Department of Surgery, The University of Tokushima, Tokushima, Japan
Department of Surgery, The University of Tokushima, Tokushima, Japan.
In Vivo. 2019 Sep-Oct;33(5):1469-1476. doi: 10.21873/invivo.11626.
The aim of this study was to evaluate the impact of pretreatment with bevacizumab on liver damage in a rat model of massive hepatectomy (Hx) model, as a surrogate model of massive Hx for liver metastasis from colorectal cancer.
Male Wister rats (n=24) were separated into the following two groups: 90% Hx and 90% Hx plus bevacizumab group. Bevacizumab (5 mg/kg) was injected intraperitoneally 7 days before Hx. Samples of blood and remnant liver tissue were obtained 24 hours after hepatectomy and the following parameters were evaluated: Biochemical analysis; liver regeneration rate; survival rate; and real-time polymerase chain reaction for interleukin-1 beta (Il1b), tumor necrosis factor alpha (Tnfa), matrix metalloproteinase (Mmp) 2 and Mmp9 mRNA. In addition, samples of whole liver tissue were obtained immediately before Hx and real-time polymerase chain reaction was performed for X-box binding protein 1 (Xbp1), activating transcription factor 6 (Atf6), C/EBP homologous protein (Chop), glucose-regulated protein 78 (Grp78) and heat-shock protein 70 (Hsp70), as markers of endoplasmic reticulum stress response.
The levels of transaminases 24 hours after Hx were significantly reduced in the group pretreated with bevacizumab compared to that not pretreated (p<0.05). The liver regeneration rate at 24 hours after Hx was significantly increased in the group pretreated with bevacizumab compared with the group which underwent Hx alone (p<0.05). The survival rate for the group pretreated with bevacizumab tended to be higher than that of the Hx-only group, 72 hours after Hx (p=0.09). The expressions of Il1b, Mmp2 and Mmp9 mRNA 24 hours after Hx in the group pretreated with bevacizumab tended to be lower than that of rats which underwent Hx alone (p=0.11, 0.09 and 0.15, respectively). The expression of Xbp1, Chop, Grp78 and Hsp70 mRNA immediately before Hx in the group pretreated with bevacizumab were significantly higher than the 90% Hx group (p<0.05).
Bevacizumab pretreatment had protective effects on liver injury after massive hepatectomy in rats, apparently via the induction of the endoplasmic reticulum stress response, i.e. the so-called unfolded protein response.
本研究旨在评估贝伐单抗预处理对大鼠 90%肝切除（Hx）模型肝损伤的影响，该模型是结直肠癌肝转移的大块肝切除模型的替代模型。
雄性 Wistar 大鼠（n=24）分为两组：90% Hx 组和 90% Hx 加贝伐单抗组。贝伐单抗（5mg/kg）于 Hx 前 7 天腹腔内注射。肝切除后 24 小时采集血样和剩余肝组织样本，评估以下参数：生化分析；肝再生率；存活率；白细胞介素 1β（Il1b）、肿瘤坏死因子 α（Tnfa）、基质金属蛋白酶（Mmp）2 和 Mmp9mRNA 的实时聚合酶链反应。此外，在进行 Hx 之前立即采集整个肝组织样本，并进行 X 盒结合蛋白 1（Xbp1）、激活转录因子 6（Atf6）、C/EBP 同源蛋白（Chop）、葡萄糖调节蛋白 78（Grp78）和热休克蛋白 70（Hsp70）的实时聚合酶链反应，作为内质网应激反应的标志物。
Hx 后 24 小时，贝伐单抗预处理组的转氨酶水平明显低于未预处理组（p<0.05）。Hx 后 24 小时，贝伐单抗预处理组的肝再生率明显高于单纯 Hx 组（p<0.05）。Hx 后 72 小时，贝伐单抗预处理组的存活率似乎高于单纯 Hx 组（p=0.09）。Hx 后 24 小时，贝伐单抗预处理组 Il1b、Mmp2 和 Mmp9mRNA 的表达明显低于单纯 Hx 组（p=0.11、0.09 和 0.15）。贝伐单抗预处理组 Hx 前的 Xbp1、Chop、Grp78 和 Hsp70mRNA 的表达明显高于 90% Hx 组（p<0.05）。
贝伐单抗预处理对大鼠 90%肝切除后肝损伤具有保护作用，这显然是通过诱导内质网应激反应，即所谓的未折叠蛋白反应来实现的。
