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Cytoplasmic domain of tissue factor promotes liver fibrosis in mice

AIM: To evaluate the role of tissue factor (TF) and protease activated receptor (PAR)-2 in liver fibrosis. METHODS: Using CCl(4) administration for eight weeks, we induced hepatic fibrosis in wild-type C57BL/6 mice and in mice with deletion of the cytoplasmic signalling domain of TF (TF(§CT/§CT)), d...

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Autores principales: Knight, Virginia, Lourensz, Dinushka, Tchongue, Jorge, Correia, Jeanne, Tipping, Peter, Sievert, William
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Baishideng Publishing Group Inc 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569283/
https://www.ncbi.nlm.nih.gov/pubmed/28883694
http://dx.doi.org/10.3748/wjg.v23.i31.5692
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author Knight, Virginia
Lourensz, Dinushka
Tchongue, Jorge
Correia, Jeanne
Tipping, Peter
Sievert, William
author_facet Knight, Virginia
Lourensz, Dinushka
Tchongue, Jorge
Correia, Jeanne
Tipping, Peter
Sievert, William
author_sort Knight, Virginia
collection PubMed
description AIM: To evaluate the role of tissue factor (TF) and protease activated receptor (PAR)-2 in liver fibrosis. METHODS: Using CCl(4) administration for eight weeks, we induced hepatic fibrosis in wild-type C57BL/6 mice and in mice with deletion of the cytoplasmic signalling domain of TF (TF(§CT/§CT)), deletion of PAR-2 (PAR-2(-/-)) and combined deletion of TF signalling domain and PAR-2 (TF(§CT/§CT)/PAR-2(-/-)). Hepatic fibrosis area was assessed by quantitative imaging of picrosirius red staining. Hepatic collagen content was assessed by hydroxyproline levels. Hepatic stellate cells (αSMA positive) and hepatic macrophages (CD68 positive) were identified by immunohistochemistry. Hepatic gene expression was determined by PCR and liver TGFβ1 content by ELISA. RESULTS: CCl(4) treated mice with deletion of the PAR-2 gene (PAR-2(-/-)) and the cytoplasmic domain of TF (TF(§CT/§CT)) developed significantly less hepatic fibrosis, characterised by reduced liver fibrosis area and hydroxyproline content, compared to control wildtype mice treated with CCl(4). The observed reduction in histological fibrosis was accompanied by a significant decrease in the hepatic content of TGFβ, the prototypic fibrogenic cytokine, as well as fewer activated hepatic stellate cells and hepatic macrophages. Deletion of the TF cytoplasmic signalling domain reduced hepatic fibrosis to levels similar to those observed in mice lacking PAR-2 signalling but combined deletion provided no added protection against fibrosis indicating a lack of mutual modulating effects that have been observed in other contexts such as angiogenic responses. CONCLUSION: Tissue factor cytoplasmic domain is involved in TF-PAR-2 signalling initiating hepatic fibrosis and is a potential therapeutic target, as its deletion would not impact coagulation.
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spelling pubmed-55692832017-09-07 Cytoplasmic domain of tissue factor promotes liver fibrosis in mice Knight, Virginia Lourensz, Dinushka Tchongue, Jorge Correia, Jeanne Tipping, Peter Sievert, William World J Gastroenterol Basic Study AIM: To evaluate the role of tissue factor (TF) and protease activated receptor (PAR)-2 in liver fibrosis. METHODS: Using CCl(4) administration for eight weeks, we induced hepatic fibrosis in wild-type C57BL/6 mice and in mice with deletion of the cytoplasmic signalling domain of TF (TF(§CT/§CT)), deletion of PAR-2 (PAR-2(-/-)) and combined deletion of TF signalling domain and PAR-2 (TF(§CT/§CT)/PAR-2(-/-)). Hepatic fibrosis area was assessed by quantitative imaging of picrosirius red staining. Hepatic collagen content was assessed by hydroxyproline levels. Hepatic stellate cells (αSMA positive) and hepatic macrophages (CD68 positive) were identified by immunohistochemistry. Hepatic gene expression was determined by PCR and liver TGFβ1 content by ELISA. RESULTS: CCl(4) treated mice with deletion of the PAR-2 gene (PAR-2(-/-)) and the cytoplasmic domain of TF (TF(§CT/§CT)) developed significantly less hepatic fibrosis, characterised by reduced liver fibrosis area and hydroxyproline content, compared to control wildtype mice treated with CCl(4). The observed reduction in histological fibrosis was accompanied by a significant decrease in the hepatic content of TGFβ, the prototypic fibrogenic cytokine, as well as fewer activated hepatic stellate cells and hepatic macrophages. Deletion of the TF cytoplasmic signalling domain reduced hepatic fibrosis to levels similar to those observed in mice lacking PAR-2 signalling but combined deletion provided no added protection against fibrosis indicating a lack of mutual modulating effects that have been observed in other contexts such as angiogenic responses. CONCLUSION: Tissue factor cytoplasmic domain is involved in TF-PAR-2 signalling initiating hepatic fibrosis and is a potential therapeutic target, as its deletion would not impact coagulation. Baishideng Publishing Group Inc 2017-08-21 2017-08-21 /pmc/articles/PMC5569283/ /pubmed/28883694 http://dx.doi.org/10.3748/wjg.v23.i31.5692 Text en ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved. http://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.
spellingShingle Basic Study
Knight, Virginia
Lourensz, Dinushka
Tchongue, Jorge
Correia, Jeanne
Tipping, Peter
Sievert, William
Cytoplasmic domain of tissue factor promotes liver fibrosis in mice
title Cytoplasmic domain of tissue factor promotes liver fibrosis in mice
title_full Cytoplasmic domain of tissue factor promotes liver fibrosis in mice
title_fullStr Cytoplasmic domain of tissue factor promotes liver fibrosis in mice
title_full_unstemmed Cytoplasmic domain of tissue factor promotes liver fibrosis in mice
title_short Cytoplasmic domain of tissue factor promotes liver fibrosis in mice
title_sort cytoplasmic domain of tissue factor promotes liver fibrosis in mice
topic Basic Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569283/
https://www.ncbi.nlm.nih.gov/pubmed/28883694
http://dx.doi.org/10.3748/wjg.v23.i31.5692
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