaving open the question of whether VEGF-induced acceleration of vasopermeability, neovascularization, and/or expression of coagulopathic tissue factors on circulating mononuclear cells may play a role in SOS pathogenesis. 32 Nakamura et al 41 hypothesized that antiangiogenic agents may protect against SOS, and chose to use sorafenib to test this hypothesis. Sorafenib is a multiple receptor tyrosine kinase inhibitor that inhibits multiple tyrosine kinases including the VEGF receptor-2 (VEGFR-2) and -3 (VEGFR-3).…”

Section: Experimental Investigation In Animalsmentioning

confidence: 99%

Sinusoidal Obstruction Syndrome (Hepatic Veno-Occlusive Disease)

Fan

Crawford

2014

Journal of Clinical and Experimental Hepatology

228

195

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“…Of these, the JNK pathway has been reported to be inhibited by sorafenib [6] and have a possibility to regulate HBV pathogenesis. [7] Therefore, we investigated if the JNK pathway is blocked by sorafenib and HBV gene expression is suppressed by JNK inhibition.…”

Section: Sorafenib Suppresses Hbv Gene Expressionmentioning

confidence: 99%

Sorafenib suppresses hepatitis B virus gene expression via inhibiting JNK pathway

et al. 2015

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Aim: Hepatitis B virus (HBV) infection is a major cause of chronic liver diseases. Sorafenib is a multikinase inhibitor and an approved anti-liver cancer drug. Here we demonstrated the antiviral effect of sorafenib on HBV gene expression. Methods: To investigate the effect of sorafenib on HBV gene expression, a luciferase assay was performed with ×1.3 Cp-luciferase HBV construct and reverse transcriptase polymerase chain reaction (PCR), real-time PCR, and Western blotting analyses were performed using HepG2 cells derived from hepatocellular carcinoma and Chang liver cells derived from a normal liver tissue. Results: Sorafenib suppressed HBV gene expression via inhibiting the JNK pathway. In this process, the farnesoid X receptor (FXR), a transcription factor that has been reported to increase HBV replication and gene expression, was under control of the JNK pathway. Notably, JNK activation increased FXR protein levels, not mRNA levels. Conclusion: Sorafenib suppressed HBV gene expression via inhibiting the JNK pathway, which regulates FXR activity.

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Sorafenib attenuates monocrotaline-induced sinusoidal obstruction syndrome in rats through suppression of JNK and MMP-9

Cited by 55 publications

References 40 publications

Extravasated platelet aggregation in the livers of rats with drug-induced hepatic sinusoidal obstruction syndrome

Extravasated platelet aggregation in the livers of rats with drug-induced hepatic sinusoidal obstruction syndrome

Sinusoidal Obstruction Syndrome (Hepatic Veno-Occlusive Disease)

Sorafenib suppresses hepatitis B virus gene expression via inhibiting JNK pathway

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