The Caspase Inhibitor IDN-6556 Attenuates Hepatic Injury and Fibrosis in the Bile Duct Ligated Mouse

Ali Canbay, Ariel Feldstein, Edwina Baskin-Bey, Steven F. Bronk, Gregory James Gores

Research output: Contribution to journalArticle

168 Citations (Scopus)

Abstract

Liver injury is characterized by hepatocyte apoptosis and collagen-producing activated hepatic stellate cells (HSC). Hepatocyte apoptosis promotes liver injury and fibrosis, whereas activated HSC apoptosis limits hepatic fibrosis. Pharmacological inhibition of liver cell apoptosis may potentially attenuate liver injury and fibrosis by blocking hepatocyte apoptosis or promote fibrosis by permitting accumulation of activated HSCs. To ascertain the net effect of inhibiting liver cell apoptosis on liver injury, inflammation, and hepatic fibrogenesis, we examined the effect of a pancaspase inhibition IDN-6556 on these parameters in the bile duct ligated (BDL) mouse. Hepatocyte apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and immunofluorescence for active caspases 3/7, and liver injury by histopathology and serum alanine aminotransferase (ALT) determinations. Real-time polymerase chain reaction was used to measure mRNA transcripts for markers of hepatic inflammation, HSC activation, and fibrosis. Immunohistochemistry for α-smooth muscle actin was performed to identify HSC activation. Collagen deposition was quantitated by Sirius red staining and digital imaging techniques. Hepatocyte apoptosis and liver injury (bile infarcts and serum ALT values) were reduced in IDN-6556-treated versus saline-treated 3-day BDL mice. Markers for liver inflammation [chemokine (C-X-C) ligand 1 and macrophage inflammatory protein-2 chemokine expression] and hepatic fibrogenesis (transforming growth factor-β and collagen I expression) were also attenuated. Consistent with these data, HSC activation as assessed by α-smooth muscle actin mRNA expression and immunohistochemistry was markedly reduced in both 3- and 10-day BDL animals. Collectively, these data suggest hepatocyte apoptosis initiates cascades culminating in liver injury and fibrosis. The pan-caspase inhibitor IDN-6556 is a promising agent for cholestatic liver injury.

Original languageEnglish (US)
Pages (from-to)1191-1196
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume308
Issue number3
DOIs
StatePublished - Mar 2004

Fingerprint

Caspase Inhibitors
Bile Ducts
Fibrosis
Liver
Wounds and Injuries
Hepatic Stellate Cells
Apoptosis
Hepatocytes
Liver Cirrhosis
Collagen
Inflammation
Alanine Transaminase
Smooth Muscle
3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid
Actins
Immunohistochemistry
Chemokine CXCL2
Caspase 7
CXC Chemokines
Messenger RNA

ASJC Scopus subject areas

  • Pharmacology

Cite this

The Caspase Inhibitor IDN-6556 Attenuates Hepatic Injury and Fibrosis in the Bile Duct Ligated Mouse. / Canbay, Ali; Feldstein, Ariel; Baskin-Bey, Edwina; Bronk, Steven F.; Gores, Gregory James.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 308, No. 3, 03.2004, p. 1191-1196.

Research output: Contribution to journalArticle

Canbay, Ali ; Feldstein, Ariel ; Baskin-Bey, Edwina ; Bronk, Steven F. ; Gores, Gregory James. / The Caspase Inhibitor IDN-6556 Attenuates Hepatic Injury and Fibrosis in the Bile Duct Ligated Mouse. In: Journal of Pharmacology and Experimental Therapeutics. 2004 ; Vol. 308, No. 3. pp. 1191-1196.
@article{f7c3d35de24d43d385010571be5825e7,
title = "The Caspase Inhibitor IDN-6556 Attenuates Hepatic Injury and Fibrosis in the Bile Duct Ligated Mouse",
abstract = "Liver injury is characterized by hepatocyte apoptosis and collagen-producing activated hepatic stellate cells (HSC). Hepatocyte apoptosis promotes liver injury and fibrosis, whereas activated HSC apoptosis limits hepatic fibrosis. Pharmacological inhibition of liver cell apoptosis may potentially attenuate liver injury and fibrosis by blocking hepatocyte apoptosis or promote fibrosis by permitting accumulation of activated HSCs. To ascertain the net effect of inhibiting liver cell apoptosis on liver injury, inflammation, and hepatic fibrogenesis, we examined the effect of a pancaspase inhibition IDN-6556 on these parameters in the bile duct ligated (BDL) mouse. Hepatocyte apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and immunofluorescence for active caspases 3/7, and liver injury by histopathology and serum alanine aminotransferase (ALT) determinations. Real-time polymerase chain reaction was used to measure mRNA transcripts for markers of hepatic inflammation, HSC activation, and fibrosis. Immunohistochemistry for α-smooth muscle actin was performed to identify HSC activation. Collagen deposition was quantitated by Sirius red staining and digital imaging techniques. Hepatocyte apoptosis and liver injury (bile infarcts and serum ALT values) were reduced in IDN-6556-treated versus saline-treated 3-day BDL mice. Markers for liver inflammation [chemokine (C-X-C) ligand 1 and macrophage inflammatory protein-2 chemokine expression] and hepatic fibrogenesis (transforming growth factor-β and collagen I expression) were also attenuated. Consistent with these data, HSC activation as assessed by α-smooth muscle actin mRNA expression and immunohistochemistry was markedly reduced in both 3- and 10-day BDL animals. Collectively, these data suggest hepatocyte apoptosis initiates cascades culminating in liver injury and fibrosis. The pan-caspase inhibitor IDN-6556 is a promising agent for cholestatic liver injury.",
author = "Ali Canbay and Ariel Feldstein and Edwina Baskin-Bey and Bronk, {Steven F.} and Gores, {Gregory James}",
year = "2004",
month = "3",
doi = "10.1124/jpet.103.060129",
language = "English (US)",
volume = "308",
pages = "1191--1196",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - The Caspase Inhibitor IDN-6556 Attenuates Hepatic Injury and Fibrosis in the Bile Duct Ligated Mouse

