Donor graft interferon regulatory factor-1 gene transfer worsens liver transplant ischemia/reperfusion injury.
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)-beta, IFN-gamma, 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.


CONCLUSIONS
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.
Kim
Kee-Hwan
KH
Starzl Transplant Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Dhupar
Rajeev
R
Ueki
Shinya
S
Cardinal
Jon
J
Pan
Pinhua
P
Cao
Zongxian
Z
Cho
Sung W
SW
Murase
Noriko
N
Tsung
Allan
A
Geller
David A
DA
D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D016031:Liver Transplantation; D020935:MAP Kinase Signaling System; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D014019:Tissue Donors
D018836:Inflammation Mediators; D050856:Interferon Regulatory Factor-1