Donor graft adenoviral iNOS gene transfer ameliorates rat liver transplant preservation injury and improves survival.
The exact role of inducible NOS (iNOS) in liver ischemia/reperfusion (I/R) injury is controversial. This study was designed to investigate whether donor liver pretreatment with adenovirus encoding iNOS (AdiNOS) ameliorates I/R injury associated with liver transplantation. Orthotopic syngeneic LEW rat liver transplantation (OLT) was performed after 18 or 24 hours' preservation in cold UW. AdiNOS or control gene vector (AdLacZ) was delivered to the liver by donor intravenous pretreatment 4 days before graft harvesting. Uninfected grafts also served as control. Recipients were sacrificed 1 to 48 hours posttransplantation. An abundant hepatic iNOS protein expression and marked serum NO elevation was observed in the AdiNOS-treated group, without affecting endothelial nitric oxide synthase (eNOS) expression, before harvesting and after OLT. AdiNOS pretreatment markedly improved liver function assessed by serum aspartate aminotransferase/alanine aminotransferase levels and reduced liver necrosis formation. AdiNOS treatment also was associated with reduced ICAM-1 mRNA expression and neutrophil accumulation in the liver graft after OLT compared with untransfected or AdLacZ-treated group. Furthermore, AdiNOS delivery significantly improved transplant survival, compared with AdLacZ or saline controls. AdiNOS pretreatment did not attenuate I/R-induced apoptotic cell death in the liver graft. Administration of a selective inhibitor for iNOS abrogated the protection afforded by AdiNOS pretreatment. In conclusion, donor pretreatment with AdiNOS led to improved liver graft injury and posttransplantation survival. Downregulation of ICAM-1 mRNA and neutrophil infiltration may be associated with the mechanisms by which AdiNOS pretreatment confer the protection against transplant-associated hepatic I/R injury.
Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Takashi
T
Kaizu
Atsushi
A
Ikeda
Atsunori
A
Nakao
Yoshihito
Y
Takahashi
Allan
A
Tsung
Junichi
J
Kohmoto
Hideyoshi
H
Toyokawa
Lifang
L
Shao
Brian T
BT
Bucher
Koji
K
Tomiyama
Michael A
MA
Nalesnik
Noriko
N
Murase
David A
DA
Geller
D000256:Adenoviridae; D000818:Animals; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006085:Graft Survival; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008107:Liver Diseases / Q000209:etiology / Q000517:prevention & control; D016031:Liver Transplantation / Q000009:adverse effects* / Q000276:immunology; D008297:Male; D020556:Neutrophil Infiltration; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D011300:Preoperative Care; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D019737:Transplants
D018799:Intercellular Adhesion Molecule-1; D052247:Nitric Oxide Synthase Type II