AU - Canbay, Ali

AU - Feldstein, Ariel

AU - Baskin-Bey, Edwina

AU - Bronk, Steven F.

AU - Gores, Gregory James

PY - 2004/3

Y1 - 2004/3

N2 - Liver injury is characterized by hepatocyte apoptosis and collagen-producing activated hepatic stellate cells (HSC). Hepatocyte apoptosis promotes liver injury and fibrosis, whereas activated HSC apoptosis limits hepatic fibrosis. Pharmacological inhibition of liver cell apoptosis may potentially attenuate liver injury and fibrosis by blocking hepatocyte apoptosis or promote fibrosis by permitting accumulation of activated HSCs. To ascertain the net effect of inhibiting liver cell apoptosis on liver injury, inflammation, and hepatic fibrogenesis, we examined the effect of a pancaspase inhibition IDN-6556 on these parameters in the bile duct ligated (BDL) mouse. Hepatocyte apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and immunofluorescence for active caspases 3/7, and liver injury by histopathology and serum alanine aminotransferase (ALT) determinations. Real-time polymerase chain reaction was used to measure mRNA transcripts for markers of hepatic inflammation, HSC activation, and fibrosis. Immunohistochemistry for α-smooth muscle actin was performed to identify HSC activation. Collagen deposition was quantitated by Sirius red staining and digital imaging techniques. Hepatocyte apoptosis and liver injury (bile infarcts and serum ALT values) were reduced in IDN-6556-treated versus saline-treated 3-day BDL mice. Markers for liver inflammation [chemokine (C-X-C) ligand 1 and macrophage inflammatory protein-2 chemokine expression] and hepatic fibrogenesis (transforming growth factor-β and collagen I expression) were also attenuated. Consistent with these data, HSC activation as assessed by α-smooth muscle actin mRNA expression and immunohistochemistry was markedly reduced in both 3- and 10-day BDL animals. Collectively, these data suggest hepatocyte apoptosis initiates cascades culminating in liver injury and fibrosis. The pan-caspase inhibitor IDN-6556 is a promising agent for cholestatic liver injury.

AB - Liver injury is characterized by hepatocyte apoptosis and collagen-producing activated hepatic stellate cells (HSC). Hepatocyte apoptosis promotes liver injury and fibrosis, whereas activated HSC apoptosis limits hepatic fibrosis. Pharmacological inhibition of liver cell apoptosis may potentially attenuate liver injury and fibrosis by blocking hepatocyte apoptosis or promote fibrosis by permitting accumulation of activated HSCs. To ascertain the net effect of inhibiting liver cell apoptosis on liver injury, inflammation, and hepatic fibrogenesis, we examined the effect of a pancaspase inhibition IDN-6556 on these parameters in the bile duct ligated (BDL) mouse. Hepatocyte apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and immunofluorescence for active caspases 3/7, and liver injury by histopathology and serum alanine aminotransferase (ALT) determinations. Real-time polymerase chain reaction was used to measure mRNA transcripts for markers of hepatic inflammation, HSC activation, and fibrosis. Immunohistochemistry for α-smooth muscle actin was performed to identify HSC activation. Collagen deposition was quantitated by Sirius red staining and digital imaging techniques. Hepatocyte apoptosis and liver injury (bile infarcts and serum ALT values) were reduced in IDN-6556-treated versus saline-treated 3-day BDL mice. Markers for liver inflammation [chemokine (C-X-C) ligand 1 and macrophage inflammatory protein-2 chemokine expression] and hepatic fibrogenesis (transforming growth factor-β and collagen I expression) were also attenuated. Consistent with these data, HSC activation as assessed by α-smooth muscle actin mRNA expression and immunohistochemistry was markedly reduced in both 3- and 10-day BDL animals. Collectively, these data suggest hepatocyte apoptosis initiates cascades culminating in liver injury and fibrosis. The pan-caspase inhibitor IDN-6556 is a promising agent for cholestatic liver injury.

UR - http://www.scopus.com/inward/record.url?scp=1342329725&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1342329725&partnerID=8YFLogxK

U2 - 10.1124/jpet.103.060129

DO - 10.1124/jpet.103.060129

M3 - Article

C2 - 14617689

AN - SCOPUS:1342329725

VL - 308

SP - 1191

EP - 1196

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -