Boc-D-Fmk对大鼠胆管结扎后肝细胞凋亡及内毒素攻击后存活率的影响。
Effect of Boc-D-Fmk on hepatocyte apoptosis after bile duct ligation in rat and survival rate after endotoxin challenge.
作者信息
Sheen-Chen Shyr-Ming, Hung Kuo-Sheng, Eng Hock-Liew
机构信息
Department of Surgery, Chang Gung Memorial Hospital, Kaohsiung Medical Center, College of Medicine, Chang Gung University, Kaohsiung Hsien, Taiwan.
出版信息
J Gastroenterol Hepatol. 2008 Aug;23(8 Pt 1):1276-9. doi: 10.1111/j.1440-1746.2008.05368.x. Epub 2008 Mar 27.
BACKGROUND AND AIM
Retention and accumulation of toxic hydrophobic bile salts within hepatocytes may cause hepatocyte toxicity by inducing apoptosis. Apoptosis is a pathway of cell death orchestrated by a family of proteases called caspases. Boc-D-FMK is a cell-permeable irreversible inhibitor of caspase and recent data suggest that it might block the processing of many caspases. The purpose of the present study was to evaluate the possible effect of Boc-D-FMK on hepatocyte apoptosis and on survival rate after bile duct ligation in the rat.
METHODS
Male Sprague-Dawley rats, weighing 280-300 g were randomized to three groups of eight rats each. Group 1 (OBBOC-D) underwent common bile duct ligation and simultaneous treatment with Boc-D-FMK-fmk (dissolved in dimethylsulfoxide [DMSO]). Group 2 (OBZFA) underwent common bile duct ligation and simultaneous treatment with ZFA-fmk (dissolved in DMSO). Group 3 (SHAM) underwent sham operation and simultaneous treatment with the same amount of dimethylsulfoxide (DMSO, n = 4) or the same amount of normal saline (n = 4). After 3 days, liver tissue was harvested for histopathological analysis and measurements of apoptosis. Survival rates were measured in a separate experiment in which animals underwent the same protocol. The animals received endotoxin (15 mg/kg) in the afternoon of the third postoperative day. Animals were observed for 48 h and the survival rates were recorded.
RESULTS
When compared with sham operation, common bile duct ligation with ZFA-fmk (placebo) significantly increased hepatocyte apoptosis (P < 0.001). When compared with the OBZFA group, Boc-D-FMK significantly diminished the increased hepatocyte apoptosis in the OBBOC-D group (P < 0.001). There is no difference in hepatocyte apoptosis (P = 0.05) between OBBOC-D and SHAM groups. After endotoxin challenge, the 48 h survival rates were 100%, 87.5% and 62.5% for the SHAM, OBBOC-D and OBZFA groups, respectively.
CONCLUSIONS
Boc-D-FMK-fmk effectively attenuated the hepatocyte apoptosis in bile duct-ligated rats and may improve the survival rates after endotoxin challenge.
背景与目的
有毒疏水性胆盐在肝细胞内的潴留和蓄积可通过诱导凋亡导致肝细胞毒性。凋亡是由一组称为半胱天冬酶的蛋白酶所调控的细胞死亡途径。Boc-D-FMK是一种可穿透细胞的不可逆半胱天冬酶抑制剂，近期数据表明它可能会阻断多种半胱天冬酶的加工过程。本研究的目的是评估Boc-D-FMK对大鼠胆管结扎后肝细胞凋亡及存活率的可能影响。
方法
体重280 - 300 g的雄性Sprague-Dawley大鼠被随机分为三组，每组8只。第1组（OBBOC-D）行胆总管结扎并同时用Boc-D-FMK-fmk（溶于二甲基亚砜[DMSO]）治疗。第2组（OBZFA）行胆总管结扎并同时用ZFA-fmk（溶于DMSO）治疗。第3组（假手术组，SHAM）行假手术并同时用等量的二甲基亚砜（DMSO，n = 4）或等量的生理盐水（n = 4）治疗。3天后，采集肝组织进行组织病理学分析和凋亡检测。在另一项单独实验中测量存活率，实验中动物采用相同方案。动物在术后第3天下午接受内毒素（15 mg/kg）。观察动物48小时并记录存活率。
结果
与假手术相比，用ZFA-fmk（安慰剂）进行胆总管结扎显著增加了肝细胞凋亡（P < 0.001）。与OBZFA组相比；Boc-D-FMK显著减少了OBBOC-D组中增加的肝细胞凋亡（P < 0.001）。OBBOC-D组和假手术组之间肝细胞凋亡无差异（P = 0.05）。内毒素攻击后，假手术组、OBBOC-D组和OBZFA组的48小时存活率分别为100%、87.5%和62.5%。
结论
Boc-D-FMK-fmk有效减轻了胆管结扎大鼠的肝细胞凋亡，并可能提高内毒素攻击后的存活率。
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