Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury

Amersi, Farin; Buelow, Roland; Kato, Hirohisa; Ke, Bibo; Coito, Ana J.; Shen, Xiu Da; Zhao, Delai; Zaky, Joseph; Melinek, Judy; Lassman, Charles; Kolls, Jay; Alam, Jawed; Ritter, Thomas; Volk, Hans‐Dieter; Farmer, Douglas G.; Ghobrial, Rafik M.; Busuttil, Ronald W.; Kupiec‐Weglinski, Jerzy W.

doi:10.1172/jci7903

Cited by 472 publications

(351 citation statements)

References 49 publications

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“…Interestingly, intrahepatic disruption of TLR4 signaling was sufficient to prevent liver IRI and did not require adjunctive treatment. This is reminiscent of our previous experiments utilizing antioxidant HO-1, 29 antiapoptotic Bag-1, 30 and Th2-type cytokine IL-13 21 gene therapy approaches in cold ischemia rat OLT models. The question arises as to how the disruption of local TLR4 signaling prevents the host immune repertoire from destroying the transplanted liver.…”

Section: Discussionmentioning

confidence: 55%

Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model

Shen

Zhai

et al. 2007

Liver Transpl

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This study analyzes how toll-like receptor 4 (TLR4) signaling in the donor organ affects the ischemia and reperfusion injury (IRI) sequel following liver transplantation. Isogenic orthotopic liver transplantations (OLTs) with rearterialization were performed in groups of wild-type (WT) and TLR4 knockout (KO) mice after donor liver preservation in University of Wisconsin solution at 4°C for 24 hours. Unlike WT OLTs, TLR4-deficient OLTs transplanted to either WT or TLR4 KO recipients suffered significantly less hepatocellular damage, as evidenced by serum alanine aminotransferase levels, and histological Suzuki's grading of liver IRI. Disruption of TLR4 signaling in OLTs decreased local neutrophil sequestration, CD4 ϩ T cell infiltration, interferon (IFN)-␥-inducible protein 10 (CXCL10) and an intercellular adhesion molecule (ICAM-1), as well as tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, IL-2, and IFN-␥, yet increased IL-4 and IL-10 expression. The well-functioning OLTs from TLR4 KO donors revealed attenuated activity of capase-3, and enhanced heme oygenase-1 (HO-1) expression, along with decreased levels of apoptotic endothelial cells/hepatocytes, as compared with WT OLTs with intact TLR4 signaling. Thus, the functional sentinel TLR4 complex in the donor organ plays a key role in the mechanism of hepatic IRI after OLT. Disruption of TLR4 pathway downregulated the early proinflammatory responses and ameliorated hepatic IRI. These results provide the rationale to locally modify innate TLR4 signaling in the donor organ to more efficiently control the adaptive posttransplantation IRI-dependent responses. Liver Transpl 13:1435-1443, 2007. © 2007 AASLD. Received February 7, 2007 accepted May 19, 2007.The ischemia and reperfusion injury (IRI), an antigenindependent event, is an unavoidable consequence of liver transplantation. The IRI causes up to 10% of early organ failure, and can lead to a higher incidence of both acute and chronic rejection. Indeed, IRI is more frequently observed with the use of marginal donors or following prolonged cold ischemia times. 1-3 Moreover, IRI contributes to the shortage of livers available for transplantation because of the higher susceptibility of marginal organs to the ischemic insult. Thus, minimizing the impact of IRI could significantly increase the number of patients successfully undergoing liver transplantation. The mechanisms of IRI include activation of Kupffer cells with production of reactive oxygen species, upregulation of the inducible nitric oxide synthase, release of proinflammatory cytokines, increased expres-

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Section: Discussionmentioning

confidence: 55%

Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model

Shen

Zhai

et al. 2007

Liver Transpl

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“…Up-regulation of these genes blocks activation of the transcription factor NF-B in endothelial cell cultures, and thereby suppresses induction of proinflammatory genes in Ag-activated endothelium (21,34). We have recently shown striking cytoprotective effects of HO-1 overexpression in rat liver models of ischemia/reperfusion injury (35), consistent with other reports documenting the role of HO-1 overexpression in xenograft "accommodation" (36), prolonged allografts survival (37), or prevention of transplant arteriosclerosis and interstitial fibrosis characteristic for chronic rejection (38). Moreover, in a parallel Fas ligand gene therapy study in rat renal allografts (39), we have recently detected down-regulation of Bag-1, a prototype of a novel type of Bcl-2-binding anti-cell death gene, which has been implicated in T cell activation-induced apoptosis (40).…”

