Halofuginone can worsen liver fibrosis in bile duct obstructed rats.
OBJECTIVE
Halofuginone (HF) is an antifibrotic agent in rat models of liver fibrosis caused by repetitive intoxications. A beneficial effect of HF on a biliary type of liver fibrosis has not been proven yet.


METHODS
Bile duct-obstructed rats were given HF from the moment of obstruction onwards and compared with no treatment. After 3 weeks, respectively, 6 weeks, aminopyrine breath test (ABT) and haemodynamic measurements including of portal pressure were carried out. Liver pieces were taken for Sirius red quantitative scoring, as well as for semiquantitative determinations of collagen type I and III RNA levels.


RESULTS
ABT was significantly worse in HF-treated rats as compared with no treatment (P=0.02). Haemodynamic data and collagen type I and III determinations were not significantly different between groups. Biliary fibrosis scores were significantly higher in HF-treated rats as compared with no treatment (P=0.03). More Sirius red staining was associated with more proliferation of bile ductules.


CONCLUSIONS
HF may worsen biliary fibrosis. This contrasts sharply with antifibrotic effects in other models of liver fibrosis. Distinctive cellular mechanisms in biliary fibrosis may explain this discrepancy. One should be cautious for chronic application of HF in man with cholestasis.
Deparment of Hepatology, University Hospital Gasthuisbergs, Catholic University of Leuven, B-3000 Leuven, Belgium. marc.vandecasteele@uz.kuleuven.ac.be
Marc
M
Van de Casteele
Tania
T
Roskams
Ingrid
I
Van der Elst
Jos F
JF
van Pelt
Johan
J
Fevery
Frederik
F
Nevens
D000632:Aminopyrine / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D001944:Breath Tests; D001651:Cholestasis, Extrahepatic / Q000209:etiology / Q000473:pathology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D008026:Ligation; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D010880:Piperidines; D017082:Portal Pressure; D011799:Quinazolines / Q000009:adverse effects*; D052999:Quinazolinones; D012333:RNA, Messenger; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D024042:Collagen Type I; D024061:Collagen Type III; D010880:Piperidines; D011799:Quinazolines; D052999:Quinazolinones; D012333:RNA, Messenger; D000632:Aminopyrine; C010176:halofuginone