title: Recombinant hepatocyte growth factor treatment in a canine model of congenital liver hypoplasia.
abstract: BACKGROUND
  Although the liver has a large regenerative capacity, in many hepatopathies, these repair mechanisms fail. The therapeutic potential of hepatocyte growth factor (HGF) has been proven in numerous toxin-induced liver failure models in rodents, but never in spontaneously occurring liver diseases in larger animal models.
  
  
  OBJECTIVE
  The aim of this study was to induce liver growth in a hypoplastic liver by the administration of exogenous recombinant HGF. The natural hypoplastic liver model used is the canine congenital portosystemic shunt (CPSS) characterized by strongly reduced liver growth and function.
  
  
  METHODS
  Recombinant HGF (rHGF), 200 μg/kg, was given twice daily during 3 weeks by an intravenous injection in six dogs with CPSS. Liver volumes were determined by computed tomography before and at 1, 2, 3 and 7 weeks after the initiation of treatment. Portosystemic shunting was evaluated with an ammonia tolerance test and liver portal perfusion was quantified with scintigraphy. Simultaneously, blood parameters for liver function were assayed and liver biopsies were taken for histology, immunohistochemistry and gene-expression measurements.
  
  
  RESULTS
  During 3 weeks of HGF treatment, hepatocyte proliferation increased and an increase in liver volume up to 44% was seen, persisting in two dogs up to 4 weeks after the termination of treatment. Ki-67 expression, gene expression of E2F1 and CDC6, phosphorylated-c-MET and phosphorylated-ERK1/2 protein levels confirmed increased hepatocyte proliferation and HGF signalling. The aberrant portal perfusion did not change during treatment.
  
  
  CONCLUSIONS
  Transient in vivo liver growth is shown using CPPS as a naturally occurring large animal model, indicating the therapeutic potential of HGF in liver disease.
authors: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands. h.s.kruitwagen@uu.nl
authors: Hedwig S
authors: HS
authors: Kruitwagen
authors: Brigitte
authors: B
authors: Arends
authors: Bart
authors: B
authors: Spee
authors: Bas
authors: B
authors: Brinkhof
authors: Ted S G A M
authors: TS
authors: van den Ingh
authors: Victor P M G
authors: VP
authors: Rutten
authors: Louis C
authors: LC
authors: Penning
authors: Tania
authors: T
authors: Roskams
authors: Jan
authors: J
authors: Rothuizen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054893:Cone-Beam Computed Tomography; D017931:DNA Primers / Q000235:genetics; D004285:Dogs; D050687:E2F1 Transcription Factor / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage / Q000494:pharmacology*; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D019394:Ki-67 Antigen / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000254:growth & development* / Q000601:surgery; D016133:Polymerase Chain Reaction; D011170:Portasystemic Shunt, Surgical; D011877:Radionuclide Imaging; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D050687:E2F1 Transcription Factor; D019394:Ki-67 Antigen; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor