Donor graft adenoviral iNOS gene transfer ameliorates rat liver transplant preservation injury and improves survival

Takashi Kaizu, Atsushi Ikeda, Atsunori Nakao, Yoshihito Takahashi, Allan Tsung, Junichi Kohmoto, Hideyoshi Toyokawa, Lifang Shao, Brian T. Bucher, Koji Tomiyama, Michael A. Nalesnik, Noriko Murase, David A. Geller

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)464-473
Number of pages10
JournalHepatology
Volume43
Issue number3
DOIs
Publication statusPublished - Mar 2006
Externally publishedYes

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Adenoviridae
Transplants
Liver
Wounds and Injuries
Genes
Reperfusion Injury
Intercellular Adhesion Molecule-1
Liver Transplantation
Messenger RNA
Neutrophil Infiltration
Nitric Oxide Synthase Type III
Nitric Oxide Synthase Type II
Aspartate Aminotransferases
Serum
Alanine Transaminase
Reperfusion
Neutrophils
Cell Death
Necrosis
Down-Regulation

ASJC Scopus subject areas

  • Hepatology

Cite this

Donor graft adenoviral iNOS gene transfer ameliorates rat liver transplant preservation injury and improves survival. / Kaizu, Takashi; Ikeda, Atsushi; Nakao, Atsunori; Takahashi, Yoshihito; Tsung, Allan; Kohmoto, Junichi; Toyokawa, Hideyoshi; Shao, Lifang; Bucher, Brian T.; Tomiyama, Koji; Nalesnik, Michael A.; Murase, Noriko; Geller, David A.

In: Hepatology, Vol. 43, No. 3, 03.2006, p. 464-473.

Research output: Contribution to journalArticle

Kaizu, T, Ikeda, A, Nakao, A, Takahashi, Y, Tsung, A, Kohmoto, J, Toyokawa, H, Shao, L, Bucher, BT, Tomiyama, K, Nalesnik, MA, Murase, N & Geller, DA 2006, 'Donor graft adenoviral iNOS gene transfer ameliorates rat liver transplant preservation injury and improves survival', Hepatology, vol. 43, no. 3, pp. 464-473. https://doi.org/10.1002/hep.21067
Kaizu, Takashi ; Ikeda, Atsushi ; Nakao, Atsunori ; Takahashi, Yoshihito ; Tsung, Allan ; Kohmoto, Junichi ; Toyokawa, Hideyoshi ; Shao, Lifang ; Bucher, Brian T. ; Tomiyama, Koji ; Nalesnik, Michael A. ; Murase, Noriko ; Geller, David A. / Donor graft adenoviral iNOS gene transfer ameliorates rat liver transplant preservation injury and improves survival. In: Hepatology. 2006 ; Vol. 43, No. 3. pp. 464-473.
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abstract = "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.",
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AU - Tsung, Allan

AU - Kohmoto, Junichi

AU - Toyokawa, Hideyoshi

AU - Shao, Lifang

AU - Bucher, Brian T.

AU - Tomiyama, Koji

AU - Nalesnik, Michael A.

AU - Murase, Noriko

AU - Geller, David A.

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N2 - 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.

AB - 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.

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