Antibody-targeted myofibroblast apoptosis reduces fibrosis during sustained liver injury.
OBJECTIVE
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.
Douglass
Angela
A
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.
Wallace
Karen
K
Parr
Rebecca
R
Park
Jennifer
J
Durward
Elaine
E
Broadbent
Ian
I
Barelle
Caroline
C
Porter
Andrew J
AJ
Wright
Matthew C
MC
D000199:Actins / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000918:Antibody Specificity; D017209:Apoptosis / Q000276:immunology*; D002251:Carbon Tetrachloride / Q000633:toxicity; D000939:Epitopes; D005347:Fibroblasts / Q000276:immunology* / Q000473:pathology*; D005912:Gliotoxin / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D008264:Macrophages / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D009000:Monocytes / Q000276:immunology; D016708:Synaptophysin / Q000276:immunology
D000199:Actins; D000911:Antibodies, Monoclonal; D000939:Epitopes; D008565:Membrane Proteins; D016708:Synaptophysin; D005912:Gliotoxin; D002251:Carbon Tetrachloride