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Native macrophages genetically modified to express heme oxygenase 1 protect rat liver transplants from ischemia/reperfusion injury
Author(s) -
Shen XiuDa,
Ke Bibo,
Uchida Yoichiro,
Ji Haofeng,
Gao Feng,
Zhai Yuan,
Busuttil Ronald W.,
KupiecWeglinski Jerzy W.
Publication year - 2011
Publication title -
liver transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.814
H-Index - 150
eISSN - 1527-6473
pISSN - 1527-6465
DOI - 10.1002/lt.22214
Subject(s) - heme oxygenase , medicine , proinflammatory cytokine , small interfering rna , liver injury , tumor necrosis factor alpha , microbiology and biotechnology , reperfusion injury , ex vivo , transfection , transplantation , immunology , pharmacology , cancer research , heme , chemistry , inflammation , biology , ischemia , biochemistry , in vitro , gene , enzyme
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. Liver Transpl 17:201–210, 2011. © 2011 AASLD.