Antibody-targeted myofibroblast apoptosis reduces fibrosis during sustained liver injury

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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