Coagulation status modulates murine hepatic fibrogenesis: implications for the development of novel therapies
Coagulation status modulates murine hepatic fibrogenesis: implications for the development of novel therapies
Background: there is strong evidence demonstrating that coagulation system activation contributes to wound healing and promotes organ fibrosis. Several epidemiological studies have now shown that prothrombotic status, including carriage of the factor (F)V Leiden mutation, is associated with rapid progression of hepatic fibrosis.
Objectives: to assess the effect of a procoagulant state on progression of hepatic fibrosis in a controlled environment and to test whether anticoagulation could attenuate fibrogenesis.
Methods: we investigated the effects of coagulation status on liver fibrosis development in a mouse model of chronic toxic liver injury. Prothrombotic FV Leiden mutant mice, C57BL/6 control animals and anticoagulated mice were studied after chronic exposure to carbon tetrachloride.
Results: carriage of the FV Leiden mutation caused a significant increase in hepatic fibrosis. Anticoagulation with warfarin significantly reduced fibrosis progression in wild-type mice but was less effective against the profibrotic FV Leiden mutation. Changes in the fibrosis scores were mirrored by changes in liver hydroxyproline content and hepatic stellate cell activation detected by alpha-smooth muscle actin expression.
Conclusions: these results demonstrate that coagulation status has a strong influence on hepatic fibrogenesis. It is likely that thrombin signaling through the proteinase-activated receptor 1 (PAR(1)) receptor expressed on hepatic stellate cells is responsible for this relationship. These results represent the first reported use of anticoagulation to slow hepatic fibrogenesis and suggest a potential novel anti-fibrotic therapeutic approach for the future.
actins/metabolism, animals, anticoagulants/therapeutic use, carbon tetrachloride/toxicity, factor V/genetics, gene expression/drug effects, hydroxyproline/metabolism, lipid peroxidation/drug effects, liver/drug effects, liver cirrhosis, experimental/blood, male, mice, mice, congenic, mice, inbred C57BL, Mice, mutant strains, mice, transgenic, point mutation, warfarin/therapeutic use
1336-43
Anstee, Q.M.
f718b024-d6b1-4210-bfc0-97b20fc0382b
Goldin, R.D.
7e31fb51-df97-46ef-a103-920f09a4f05e
Wright, M.
43325ef9-3459-4c75-b3bf-cf8d8dac2a21
Martinelli, A.
08d3ffd5-cf78-4a97-bcd2-8d63589d26a0
Cox, R.
5e66a2a5-d3fe-40e5-9bfe-3b9841b9d324
Thursz, M.R.
efe8e73d-555b-4b44-a8be-e77a8809208d
22 December 2022
Anstee, Q.M.
f718b024-d6b1-4210-bfc0-97b20fc0382b
Goldin, R.D.
7e31fb51-df97-46ef-a103-920f09a4f05e
Wright, M.
43325ef9-3459-4c75-b3bf-cf8d8dac2a21
Martinelli, A.
08d3ffd5-cf78-4a97-bcd2-8d63589d26a0
Cox, R.
5e66a2a5-d3fe-40e5-9bfe-3b9841b9d324
Thursz, M.R.
efe8e73d-555b-4b44-a8be-e77a8809208d
Anstee, Q.M., Goldin, R.D., Wright, M., Martinelli, A., Cox, R. and Thursz, M.R.
(2022)
Coagulation status modulates murine hepatic fibrogenesis: implications for the development of novel therapies.
Journal of Thrombosis and Haemostasis, 6 (8), .
(doi:10.1111/j.1538-7836.2008.03015.x).
Abstract
Background: there is strong evidence demonstrating that coagulation system activation contributes to wound healing and promotes organ fibrosis. Several epidemiological studies have now shown that prothrombotic status, including carriage of the factor (F)V Leiden mutation, is associated with rapid progression of hepatic fibrosis.
Objectives: to assess the effect of a procoagulant state on progression of hepatic fibrosis in a controlled environment and to test whether anticoagulation could attenuate fibrogenesis.
Methods: we investigated the effects of coagulation status on liver fibrosis development in a mouse model of chronic toxic liver injury. Prothrombotic FV Leiden mutant mice, C57BL/6 control animals and anticoagulated mice were studied after chronic exposure to carbon tetrachloride.
Results: carriage of the FV Leiden mutation caused a significant increase in hepatic fibrosis. Anticoagulation with warfarin significantly reduced fibrosis progression in wild-type mice but was less effective against the profibrotic FV Leiden mutation. Changes in the fibrosis scores were mirrored by changes in liver hydroxyproline content and hepatic stellate cell activation detected by alpha-smooth muscle actin expression.
Conclusions: these results demonstrate that coagulation status has a strong influence on hepatic fibrogenesis. It is likely that thrombin signaling through the proteinase-activated receptor 1 (PAR(1)) receptor expressed on hepatic stellate cells is responsible for this relationship. These results represent the first reported use of anticoagulation to slow hepatic fibrogenesis and suggest a potential novel anti-fibrotic therapeutic approach for the future.
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e-pub ahead of print date: 19 December 2007
Published date: 22 December 2022
Keywords:
actins/metabolism, animals, anticoagulants/therapeutic use, carbon tetrachloride/toxicity, factor V/genetics, gene expression/drug effects, hydroxyproline/metabolism, lipid peroxidation/drug effects, liver/drug effects, liver cirrhosis, experimental/blood, male, mice, mice, congenic, mice, inbred C57BL, Mice, mutant strains, mice, transgenic, point mutation, warfarin/therapeutic use
Identifiers
Local EPrints ID: 478290
URI: http://eprints.soton.ac.uk/id/eprint/478290
ISSN: 1538-7933
PURE UUID: 444d777f-2185-4307-869f-b25e20b29ae4
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Date deposited: 27 Jun 2023 17:18
Last modified: 17 Mar 2024 02:13
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Contributors
Author:
Q.M. Anstee
Author:
R.D. Goldin
Author:
M. Wright
Author:
A. Martinelli
Author:
R. Cox
Author:
M.R. Thursz
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