Nakamura Kojiro, Hatano Etsuro, Miyagawa-Hayashino Aya, Okuno Masayuki, Koyama Yukinori, Narita Masato, Seo Satoru, Taura Kojiro, Uemoto Shinji
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Liver Int. 2014 Nov;34(10):1473-87. doi: 10.1111/liv.12420. Epub 2014 Feb 6.
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.
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.
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.
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.
rTM preserved SECs and attenuated MCT-induced SOS in rats through suppression of circulatory HMGB1 and neutrophil accumulation, resulting in improved survival after hepatectomy.
窦性阻塞综合征（SOS）是一种由抗癌治疗引起的药物性肝损伤，如在肝结肠转移患者中使用基于奥沙利铂的化疗。SOS也与肝切除术后的发病率相关。
本研究旨在探讨重组人可溶性血栓调节蛋白（rTM）在大鼠野百合碱（MCT）诱导的SOS模型中的作用。
大鼠在给予MCT的同时，通过静脉注射（3mg/kg）和皮下注射（3mg/kg）给予rTM。其他大鼠接受相同体积的生理盐水（NS）和MCT。在给予MCT后48小时收集肝组织和血液以评估SOS。两组还均研究了30%部分肝切除术后的生存率。使用电子显微镜和免疫组织化学检查肝窦内皮细胞（SEC）。还测量了血清高迁移率族蛋白B1（HMGB1）浓度和中性粒细胞聚集情况。
在NS组中，肝脏组织学显示出SOS表型。在rTM组中，这些变化受到抑制，与NS组相比，总SOS评分显著降低，血清转氨酶水平显著降低。rTM组30%肝切除术后的生存率显著更高（57%对22%，P = 0.0070）。电子显微镜和免疫组织化学显示rTM对SEC有保护作用。rTM还降低了血清HMGB1水平（9.2对19.6 ng/ml，P = 0.0086）、活性中性粒细胞募集和髓过氧化物酶活性。
rTM通过抑制循环中的HMGB1和中性粒细胞聚集，保护SEC并减轻大鼠MCT诱导的SOS，从而提高肝切除术后的生存率。
