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J Hepatol. 2008 Jul;49(1):88-98. doi: 10.1016/j.jhep.2008.01.032. Epub 2008 Mar 13.

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

Author information

1
Institute of Cellular Medicine, School of Clinical and Laboratory Sciences, University of Newcastle Upon Tyne, Level 2 Leech Building, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.

Erratum in

  • J Hepatol. 2010 May;52(5):779.

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.

PMID:
18394744
DOI:
10.1016/j.jhep.2008.01.032
[Indexed for MEDLINE]

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