Effect of Boc-D-Fmk on hepatocyte apoptosis after bile duct ligation in rat and survival rate after endotoxin challenge

Shyr Ming Sheen-Chen, Kuo Sheng Hung, Hock Liew Eng

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1276-1279
Number of pages4
JournalJournal of Gastroenterology and Hepatology (Australia)
Volume23
Issue number8 PART1
DOIs
Publication statusPublished - 2008
Externally publishedYes

Fingerprint

Bile Ducts
Endotoxins
Ligation
Hepatocytes
Apoptosis
Dimethyl Sulfoxide
Common Bile Duct
Caspases
Caspase Inhibitors
Poisons
Bile Acids and Salts
Sprague Dawley Rats
Peptide Hydrolases
Cell Death
Therapeutics
Placebos
Boc-D-FMK
Liver
salicylhydroxamic acid

Keywords

  • Bile duct ligation
  • Boc-D-fmk
  • Hepatocyte apoptosis

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology

Cite this

Effect of Boc-D-Fmk on hepatocyte apoptosis after bile duct ligation in rat and survival rate after endotoxin challenge. / Sheen-Chen, Shyr Ming; Hung, Kuo Sheng; Eng, Hock Liew.

In: Journal of Gastroenterology and Hepatology (Australia), Vol. 23, No. 8 PART1, 2008, p. 1276-1279.

Research output: Contribution to journalArticle

@article{f72b531365e947cc9bf6f971df4e4e0f,
title = "Effect of Boc-D-Fmk on hepatocyte apoptosis after bile duct ligation in rat and survival rate after endotoxin challenge",
abstract = "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.",
keywords = "Bile duct ligation, Boc-D-fmk, Hepatocyte apoptosis",
author = "Sheen-Chen, {Shyr Ming} and Hung, {Kuo Sheng} and Eng, {Hock Liew}",
year = "2008",
doi = "10.1111/j.1440-1746.2008.05368.x",
language = "English",
volume = "23",
pages = "1276--1279",
journal = "Journal of Gastroenterology and Hepatology (Australia)",
issn = "0815-9319",
publisher = "Wiley-Blackwell",
number = "8 PART1",

}

TY - JOUR

T1 - Effect of Boc-D-Fmk on hepatocyte apoptosis after bile duct ligation in rat and survival rate after endotoxin challenge

AU - Sheen-Chen, Shyr Ming

AU - Hung, Kuo Sheng

AU - Eng, Hock Liew

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

KW - Bile duct ligation

KW - Boc-D-fmk

KW - Hepatocyte apoptosis

UR - http://www.scopus.com/inward/record.url?scp=48549086068&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=48549086068&partnerID=8YFLogxK

U2 - 10.1111/j.1440-1746.2008.05368.x

DO - 10.1111/j.1440-1746.2008.05368.x

M3 - Article

VL - 23

SP - 1276

EP - 1279

JO - Journal of Gastroenterology and Hepatology (Australia)

JF - Journal of Gastroenterology and Hepatology (Australia)

SN - 0815-9319

IS - 8 PART1

ER -