Antibody-targeted myofibroblast apoptosis reduces fibrosis during sustained liver injury.

Abstract

BACKGROUND/AIMS:

Myofibroblast apoptosis promotes the resolution of liver fibrosis. However, retaining macrophages may enhance reversal. The effects of specifically stimulating myofibroblast apoptosis in vivo were assessed.

METHODS:

A single chain antibody (C1-3) to an extracellular domain of a myofibroblast membrane protein was injected as a fluorescent- or gliotoxin conjugate into mice with liver fibrosis.

RESULTS:

C1-3 specifically targeted alpha-smooth muscle actin positive liver myofibroblasts within scar regions of the liver in vivo and did not co-localise with liver monocytes/macrophages. Injection of free gliotoxin stimulated a 2-fold increase in non-parenchymal cell apoptosis and depleted liver myofibroblasts by 30% and monocytes/macrophages by 50% but had no effect on fibrosis severity in the sustained injury model employed. In contrast, C1-3-targeted gliotoxin stimulated a 5-fold increase in non-parenchymal cell apoptosis, depleted liver myofibroblasts by 60%, did not affect the number of monocytes/macrophages and significantly reduced fibrosis severity. Fibrosis reduction was associated with increased metalloproteinase-13 levels.

CONCLUSIONS:

These data demonstrate that specific targeting of liver myofibroblast apoptosis is the most effective anti-fibrogenic therapy, supporting a role for liver monocytes and/or macrophages in the promotion of liver fibrosis reduction.

• Authors: Angela Douglass, Karen Wallace, Rebecca Parr, Jennifer Park, Elaine Durward, Ian Broadbent, Caroline Barelle, Andrew J Porter, Matthew C Wright
• Journal: Journal of hepatology (J Hepatol) Vol. 49 Issue 1 Pg. 88-98 (Jul 2008) ISSN: 0168-8278 [Print] Netherlands
• PMID: 18394744 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Antibodies, Monoclonal
• Epitopes
• Membrane Proteins
• Synaptophysin
• Gliotoxin
• Carbon Tetrachloride

Topics

• Actins (immunology)
• Animals
• Antibodies, Monoclonal (pharmacology)
• Antibody Specificity
• Apoptosis (immunology)
• Carbon Tetrachloride (toxicity)
• Epitopes
• Fibroblasts (immunology, pathology)
• Gliotoxin (pharmacology)
• Immunotherapy (methods)
• Liver Cirrhosis (chemically induced, immunology, pathology)
• Macrophages (immunology)
• Male
• Membrane Proteins (immunology)
• Mice
• Monocytes (immunology)
• Synaptophysin (immunology)