Journal
LIVER INTERNATIONAL
Volume 29, Issue 5, Pages 642-649Publisher
WILEY
DOI: 10.1111/j.1478-3231.2008.01841.x
Keywords
alpha CGRP; concanavalin A; fibrosis; knockout mouse
Categories
Funding
- Takeda Medical Research Foundation
- Japan Heart Foundation Research Grant
- Grant for Research on Cardiovascular Disease from the Tanabe Medical Conference
- Novartis Foundation for Gerontological Research
- Astra Zeneca Research Grant
- Mitsui Life Social Welfare Foundation
- Ichiro Kanehara Foundation
- Uehara Memorial Foundation
- Sankyo Foundation of Life Science
- Naito Foundation
- Mitsubishi Pharma Research Foundation
- Salt Science Research Foundation
- Ministry of Health, Labour and Welfare [19C-7]
- Ministry of Education, Culture, Sports, Science and Technology, Japan
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alpha-Calcitonin gene-related peptide (alpha CGRP) is a 37-amino acid pleiotropic peptide that we previously showed to exert a hepatoprotective effect during concanavalin A (Con A)-induced acute hepatitis. In the present study, we used alpha CGRP(-/-) mice to further investigate the antifibrogenic and hepatoprotective effects of endogenous alpha CGRP in Con A-induced chronic hepatitis. Chronic hepatitis was induced in alpha CGRP(-/-) and wild-type mice by repeated administration of Con A. Serum transaminases were measured to assess hepatic injury. The severity of fibrosis and the activation of hepatic stellate cells (HSCs) were analysed by Masson trichrome staining and immunohistochemical staining of alpha-smooth muscle actin (alpha-SMA) respectively. Altered expression of fibrosis- and inflammation-related genes was evaluated using a quantitative real-time polymerase chain reaction. Activation and proliferation of HSCs were analysed using both primary cultured HSCs from the mice and the LI90 HSC cell line. alpha CGRP(-/-) mice showed more severe liver fibrosis than wild-type mice in a Con A-induced chronic hepatitis model. In histological and gene expression analyses, alpha CGRP(-/-) mice showed greater inflammatory and fibrotic changes, greater HSC activation and a higher incidence of apoptosis among nonparenchymal cells than wild-type mice. Endogenous alpha CGRP mitigates liver fibrosis in chronic hepatitis induced by repeated administration of Con A. alpha CGRP could be a useful therapeutic target for the treatment of chronic hepatitis.
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