Targeting liver myofibroblasts: a novel approach in anti-fibrogenic therapy

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Targeting liver myofibroblasts: a novel approach in anti-fibrogenic therapy

Journal

Hepatology International

Publisher

Springer New York

ISSN

1936-0533 (Print) 1936-0541 (Online)

Category

Review Article

DOI

10.1007/s12-y

Subject Collection

Medicine

SpringerLink Date

Wednesday, September 03, 2008

s1, 2, 3, Wallace1, Koruth3, Caroline Barelle2, J. Porter3 and C. 1

(1)

Institute of Cellular Medicine, School of Clinical & Laboratory Sciences, University of Newcastle Upon Tyne, Level 2 Leech Building, Medical School, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK

(2)

Wyeth Research, Polwarth Building, Foresterhill, Aberdeen, UK

(3)

School of Medical Sciences, University of Aberdeen, Aberdeen, UK

Received: 26 February 2008 Accepted: 21 July 2008 Published online: 3 September 2008

Abstract Chronic liver disease results in a liver-scarring response termed fibrosis. Excessive scarring leads to cirrhosis, which is associated with high morbidity and mortality. The only treatment for liver cirrhosis is liver transplantation; therefore, much attention has been directed toward therapies that will slow or reverse fibrosis. Although anti-fibrogenic therapies have been shown to be effective in experimental animal models, licensed therapies have yet to emerge. A potential problem for any anti-fibrogenic therapy in the liver is the existence of the body’s major drug metabolising cell (the hepatocyte) adjacent to the primary fibrosis-causing cell, the myofibroblast. This article reviews the development of a human recombinant single-chain antibody (scAb) that binds to the surface of myofibroblasts. This antibody binds specifically to myofibroblasts in fibrotic mouse livers. When conjugated with a compound that stimulates myofibroblast apoptosis, the antibody directs the specific apoptosis of myofibroblasts with greater specificity and efficacy than the free compound. The antibody also reduces the adverse effect of liver macrophage apoptosis and—in contrast to the free compound—reversed fibrosis in the sustained injury model used. These data suggest that specifically stimulating the apoptosis of liver myofibroblasts using a targeting antibody has potential in the treatment of liver fibrosis.

Keywords C1-3 - Gliotoxin - Hepatic stellate cell - Fibrosis - Kupffer cell - Matrix metalloproteinase 13