Halofuginone, a collagen type I inhibitor improves liver regeneration in cirrhotic rats.
OBJECTIVE
Hepatic fibrosis involves excess deposition of extracellular connective tissue of which collagen type I fibers form the predominant component. Left untreated it develops into cirrhosis, often linked with hepatocellular carcinoma. Owing to the fact that cirrhotic liver regeneration is impaired, resection of hepatocellular carcinoma associated with cirrhosis is questionable. The aim of the present study was to determine the potential of halofuginone, a collagen type I inhibitor, in improving liver regeneration in cirrhotic rats.


METHODS
Partial hepatectomy (70%) was performed in thioacetamide-induced cirrhotic rats fed a halofuginone-containing diet. Liver regeneration was monitored by mass and proliferating cell nuclear antigen. The Ishak staging system and hydroxyproline content were used to evaluate the level of fibrosis.


RESULTS
Halofuginone administered prior to and following partial hepatectomy did not inhibit normal liver regeneration despite the reduced levels of collagen type I mRNA. When given to rats with established fibrosis, it caused a significant reduction in alpha smooth muscle actin, TIMP-2, collagen type I gene expression and collagen deposition. Such animals demonstrated improved capacity for regeneration.


CONCLUSIONS
Halofuginone may prove useful in improving survival of patients with hepatocellular carcinoma and cirrhosis undergoing surgical resection.
Spira
Gadi
G
Department of Anatomy and Cell Biology, The Bruce Rappaport Faculty of Medicine, Rappaport Family Institute for Research in the Medical Sciences, Technion, Haifa, Israel. spira@tx.technion.ac.il
Mawasi
Nidal
N
Paizi
Melia
M
Anbinder
Natali
N
Genina
Olga
O
Alexiev
Rosaly
R
Pines
Mark
M
D000818:Animals; D024042:Collagen Type I / Q000037:antagonists & inhibitors*; D005109:Extracellular Matrix / Q000187:drug effects; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D010880:Piperidines; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D052999:Quinazolinones; D051381:Rats; D017207:Rats, Sprague-Dawley; D013853:Thioacetamide
D024042:Collagen Type I; D010880:Piperidines; D011500:Protein Synthesis Inhibitors; D011799:Quinazolines; D052999:Quinazolinones; D013853:Thioacetamide; C010176:halofuginone