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

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.