Skip to main content

Advertisement

SpringerLink
Log in

Treating liver cirrhosis in dogs with hepatocyte growth factor gene therapy via the hepatic artery

  • Original article
  • Published:
Journal of Hepato-Biliary-Pancreatic Surgery

Abstract

Background/purpose

Liver cirrhosis, an irreversible result of chronic liver disease, has had no effective therapy except liver transplantation. We previously reported successful therapy of liver cirrhosis in rats using the hepatocyte growth factor gene. We presently performed hepatocyte growth factor gene therapy in dogs with liver cirrhosis to examine the feasibility for clinical use.

Methods

Liver cirrhosis was established in beagles by administrating dimethylnitrosamine. Naked human hepatocyte growth factor gene or naked LacZ gene was injected repeatedly into livers via the hepatic artery using a porter catheter in dogs with cirrhosis.

Results

Human hepatocyte growth factor gene expression was detected in livers by immunohistochemical staining and an enzyme-linked immunosorbent assay. Serum liver function test results improved with hepatocyte growth factor gene therapy, which also inhibited hepatic transforming growth factor-β1expression and reversed fibrosis in cirrhotic liver, improving survival of the dogs.

Conclusion

As naked hepatocyte growth factor gene therapy via the hepatic artery proved simple, safe, and effective in larger animals with cirrhosis, this therapy may be clinically applicable.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

HGF:

Hepatocyte growth factor

TGF-β1:

Transforming growth factor-β1

DMN:

Dimethylnitrosamine

References

  1. Conn HO, Attenbury CE. Liver cirrhosis. In: Schiff L, Schiff E, editors. Disease of the liver. Philadelphia: Lippencott; 1993. p. 875–941.

    Google Scholar 

  2. Strong R. Living-donor liver transplantation: an overview. J Hepatobiliary Pancreat Surg. 2006;13:370–7.

    Article  PubMed  Google Scholar 

  3. Sugawara Y, Mkuuchi M. Liver transplantation for hepatitis B-related cirrhosis: recent advances. J Hepatobiliary Pancreat Surg. 2006;13:378–81.

    Article  PubMed  Google Scholar 

  4. Marubashi S, Dono K, Miyamoto A, Takeda Y, Nagano H, Umeshita K, et al. Liver transplantation for hepatitis C. J Hepatobiliary Pancreat Surg. 2006;13:382–92.

    Article  PubMed  Google Scholar 

  5. Miyazawa K, Tsubouchi H, Naka D, Takahashi K, Okigaki M, Arakaki N, et al. Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor. Biochem Biophys Res Commun. 1989;163:967–73.

    Article  PubMed  CAS  Google Scholar 

  6. Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, et al. Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989;342:440–3.

    Article  PubMed  CAS  Google Scholar 

  7. Matsumoto K, Nakamura T. Hepatocyte growth factor: molecular structure, roles in liver regeneration, and other biological functions. Crit Rev Oncog. 1992;3:27–54.

    PubMed  CAS  Google Scholar 

  8. Ueki T, Kaneda Y, Tsutsui H, Nakanishi K, Sawa Y, Morishita R, et al. Hepatocyte growth factor gene therapy of liver cirrhosis in rats. Nat Med. 1999;5:226–30.

    Article  PubMed  CAS  Google Scholar 

  9. Kaneda Y, Iwaki K, Uchida T. Increased expression of DNA cointroduced with nuclear protein in adult rat liver. Science. 1989;243:375–8.

    Article  PubMed  CAS  Google Scholar 

  10. Liu F, Song Y, Liu D. Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Ther. 1999;6:1258–66.

    Article  PubMed  CAS  Google Scholar 

  11. Madden J, Gertman PM, Peacock EE. Dimethylnitrosamine-induced hepatic cirrhosis: a new canine model of an ancient human disease. Surgery. 1970;68:260–8.

    PubMed  CAS  Google Scholar 

  12. Mwanza T, Miyamoto T, Okumura M, Kadosawa T, Fujinaga T. Ultrasonography, biochemical and hematological profiles in liver disease caused by intravenous administration of dimethylnitrosamine in dogs. Jpn J Vet Res. 1997;45:153–61.

    PubMed  CAS  Google Scholar 

  13. Hirano T, Fujimoto J, Ueki T, Yamamoto H, Takeuchi M, Okamoto E, et al. HVJ-liposome mediated gene transfer into hepatocyte in vivo. J Hepatol. 1998;29:910–4.

    Article  PubMed  CAS  Google Scholar 

  14. Kivirikko KI, Laitinen O, Prockop DJ. Modifications of specific assay for hydroxyproline in urine. Anal Biochem. 1967;19:249–55.

    Article  PubMed  CAS  Google Scholar 

  15. Bros P, Miller CM. Hepatocyte growth factor: a multifunctional cytokine. Lancet. 1995;345:293–5.

    Article  Google Scholar 

  16. Mizuno S, Kurosawa T, Matsumoto K, Nakamura T. Hepatocyte growth factor prevents renal fibrosis and dysfunction in a mouse model of chronic renal disease. J Clin Invest. 1998;101:1827–34.

    Article  PubMed  CAS  Google Scholar 

  17. Watanabe M, Ebina M, Orson FM, Nakanuma A, Kubota K, Kinoue O, et al. Hepatocyte growth factor to alveolar septa for effective suppression of lung fibrosis. Mol Ther. 2005;12:58–67.

    Article  PubMed  CAS  Google Scholar 

  18. Ferry N, Duplessis O, Houssin D, Dangos O, Heard JM. Retroviral-mediated gene transfer into hepatocytes in vivo. Proc Natl Acad Sci. 1991;88:8377–81.

    Article  PubMed  CAS  Google Scholar 

  19. Mulligan RC. The basic science of gene therapy. Science. 1993;260:926–32.

    Article  PubMed  CAS  Google Scholar 

  20. Wolff JA, Malone RW, Williams P, Chong W, Acsadi G, Jani A, et al. Direct gene transfer into mouse muscle in vivo. Science. 1990;23(247):1465–8.

    Article  Google Scholar 

  21. Miller AD. Putting muscle to work for gene therapy. Nat Med. 1997;3:278–9.

    Article  PubMed  CAS  Google Scholar 

  22. Zhang G, Vargo D, Budker V, Armstrong N, Knechtle S, Wolff JA. Expression of naked plasmid DNA injected into afferent and efferent vessels of rodent and dog livers. Hum Gene Ther. 1997;8:1763–72.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo, 663-8501, Japan

    Kiyoshi Horiguchi, Tadamichi Hirano, Takahiro Ueki, Kazuhide Hirakawa & Jiro Fujimoto

Authors
  1. Kiyoshi Horiguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tadamichi Hirano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takahiro Ueki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazuhide Hirakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiro Fujimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jiro Fujimoto.

About this article

Cite this article

Horiguchi, K., Hirano, T., Ueki, T. et al. Treating liver cirrhosis in dogs with hepatocyte growth factor gene therapy via the hepatic artery. J Hepatobiliary Pancreat Surg 16, 171–177 (2009). https://doi.org/10.1007/s00534-008-0029-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00534-008-0029-7

Keywords

Search

Navigation