Transforming growth factor beta-1 signalling in canine hepatic diseases: new models for human fibrotic liver pathologies.
OBJECTIVE
The purpose of this study was to validate spontaneous chronic hepatitis and cirrhosis in dogs as a potential large animal model for fibrotic liver disease in humans by evaluating their molecular pathophysiology.


METHODS
Transforming growth factor-beta1 (TGF-beta1) signalling was analysed in liver samples of dogs with acute hepatitis (AH), chronic hepatitis (CH), cirrhosis (CIRR), and a specific form of cirrhosis, lobular dissecting hepatitis (LDH), in comparison with human cirrhotic samples from alcohol abuse (ALC) and hepatitis C (HC).


RESULTS
Canine samples were investigated with quantitative real-time PCR (Q-PCR) and Western blotting on TGF-beta1 signalling including Smad2/3 phosphorylation. Immunohistochemistry on collagens I and III was performed. Q-PCR showed an increase in TGF-beta1 levels and downstream effector gene products in CH, LDH, and CIRR. The same fibrotic diseases also showed an increase in phosphorylated Smad2/3 and a higher deposition of collagens I and III. In contrast, in AH neither active TGF-beta1 signalling nor collagen deposition was observed. Western blot analysis on human ALC and HC indicated a high similarity with canine samples in TGF-beta1 expression and Smad2/3 phosphorylation.


CONCLUSIONS
Our results demonstrate that fibrosis in spontaneous dog liver diseases is highly comparable to their human counterparts and might serve as models for anti-fibrotic strategies.
Spee
Bart
B
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands. B.Spee@vet.uu.nl
Arends
Brigitte
B
van den Ingh
Ted S G A M
TS
Brinkhof
Bas
B
Nederbragt
Hubertus
H
Ijzer
Jooske
J
Roskams
Tania
T
Penning
Louis C
LC
Rothuizen
Jan
J
D000818:Animals; D001483:Base Sequence; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D004285:Dogs; D015870:Gene Expression; D006526:Hepatitis C / Q000378:metabolism / Q000473:pathology; D006520:Hepatitis, Animal / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D053773:Transforming Growth Factor beta1; D003094:Collagen