Recombinant hepatocyte growth factor treatment in a canine model of congenital liver hypoplasia

Authors

  • Hedwig S. Kruitwagen,

    1. Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
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    • *Contributed equally.

  • Brigitte Arends,

    1. Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
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    • *Contributed equally.

  • Bart Spee,

    1. Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
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  • Bas Brinkhof,

    1. Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
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  • Ted S.G.A.M. van den Ingh,

    1. TCCI Consultancy BV, Utrecht, the Netherlands
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  • Victor P.M.G. Rutten,

    1. Department of Infectious Diseases and Immunology, Division of Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
    2. Department of Veterinary Tropical Diseases, Faculty of Veterinary Science, University of Pretoria, Onderstepoort, South Africa
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  • Louis C. Penning,

    1. Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
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  • Tania Roskams,

    1. Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium
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  • Jan Rothuizen

    1. Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
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Correspondence
Hedwig S. Kruitwagen, Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, 3584CM Utrecht, the Netherlands
Tel: +31 2534647
Fax: +31 30 2518126
e-mail: h.s.kruitwagen@uu.nl

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.

Aim: 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.

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