Section: Discussionmentioning

confidence: 96%

Regulatory Cells Potentiate the Efficacy of IL-4 Gene Transfer by Up-Regulating Th2-Dependent Expression of Protective Molecules in the Infectious Tolerance Pathway in Transplant Recipients

Ritter

Kato

et al. 2000

The Journal of Immunology

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We have previously shown that the tolerant state in allograft recipients can be maintained and perpetuated by an “infectious” T cell-dependent regulatory mechanism. Hence, 1) treatment of LEW rats with RIB-5/2, a CD4 nondepleting mAb, produces indefinite survival of LBNF1 cardiac allografts; 2) donor-specific tolerance can be then transferred by spleen cells into new cohorts of test allograft recipients; and 3) putative regulatory CD4+ Th2-like cells are instrumental in this tolerance model. We now report on studies aimed at exposing mechanisms underlying the infectious tolerance pathway, with emphasis on the interactions between intragraft adenovirus-IL-4 gene transfer and systemic infusion of regulatory cells from tolerant hosts. Unlike individual treatment regimens, adjunctive therapy with adenovirus-IL-4 and suboptimal doses of regulatory spleen cells was strongly synergistic and extended donor-type test cardiac allograft survival to about 2 mo. RT-PCR-based expression of intragraft mRNA coding for IL-2 and IFN-γ remained depressed, whereas that of IL-4 and IL-10 reciprocally increased selectively in the combined treatment group, data supported by ELISA studies. In parallel, only adjunctive treatment triggered intragraft induction of molecules with anti-oxidant (HO-1) and anti-apoptotic (Bcl-xL/Bag-1) but not with pro-apoptotic (CPP-32) functions, both in the early and late posttransplant phases. Hence, systemic infusion of regulatory cells potentiates the effects of local adenovirus-IL-4 gene transfer in transplant recipients. Th2-driven up-regulation of protective molecule programs at the graft site, such as of anti-oxidant HO-1 and/or anti-apoptotic Bcl-xL and Bag-1, may contribute, at least in part, to the maintenance of the infectious tolerance pathway in transplant recipients.

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“…[16][17][18][28][29][30] In most of these studies, the introduction of HO-1 in grafts is achieved by metalloporphyrin (mainly cobalt protoporphyrin), gene transfer or transgenic engineering. These methods need to treat grafts in advance or are limited on transgenic animal models.…”

Section: Discussionmentioning

confidence: 99%

“…Copious studies show that HO-1 and its products can maintain cellular homeostasis based on its anti-inflammatory, 11 antioxidative 12,13 and/or antiapoptotic 14,15 properties. In different models of transplantation, induction of HO-1 can protect grafts from I/R injury, [16][17][18] acute 14,19 and chronic rejection. 20 Protein transduction domains (PTDs) are short peptides which can freely pass through cell membrane independent of classical receptors or endocytosis.…”

Section: Introductionmentioning

confidence: 99%

A cell penetrating heme oxygenase protein protects heart graft against ischemia/reperfusion injury

Ma¹,

Lau

Obed³

et al. 2008

Gene Ther

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Ischemia/reperfusion (I/R) injury is an unavoidable barrier that significantly affects outcome of solid organ transplantation. Here, we establish a protein transduction system to extend graft preservation time and to prevent I/R injury in heart transplantation. We generated a recombinant heme oxygenase-1 (HO-1) protein containing a modified protein transduction domain (PTD). PTD could cross cover cell membrane and carry target molecule to parenchymal cells of cold-preserved heart grafts. The newly generated PTD-HO-1 protein localized mainly in subcellular membrane organelle and nucleus after delivery that significantly prolonged cold preservation of heart grafts. This effect was associated with significantly less endothelial cell activation, less neutrophil and macrophage infiltration in PTD-HO-1-transduced heart grafts after reperfusion as compared with controls. In addition, transduction of PTD-HO-1 protein to heart graft significantly suppressed the I/R injury-associated myocardiocyte apoptosis. The infarct areas of heart graft after I/R injury were significantly reduced after PTD-HO-1 protein treatment. We show here for the first time that PTD can maintain its biological activities during cold preservation. Transduction of cell penetrating HO-1 protein significantly prolongs the cold preservation time and protects the graft from the I/R injury. This approach represents a novel method for the improvement of the overall outcome of organ transplantation.

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Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury

Cited by 472 publications

References 49 publications

Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model

Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model

Regulatory Cells Potentiate the Efficacy of IL-4 Gene Transfer by Up-Regulating Th2-Dependent Expression of Protective Molecules in the Infectious Tolerance Pathway in Transplant Recipients

A cell penetrating heme oxygenase protein protects heart graft against ischemia/reperfusion injury

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