Clinically relevant model of oxaliplatin-induced sinusoidal obstruction syndrome

被引：2

作者：

Toda, Rei ^{[1
]}

Seo, Satoru ^{[1
]}

Uemoto, Yusuke ^{[1
]}

Morino, Koshiro ^{[1
]}

Nishino, Hiroto ^{[1
]}

Nakamura, Naohiko ^{[2
]}

Okuno, Masayuki ^{[3
]}

Iguchi, Kohta ^{[4
]}

Sato, Motohiko ^{[1
]}

Nakamura, Kojiro ^{[1
,5
]}

Taura, Kojiro ^{[1
]}

Nakagawa, Shunsaku ^{[6
]}

Nakagawa, Takayuki ^{[6
]}

Tsuruyama, Tatsuaki ^{[7
,8
]}

Manabe, Toshiaki ^{[9
]}

Kawaguchi, Hiroaki ^{[10
]}

Iwaisako, Keiko ^{[1
,11
]}

Ikegawa, Masaya ^{[11
]}

Uemoto, Shinji ^{[1
,12
]}

Hatano, Etsuro ^{[1
]}

机构：

[1] Kyoto Univ, Grad Sch Med, Dept Surg, Kyoto, Japan

[2] Kanazawa Med Univ, Dept Surg, Kanazawa, Ishikawa, Japan

[3] Hyogo Med Univ, Dept Gastroenterol Surg, Nishinomiya, Hyogo, Japan

[4] Kitano Hosp, Tazuke Kofukai Med Res Inst, Dept Gastrointestinal Med & Surg, Osaka, Japan

[5] Kobe City Nishi Kobe Med Ctr, Dept Surg, Kobe, Hyogo, Japan

[6] Kyoto Univ, Grad Sch Med, Dept Clin Pharmacol & Therapeut, Kyoto, Japan

[7] Kyoto Univ, Grad Sch Med, Dept Drug Discovery Med, Div Pathol, Kyoto, Japan

[8] Kyoto Univ, Grad Sch Med, Dept Diagnost & Pathol, Kyoto, Japan

[9] Gen Inc Assoc PaLaNA Initiat, Dept Diagnost & Pathol, Otsu, Shiga, Japan

[10] Kitasato Univ, Sch Vet Med, Lab Vet Pathol, Aomori, Japan

[11] Doshisha Univ, Fac Life & Med Sci, Dept Med Life Syst, Kyotanabe, Japan

[12] Shiga Univ Med Sci, Otsu, Shiga, Japan

来源：

HEPATOLOGY RESEARCH | 2023年 / 53卷 / 02期

基金：

日本学术振兴会;

关键词：

colorectal liver metastasis; liver sinusoidal endothelial cell; matrix metalloproteinase 9; micro-minipig; oxaliplatin; sinusoidal obstruction syndrome; COLORECTAL LIVER METASTASES; TUMOR-RELATED FACTORS; PREOPERATIVE CHEMOTHERAPY; VENOOCCLUSIVE DISEASE; POTENTIAL CONTRIBUTION; MAJOR HEPATECTOMY; RAT MODEL; FOLFOX; DEFIBROTIDE; SUPPRESSION;

D O I：

10.1111/hepr.13842

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Aim Sinusoidal obstruction syndrome (SOS) induced by oxaliplatin-including chemotherapies (OXCx) is associated with impaired hepatic reserve and higher morbidity after hepatic resection. However, in the absence of an appropriate animal experimental model, little is known about its pathophysiology. This study aimed to establish a clinically relevant reproducible model of FOLFOX-induced SOS and to compare the clinical/histopathological features between the clinical and animal SOS settings. Methods We performed clinical/pathological analyses of colorectal liver metastasis (CRLM) patients who underwent hepatectomy with/without preoperative treatment of FOLFOX (n = 22/18). Male micro-minipigs were treated with 50% of the standard human dosage of the FOLFOX regimen. Results In contrast to the monocrotaline-induced SOS model in rats, hepatomegaly, ascites, congestion, and coagulative necrosis of hepatocytes were absent in patients with CRLM with OXCx pretreatment and OXCx-treated micro-minipigs. In parallel to CRLM cases with OXCx pretreatment, OXCx-challenged micro-minipigs exhibited deteriorated indocyanine green clearance, morphological alteration of liver sinusoidal endothelial cells, and upregulated matrix metalloproteinase-9. Using our novel porcine SOS model, we identified the hepatoprotective influence of recombinant human soluble thrombomodulin in OXCx-SOS. Conclusions With distinct differences between monocrotaline-induced rat SOS and human/pig OXCx-SOS, our pig OXCx-SOS model serves as a preclinical platform for future investigations to dissect the pathophysiology of OXCx-SOS and seek preventive strategies.

引用

页码：145 / 159

页数：15

共 42 条

[1]

Adam R, 2004, ANN SURG, V240, P644, DOI 10.1097/01.sla.0000141198.92114.16

[2] Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases [J].