Transforming growth factor β neutralization ameliorates pre-existing hepatic fibrosis and reduces cholangiocarcinoma in thioacetamide-treated rats.
Considerable evidence has demonstrated that transforming growth factor β (TGF-β) plays a key role in hepatic fibrosis, the final common pathway for a variety of chronic liver diseases leading to liver insufficiency. Although a few studies have reported that blocking TGF-β with soluble receptors or siRNA can prevent the progression of hepatic fibrosis, as yet no evidence has been provided that TGF-β antagonism can improve pre-existing hepatic fibrosis. The aim of this study was to examine the effects of a murine neutralizing TGF-β monoclonal antibody (1D11), in a rat model of thioacetamide (TAA)-induced hepatic fibrosis. TAA administration for 8 weeks induced extensive hepatic fibrosis, whereupon 1D11 dosing was initiated and maintained for 8 additional weeks. Comparing the extent of fibrosis at two time points, pre- and post-1D11 dosing, we observed a profound regression of tissue injury and fibrosis upon treatment, as reflected by a reduction of collagen deposition to a level significantly less than that observed before 1D11 dosing. Hepatic TGF-β1 mRNA, tissue hydroxyproline, and plasminogen activator inhibitor 1 (PAI-1) levels were significantly elevated at the end of the 8 week TAA treatment. Vehicle and antibody control groups demonstrated progressive injury through 16 weeks, whereas those animals treated for 8 weeks with 1D11 showed striking improvement in histologic and molecular endpoints. During the course of tissue injury, TAA also induced cholangiocarcinomas. At the end of study, the number and area of cholangiocarcinomas were significantly diminished in rats receiving 1D11 as compared to control groups, presumably by the marked reduction of supporting fibrosis/stroma. The present study demonstrates that 1D11 can reverse pre-existing hepatic fibrosis induced by extended dosing of TAA. The regression of fibrosis was accompanied by a marked reduction in concomitantly developed cholangiocarcinomas. These data provide evidence that therapeutic dosing of a TGF-β antagonist can diminish and potentially reverse hepatic fibrosis and also reduce the number and size of attendant cholangiocarcinomas.
Tissue Protection and Repair, Sanofi-Genzyme R&D Center, Framingham, Massachusetts, USA. Hong.ling@genzyme.com
Hong
H
Ling
Eric
E
Roux
Donna
D
Hempel
Jingzang
J
Tao
Mandy
M
Smith
Scott
S
Lonning
Anna
A
Zuk
Cynthia
C
Arbeeny
Steve
S
Ledbetter
D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage*; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013853:Thioacetamide / Q000633:toxicity; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*
D058846:Antibodies, Monoclonal, Murine-Derived; D017395:Plasminogen Activator Inhibitor 1; D016212:Transforming Growth Factor beta; D013853:Thioacetamide