Native macrophages genetically modified to express heme oxygenase 1 protect rat liver transplants from ischemia/reperfusion injury

Xiu Da Shen, Bibo Ke, Yoichiro Uchida, Haofeng Ji, Feng Gao, Yuan Zhai, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


We investigated whether native macrophages overexpressing heme oxygenase 1 (HO-1) could protect rat orthotopic liver transplant (OLT) against cold ischemia/reperfusion injury (IRI). Livers from Sprague-Dawley rats were stored at 4°C in University of Wisconsin solution for 24 hours, and then they were transplanted into syngeneic recipients. Bone marrow-derived macrophages (BMMs) that were transfected ex vivo with heme oxygenase 1 adenovirus (Ad-HO-1), β-galactosidase adenovirus (Ad-β-gal), or HO-1 small interfering RNA (siRNA) were infused directly into the OLT before reperfusion. Controls were OLT conditioned with unmodified or scrambled siRNA-transfected cells. The transfer of Ad-HO-1/BMMs increased the survival of OLT to 100% (versus 40%-50% for controls) and decreased serum alanine aminotransferase levels and histological features of hepatocellular damage. In contrast, an infusion of macrophages transfected with HO-1 siRNA/Ad-β-gal failed to affect IRI. Gene therapy-induced HO-1 suppressed toll-like receptor 4 expression, decreased expression of proinflammatory tumor necrosis factor α, interleukin-1β, monocyte chemoattractant protein 1, and chemokine (C-X-C motif) ligand 10, and attenuated endothelial intercellular cell adhesion molecule 1 expression with resultant diminished OLT leukocyte sequestration. Although Ad-HO-1/BMMs decreased the frequency of apoptotic cells positive for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and ameliorated caspase-3 activity, the expression of interleukin-10 and antiapoptotic B cell lymphoma 2/B cell lymphoma extra large increased in well-functioning OLT. Thus, the transfer of native macrophages transfected ex vivo with HO-1 can rescue rat iso-OLT from IRI. Our study validates a novel and clinically attractive concept: native macrophages transfected ex vivo with the antioxidant HO-1 can be applied at the time of transplantation to mitigate otherwise damaging antigen-independent liver inflammation and injury resulting from the peritransplant harvesting insult. If this new, refined strategy is proven to be effective in allo-OLT recipients, it should be considered in clinical settings to increase the supply of usable donor organs and ultimately improve the overall success of liver transplantation

Original languageEnglish (US)
Pages (from-to)201-210
Number of pages10
JournalLiver Transplantation
Issue number2
StatePublished - Feb 2011

ASJC Scopus subject areas

  • Surgery
  • Hepatology
  • Transplantation


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