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

Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats
Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats
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 (-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.
0016-5085
685-698
Wright, Matthew C.
8c69c9f3-9230-4014-833b-b2f3babd671e
Issa, Razo
82704844-4c26-4c70-8fe3-8cf4a8c8e5a9
Smart, David E.
fcac679f-6eab-4df5-81da-be0017b87984
Trim, Nathan
afa06514-3691-4aa3-89b3-c5c3853102ba
Murray, Graeme I.
35ca95fd-3168-4db6-a842-531ad24812f5
Primrose, John N.
d85f3b28-24c6-475f-955b-ec457a3f9185
Arthur, Michael J.P.
d61d056b-6470-4afc-bafb-7a20be9cc413
Iredale, John P.
607673ce-77b2-4418-b317-2aa778110ee2
Mann, Derek A.
7a0eb3d7-c2ca-432f-82a0-f4b0df08755d
Wright, Matthew C.
8c69c9f3-9230-4014-833b-b2f3babd671e
Issa, Razo
82704844-4c26-4c70-8fe3-8cf4a8c8e5a9
Smart, David E.
fcac679f-6eab-4df5-81da-be0017b87984
Trim, Nathan
afa06514-3691-4aa3-89b3-c5c3853102ba
Murray, Graeme I.
35ca95fd-3168-4db6-a842-531ad24812f5
Primrose, John N.
d85f3b28-24c6-475f-955b-ec457a3f9185
Arthur, Michael J.P.
d61d056b-6470-4afc-bafb-7a20be9cc413
Iredale, John P.
607673ce-77b2-4418-b317-2aa778110ee2
Mann, Derek A.
7a0eb3d7-c2ca-432f-82a0-f4b0df08755d

Wright, Matthew C., Issa, Razo, Smart, David E., Trim, Nathan, Murray, Graeme I., Primrose, John N., Arthur, Michael J.P., Iredale, John P. and Mann, Derek A. (2001) Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats. Gastroenterology, 121 (3), 685-698. (doi:10.1053/gast.2001.27188).

Record type: Article

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 (-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.

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Published date: 2001

Identifiers

Local EPrints ID: 26671
URI: http://eprints.soton.ac.uk/id/eprint/26671
ISSN: 0016-5085
PURE UUID: 9aed9e39-37c2-4a6b-8e8c-4623e27852a0
ORCID for John N. Primrose: ORCID iD orcid.org/0000-0002-2069-7605

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Date deposited: 24 Apr 2006
Last modified: 16 Mar 2024 02:47

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Contributors

Author: Matthew C. Wright
Author: Razo Issa
Author: David E. Smart
Author: Nathan Trim
Author: Graeme I. Murray
Author: Michael J.P. Arthur
Author: John P. Iredale
Author: Derek A. Mann

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