Surgery
Volume 146, Issue 2 , Pages 181-189, August 2009

Donor graft interferon regulatory factor-1 gene transfer worsens liver transplant ischemia/reperfusion injury

  • Kee-Hwan Kim, MD

      Affiliations

    • Starzl Transplant Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA
    • Department of Surgery, The Catholic University of Korea, Seoul, Korea
    • ,
  • Rajeev Dhupar, MD

      Affiliations

    • Starzl Transplant Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA
    • ,
  • Shinya Ueki, MD

      Affiliations

    • Starzl Transplant Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA
    • ,
  • Jon Cardinal, MD

      Affiliations

    • Starzl Transplant Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA
    • ,
  • Pinhua Pan, MD

      Affiliations

    • Starzl Transplant Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA
    • ,
  • Zongxian Cao, MD

      Affiliations

    • Starzl Transplant Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA
    • ,
  • Sung W. Cho, MD

      Affiliations

    • Starzl Transplant Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA
    • ,
  • Noriko Murase, MD

      Affiliations

    • Starzl Transplant Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA
    • ,
  • Allan Tsung, MD

      Affiliations

    • Starzl Transplant Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA
    • ,
  • David A. Geller, MD

      Affiliations

    • Starzl Transplant Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA
    • Corresponding Author InformationReprint requests: David A. Geller, MD, UPMC Liver Cancer Center, 3471 Fifth Avenue, Kaufmann Medical Building, Suite 300, Pittsburgh, PA 15213.

Accepted 12 June 2009.

Background

Liver ischemia and reperfusion (IR) injury is a phenomenon that leads to graft dysfunction after liver transplantation. Understanding the molecular mechanisms behind this process is crucial to developing strategies to prevent short- and long-term graft dysfunction. The purpose of this study was to explore the role of the transcription factor interferon regulatory factor-1 (IRF-1) in a model of orthotopic rat liver transplantation.

Methods

Orthotopic syngeneic LEW rat liver transplantation (OLT) was performed after 18 or 3 hours preservation in cold University of Wisconsin solution. Adenovirus-expressing IRF-1 (AdIRF-1) or control gene vector (Adnull) was delivered to the liver by donor intravenous pretreatment 4 days before graft harvesting. Uninfected grafts also served as controls. Recipients were humanely killed 1–24 hours post-transplantation.

Results

Rats that underwent OLT with long-term preserved grafts (18 hours) displayed increased hepatic nuclear expression of IRF-1 protein at 1 and 3 hours. Rats pretreated with AdIRF-1 before transplantation had elevated alanine aminotransferase levels and increased expression of interferon (IFN)-β, IFN-γ, interleukin-12, and inducible nitric oxide synthase in the short-term period (3 hours) when compared with donor livers pretreated with Adnull. AdIRF-1 pretreated donor livers also exhibited increased susceptibility to early apoptosis in the transplanted grafts as shown by increased terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining and expression of cleaved caspase-3. Additionally, AdIRF-1 pretreated donor livers had increased activation of the MAP kinase Jun N-terminal kinase as compared with Adnull pretreated donor livers.

Conclusion

IRF-1 is an important regulator of IR injury after OLT in rats. Targeting of IRF-1 may be a potential strategy to ameliorate ischemic liver injury after transplantation to minimize organ dysfunction.

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 Presented at the 2009 Academic Surgical Congress.

 Supported by the Howard Hughes Medical Institute Physician-Student Award (A.T.), American College of Surgeons Research Fellowship (A.T.), NIH grant DK54232 (N.M.), NIH grant R01-GM52021 and R01-DK62313 (D.A.G.).

PII: S0039-6060(09)00346-8

doi:10.1016/j.surg.2009.06.011

Surgery
Volume 146, Issue 2 , Pages 181-189, August 2009

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