The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis
The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis
Liver fibrosis and its end-stage disease cirrhosis are major world health problems arising from chronic injury of the liver by a variety of etiological factors including viruses, alcohol and drug abuse, the metabolic syndrome, autoimmune disease and hereditary disorders of metabolism. Fibrosis is a progressive pathological process in which wound-healing myofibroblasts of the liver respond to injury by promoting replacement of the normal hepatic tissue with a scar-like matrix composed of cross-linked collagen. Until recently it was believed that this process was irreversible. However emerging experimental and clinical evidence is starting to show that even cirrhosis is potentially reversible. Key to this is the discovery that reversion of fibrosis is accompanied by clearance of hepatic stellate cells (HSC) by apoptosis. Furthermore, proof-of-concept studies in rodents have demonstrated that experimental augmentation of HSC apoptosis will promote the resolution of fibrosis. Consequently there is now considerable interest in determining the molecular events that regulate HSC apoptosis and the discovery of drugs that will stimulate HSC apoptosis in a selective manner. This review will consider the regulatory role played by growth factors (e.g. NGF, IGF-1, TGF?), death receptor ligands (TRAIL, FAS), components and regulators of extracellular matrix (integrins, collagen, matrix metalloproteinases and their tissue inhibitors) and signal transduction proteins and transcription factors (Rho/Rho kinase, Jun N-terminal Kinase (JNK), IkappaKinase (IKK), NF-? B). The potential for known pharmacological agents such as gliotoxin, sulfasalazine, benzodiazepine ligands, curcumin and tanshinone I to induce HSC apoptosis and therefore to be used therapeutically will be explored.
apoptosis, hepatic stellate cells, liver fibrosis, NF-kB
927-939
Elsharkawy, A.M.
9f68fe40-a632-4fab-ada6-f50f2fe9c7a4
Oakley, F.
f226e690-1d98-4604-9add-f1c4c2721f5d
Mann, D.A.
54e772bb-f94f-4485-98c8-b2339a929d86
2005
Elsharkawy, A.M.
9f68fe40-a632-4fab-ada6-f50f2fe9c7a4
Oakley, F.
f226e690-1d98-4604-9add-f1c4c2721f5d
Mann, D.A.
54e772bb-f94f-4485-98c8-b2339a929d86
Elsharkawy, A.M., Oakley, F. and Mann, D.A.
(2005)
The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis.
Apoptosis, 10 (5), .
(doi:10.1007/s10495-005-1055-4).
Abstract
Liver fibrosis and its end-stage disease cirrhosis are major world health problems arising from chronic injury of the liver by a variety of etiological factors including viruses, alcohol and drug abuse, the metabolic syndrome, autoimmune disease and hereditary disorders of metabolism. Fibrosis is a progressive pathological process in which wound-healing myofibroblasts of the liver respond to injury by promoting replacement of the normal hepatic tissue with a scar-like matrix composed of cross-linked collagen. Until recently it was believed that this process was irreversible. However emerging experimental and clinical evidence is starting to show that even cirrhosis is potentially reversible. Key to this is the discovery that reversion of fibrosis is accompanied by clearance of hepatic stellate cells (HSC) by apoptosis. Furthermore, proof-of-concept studies in rodents have demonstrated that experimental augmentation of HSC apoptosis will promote the resolution of fibrosis. Consequently there is now considerable interest in determining the molecular events that regulate HSC apoptosis and the discovery of drugs that will stimulate HSC apoptosis in a selective manner. This review will consider the regulatory role played by growth factors (e.g. NGF, IGF-1, TGF?), death receptor ligands (TRAIL, FAS), components and regulators of extracellular matrix (integrins, collagen, matrix metalloproteinases and their tissue inhibitors) and signal transduction proteins and transcription factors (Rho/Rho kinase, Jun N-terminal Kinase (JNK), IkappaKinase (IKK), NF-? B). The potential for known pharmacological agents such as gliotoxin, sulfasalazine, benzodiazepine ligands, curcumin and tanshinone I to induce HSC apoptosis and therefore to be used therapeutically will be explored.
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Published date: 2005
Keywords:
apoptosis, hepatic stellate cells, liver fibrosis, NF-kB
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Local EPrints ID: 27038
URI: http://eprints.soton.ac.uk/id/eprint/27038
ISSN: 1360-8185
PURE UUID: d7a64068-d7bc-42af-9635-178debd9202f
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Date deposited: 24 Apr 2006
Last modified: 15 Mar 2024 07:15
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Author:
A.M. Elsharkawy
Author:
F. Oakley
Author:
D.A. Mann
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