title: Targeted elimination of activated hepatic stellate cells by an anti-epidermal growth factor-receptor single chain fragment variable antibody-tumor necrosis factor-related apoptosis-inducing ligand (scFv425-sTRAIL).
abstract: BACKGROUND
  Progressive liver fibrosis is the result of chronic liver injury and is characterized by the excessive accumulation of extracellular matrix that may result in liver failure. Activated hepatic stellate cells are known to play a central role in this process and their elimination is a crucial step towards the resolution and reversion of liver fibrosis. In the present study, we investigated the potential application of an anti-epidermal growth factor receptor single chain fragment variable antibody-tumor necrosis factor-related apoptosis-inducing ligand (scFv425-sTRAIL) fusion protein in the targeted elimination of activated hepatic stellate cells.
  
  
  METHODS
  Activated hepatic stellate cells (LX2 cells) were treated by adenovirus-derived scFv425-sTRAIL to evaluate its effect on the viability and extracellular matrix production of this type of cells.
  
  
  RESULTS
  In vitro treatment of activated hepatic stellate cells with scFv425-sTRAIL induced a significant reduction in viability (up to 100% reduction) and extracellular matrix production (60% reduction), yet no significant effect was observed on hepatic parenchymal cells. Blockage of the epidermal growth factor receptor (EGFR) by a monoclonal antibody significantly reduced the effectiveness of scFv425-sTRAIL in activated hepatic stellate cells, whereas a reduced effectivity was also observed after inhibition of the caspase pathway.
  
  
  CONCLUSIONS
  Evidence is presented for the successful application of the scFv425-sTRAIL fusion protein in the targeted elimination of activated hepatic stellate cells via EGFR and simultaneous activation of the caspase pathway. scFv425-sTRAIL may thus represent a new therapeutic compound against liver fibrosis.
authors.affiliation: Department of Pharmaceutical Gene Modulation, University of Groningen, Groningen, The Netherlands.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Arabpour
authors.forename: Klaas
authors.initials: K
authors.lastname: Poelstra
authors.forename: Wijnand
authors.initials: W
authors.lastname: Helfrich
authors.forename: Edwin
authors.initials: E
authors.lastname: Bremer
authors.forename: Hidde J
authors.initials: HJ
authors.lastname: Haisma
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D057127:Single-Chain Antibodies / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D024042:Collagen Type I; D057127:Single-Chain Antibodies; D053221:TNF-Related Apoptosis-Inducing Ligand; C114035:scFv 425; D066246:ErbB Receptors; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7
keywords: EGFR; TRAIL; liver fibrosis; targeted therapy