title: Antibody-targeted myofibroblast apoptosis reduces fibrosis during sustained liver injury.
abstract: 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.
authors.affiliation: 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.
authors.forename: Angela
authors.initials: A
authors.lastname: Douglass
authors.forename: Karen
authors.initials: K
authors.lastname: Wallace
authors.forename: Rebecca
authors.initials: R
authors.lastname: Parr
authors.forename: Jennifer
authors.initials: J
authors.lastname: Park
authors.forename: Elaine
authors.initials: E
authors.lastname: Durward
authors.forename: Ian
authors.initials: I
authors.lastname: Broadbent
authors.forename: Caroline
authors.initials: C
authors.lastname: Barelle
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Porter
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Wright
mesh_terms: 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
chemical_list: D000199:Actins; D000911:Antibodies, Monoclonal; D000939:Epitopes; D008565:Membrane Proteins; D016708:Synaptophysin; D005912:Gliotoxin; D002251:Carbon Tetrachloride