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PMID: 10535989 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

In vivo inhibition of rat stellate cell activation by soluble transforming growth factor beta type II receptor: a potential new therapy for hepatic fibrosis.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 22 ·1999-10-26 ·Pages 12719-24

George J, Roulot D, Koteliansky VE, Bissell DM

Abstract

Transforming growth factor beta (TGF-beta) is a well characterized cytokine that appears to play a major role in directing the cellular response to injury, driving fibrogenesis, and, thus, potentially underlying the progression of chronic injury to fibrosis. In this study, we report the use of a novel TGF-beta receptor antagonist to block fibrogenesis induced by ligation of the common bile duct in rats. The antagonist consisted of a chimeric IgG containing the extracellular portion of the TGF-beta type II receptor. This "soluble receptor" was infused at the time of injury; in some experiments it was given at 4 days after injury, as a test of its ability to reverse fibrogenesis. The latter was assessed by expression of collagen, both as the mRNA in stellate cells isolated from control or injured liver and also by quantitative histochemistry of tissue sections. When the soluble receptor was administered at the time of injury, collagen I mRNA in stellate cells from the injured liver was 26% of that from animals receiving control IgG (P < 0.0002); when soluble receptor was given after injury induction, collagen I expression was 35% of that in control stellate cells (P < 0.0001). By quantitative histochemistry, hepatic fibrosis in treated animals was 55% of that in controls. We conclude that soluble TGF-beta receptor is an effective inhibitor of experimental fibrogenesis in vivo and merits clinical evaluation as a novel agent for controlling hepatic fibrosis in chronic liver injury.

MeSH Terms
Animals Collagen/metabolism Liver/cytology Liver Cirrhosis, Experimental/drug therapy,metabolism Male Protein Serine-Threonine Kinases Rats Rats, Sprague-Dawley Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta/physiology Transforming Growth Factor beta/antagonists & inhibitors
Chemicals
Receptors, Transforming Growth Factor beta Transforming Growth Factor beta Collagen Protein Serine-Threonine Kinases Receptor, Transforming Growth Factor-beta Type II
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
George J
The Liver Center, Department of Medicine, University of California, San Francisco, CA 94143, and Biogen Inc., Cambridge, MA 02142, USA.
Roulot D
Koteliansky V E
Bissell D M
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.22.12719
Published
1999-10-26
Pages
12719-24
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC23066
Subset
IM
Grants
NIDDK NIH HHS · P30 DK026743 · United States
NIDDK NIH HHS · DK26743 · United States
NIDDK NIH HHS · DK31198 · United States
FIC NIH HHS · R03 TW00717 · United States
External Links
PubMed source DOI: 10.1073/pnas.96.22.12719 PMC Full Text View journal details
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