Endogenous alpha-calcitonin gene-related peptide mitigates liver fibrosis in chronic hepatitis induced by repeated administration of concanavalin A.
BACKGROUND
Alpha-calcitonin gene-related peptide (alphaCGRP) 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 alphaCGRP(-/-) mice to further investigate the antifibrogenic and hepatoprotective effects of endogenous alphaCGRP in Con A-induced chronic hepatitis.


METHODS
Chronic hepatitis was induced in alphaCGRP(-/-) 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.


RESULTS
alphaCGRP(-/-) mice showed more severe liver fibrosis than wild-type mice in a Con A-induced chronic hepatitis model. In histological and gene expression analyses, alphaCGRP(-/-) mice showed greater inflammatory and fibrotic changes, greater HSC activation and a higher incidence of apoptosis among nonparenchymal cells than wild-type mice.


CONCLUSIONS
Endogenous alphaCGRP mitigates liver fibrosis in chronic hepatitis induced by repeated administration of Con A. alphaCGRP could be a useful therapeutic target for the treatment of chronic hepatitis.
Kamiyoshi
Akiko
A
Department of Organ Regeneration, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
Sakurai
Takayuki
T
Ichikawa-Shindo
Yuka
Y
Iinuma
Nobuyoshi
N
Kawate
Hisaka
H
Yoshizawa
Takahiro
T
Koyama
Teruhide
T
Muto
Shin-ichi
S
Shindo
Takayuki
T
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000150:complications*; D003208:Concanavalin A / Q000008:administration & dosage / Q000633:toxicity*; D017931:DNA Primers / Q000235:genetics; D055166:Hepatic Stellate Cells / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D003208:Concanavalin A; D015740:Calcitonin Gene-Related Peptide