Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats

Matthew Christopher Wright; R. Issa; N. Trim; J. N. Primrose; M. J. Arthur; J. P. Iredale; D. A. Mann; D. E. Smart; Graeme Ian Murray

doi:10.1053/gast.2001.27188

Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats

Matthew Christopher Wright, R. Issa, N. Trim, J. N. Primrose, M. J. Arthur, J. P. Iredale, D. A. Mann, D. E. Smart, Graeme Ian Murray

Applied Medicine

Research output: Contribution to journal › Article › peer-review

331 Citations (Scopus)

Abstract

Background & Aims: Hepatic stellate cells (HSCs) play a pivotal role in liver fibrosis and stimulating their apoptosis could be an effective treatment for liver fibrosis. Methods: Activated HSCs, hepatocytes, and rats with liver fibrosis were treated with gliotoxin. Results; Addition of gliotoxin to activated (a-smooth muscle actin positive) rat and human HSCs resulted in morphologic alterations typical of apoptosis. Within 2-3 hours of incubation, caspase 3 activity was markedly induced and caspase inhibitor 1 (Z-VAD-FMK)-sensitive oligonucleosome-length DNA fragments were detectable by gel electrophoresis of low molecular weight DNA. Apoptosis was widespread as judged by fluorescence-activated cell sorter analysis and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining in both rat and human HSCs at concentrations that had no effect on the viability of rat hepatocytes. Gliotoxin treatment significantly reduced the number of activated stellate cells and mean thickness of bridging fibrotic septae in livers from rats treated with carbon tetrachloride. Conclusions: These data demonstrate proof-of-concept that by up-regulating HSC apoptosis, the extent of fibrosis can be decreased in inflammatory liver injury.

Original language	English
Pages (from-to)	685-698
Number of pages	13
Journal	Gastroenterology
Volume	121
Issue number	3
DOIs	https://doi.org/10.1053/gast.2001.27188
Publication status	Published - 2001

Keywords

NF-KAPPA-B
MITOCHONDRIAL PERMEABILITY TRANSITION
TISSUE INHIBITOR
CYTOCHROME-C
CA2+ RELEASE
ACTIVATION
INDUCTION
TRANSCRIPTION
PROTEINS
EXPRESSION

Access to Document

10.1053/gast.2001.27188

Cite this

@article{a20deb70c3324944805dfccae34f247b,

title = "Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats",

abstract = "Background & Aims: Hepatic stellate cells (HSCs) play a pivotal role in liver fibrosis and stimulating their apoptosis could be an effective treatment for liver fibrosis. Methods: Activated HSCs, hepatocytes, and rats with liver fibrosis were treated with gliotoxin. Results; Addition of gliotoxin to activated (a-smooth muscle actin positive) rat and human HSCs resulted in morphologic alterations typical of apoptosis. Within 2-3 hours of incubation, caspase 3 activity was markedly induced and caspase inhibitor 1 (Z-VAD-FMK)-sensitive oligonucleosome-length DNA fragments were detectable by gel electrophoresis of low molecular weight DNA. Apoptosis was widespread as judged by fluorescence-activated cell sorter analysis and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining in both rat and human HSCs at concentrations that had no effect on the viability of rat hepatocytes. Gliotoxin treatment significantly reduced the number of activated stellate cells and mean thickness of bridging fibrotic septae in livers from rats treated with carbon tetrachloride. Conclusions: These data demonstrate proof-of-concept that by up-regulating HSC apoptosis, the extent of fibrosis can be decreased in inflammatory liver injury.",

keywords = "NF-KAPPA-B, MITOCHONDRIAL PERMEABILITY TRANSITION, TISSUE INHIBITOR, CYTOCHROME-C, CA2+ RELEASE, ACTIVATION, INDUCTION, TRANSCRIPTION, PROTEINS, EXPRESSION",

author = "Wright, {Matthew Christopher} and R. Issa and N. Trim and Primrose, {J. N.} and Arthur, {M. J.} and Iredale, {J. P.} and Mann, {D. A.} and Smart, {D. E.} and Murray, {Graeme Ian}",

year = "2001",

doi = "10.1053/gast.2001.27188",

language = "English",

volume = "121",

pages = "685--698",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W B SAUNDERS CO-ELSEVIER INC",

number = "3",

}

TY - JOUR

T1 - Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats

AU - Wright, Matthew Christopher

AU - Issa, R.

AU - Trim, N.

AU - Primrose, J. N.

AU - Arthur, M. J.

AU - Iredale, J. P.

AU - Mann, D. A.

AU - Smart, D. E.

AU - Murray, Graeme Ian

PY - 2001

Y1 - 2001

N2 - Background & Aims: Hepatic stellate cells (HSCs) play a pivotal role in liver fibrosis and stimulating their apoptosis could be an effective treatment for liver fibrosis. Methods: Activated HSCs, hepatocytes, and rats with liver fibrosis were treated with gliotoxin. Results; Addition of gliotoxin to activated (a-smooth muscle actin positive) rat and human HSCs resulted in morphologic alterations typical of apoptosis. Within 2-3 hours of incubation, caspase 3 activity was markedly induced and caspase inhibitor 1 (Z-VAD-FMK)-sensitive oligonucleosome-length DNA fragments were detectable by gel electrophoresis of low molecular weight DNA. Apoptosis was widespread as judged by fluorescence-activated cell sorter analysis and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining in both rat and human HSCs at concentrations that had no effect on the viability of rat hepatocytes. Gliotoxin treatment significantly reduced the number of activated stellate cells and mean thickness of bridging fibrotic septae in livers from rats treated with carbon tetrachloride. Conclusions: These data demonstrate proof-of-concept that by up-regulating HSC apoptosis, the extent of fibrosis can be decreased in inflammatory liver injury.

AB - Background & Aims: Hepatic stellate cells (HSCs) play a pivotal role in liver fibrosis and stimulating their apoptosis could be an effective treatment for liver fibrosis. Methods: Activated HSCs, hepatocytes, and rats with liver fibrosis were treated with gliotoxin. Results; Addition of gliotoxin to activated (a-smooth muscle actin positive) rat and human HSCs resulted in morphologic alterations typical of apoptosis. Within 2-3 hours of incubation, caspase 3 activity was markedly induced and caspase inhibitor 1 (Z-VAD-FMK)-sensitive oligonucleosome-length DNA fragments were detectable by gel electrophoresis of low molecular weight DNA. Apoptosis was widespread as judged by fluorescence-activated cell sorter analysis and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining in both rat and human HSCs at concentrations that had no effect on the viability of rat hepatocytes. Gliotoxin treatment significantly reduced the number of activated stellate cells and mean thickness of bridging fibrotic septae in livers from rats treated with carbon tetrachloride. Conclusions: These data demonstrate proof-of-concept that by up-regulating HSC apoptosis, the extent of fibrosis can be decreased in inflammatory liver injury.

KW - NF-KAPPA-B

KW - MITOCHONDRIAL PERMEABILITY TRANSITION

KW - TISSUE INHIBITOR

KW - CYTOCHROME-C

KW - CA2+ RELEASE

KW - ACTIVATION

KW - INDUCTION

KW - TRANSCRIPTION

KW - PROTEINS

KW - EXPRESSION

U2 - 10.1053/gast.2001.27188

DO - 10.1053/gast.2001.27188

M3 - Article

SN - 0016-5085

VL - 121

SP - 685

EP - 698

JO - Gastroenterology

JF - Gastroenterology

IS - 3

ER -

Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats

Abstract

Keywords

Access to Document

Fingerprint

Cite this