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Title: | Cytoplasmic domain of tissue factor promotes liver fibrosis in mice. | Authors: | Correia J.;Sievert W. ;Knight V.;Tipping P.;Tchongue J.;Lourensz D. | Institution: | (Knight, Lourensz, Tchongue, Correia, Tipping, Sievert) Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences, Monash University, 246 Clayton Road, Melbourne, Victoria 3168, Australia (Knight, Sievert) Gastroenterology and Hepatology Unit, Monash Health, Melbourne, Victoria 3168, Australia | Issue Date: | 31-Aug-2017 | Copyright year: | 2017 | Publisher: | Baishideng Publishing Group Co., Limited (8226 Regency Drive, Pleasanton, California 94588, United States. E-mail: wejd@public.bta.cn) Baishideng Publishing Group Co |
Place of publication: | China | Publication information: | World Journal of Gastroenterology. 23 (31) (pp 5692-5699), 2017. Date of Publication: 21 Aug 2017. | Journal: | World Journal of Gastroenterology | Abstract: | AIM To evaluate the role of tissue factor (TF) and protease activated receptor (PAR)-2 in liver fibrosis. METHODS Using CCl4 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 (TFCT/CT), deletion of PAR-2 (PAR-2-/-) and combined deletion of TF signalling domain and PAR-2 (TFCT/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 (alphaSMA positive) and hepatic macrophages (CD68 positive) were identified by immunohistochemistry. Hepatic gene expression was determined by PCR and liver TGFbeta1 content by ELISA. RESULTS CCl4 treated mice with deletion of the PAR-2 gene (PAR-2-/-) and the cytoplasmic domain of TF (TFCT/CT) developed significantly less hepatic fibrosis, characterised by reduced liver fibrosis area and hydroxyproline content, compared to control wildtype mice treated with CCl4. The observed reduction in histological fibrosis was accompanied by a significant decrease in the hepatic content of TGFbeta, 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.Copyright © The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.3748/wjg.v23.i31.5692 | Link to associated publication: | Click here for full text options | PubMed URL: | 28883694 [http://www.ncbi.nlm.nih.gov/pubmed/?term=28883694] | ISSN: | 1007-9327 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/27012 | Type: | Article | Subjects: | *thromboplastin/ec [Endogenous Compound] transforming growth factor beta/ec [Endogenous Compound] cytoplasmic domain protein domain animal experiment animal model animal tissue article *carbon tetrachloride-induced liver fibrosis/et [Etiology] controlled study gene expression hepatic stellate cell macrophage mouse nonhuman signal transduction alpha smooth muscle actin/ec [Endogenous Compound] CD68 antigen/ec [Endogenous Compound] collagen/ec [Endogenous Compound] gelatinase A/ec [Endogenous Compound] hydroxyproline/ec [Endogenous Compound] messenger RNA/ec [Endogenous Compound] proteinase activated receptor 2/ec [Endogenous Compound] Article animal tissue animal model *carbon tetrachloride-induced liver fibrosis / *etiology animal experiment controlled study gene expression hepatic stellate cell macrophage mouse nonhuman protein domain signal transduction |
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