Caspase 3 Inhibition Improves Survival and Reduces Early Graft Injury After Ischemia and Reperfusion in Rat Liver Transplantation

Mueller, Thomas; Kienle, Klaus; Beham, A.; Geissler, Edward K.; Jauch, Karl Walter; Rentsch, Markus

doi:10.1097/01.tp.0000141095.06273.10

Cited by 49 publications

(36 citation statements)

References 42 publications

(50 reference statements)

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“…Blocking the early pathway of apoptosis can prevent hepatic injury and improve animal survival after reperfusion. In fact, inhibition of caspase-3 improves survival and reduces early graft injury after IRI in OLT (41). Furthermore, apoptosis is controlled through the expression of specific genes.…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization of Rat Leukocyte P-Selectin Glycoprotein Ligand-1 and Effect of Its Blockade: Protection from Ischemia-Reperfusion Injury in Liver Transplantation

Tsuchihashi

Fondevila

Shaw³

et al. 2006

The Journal of Immunology

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P-selectin glycoprotein ligand-1 (PSGL-1) mediates the initial tethering of leukocytes to activated platelets and endothelium. We report molecular cloning and characterization of the rat PSGL-1 gene. A neutralizing Ab was generated, and its binding epitope was mapped to the N-terminal binding region of rat PSGL-1. We examined the effects of early PSGL-1 blockade in rat liver models of cold ischemia, followed by ex vivo reperfusion or transplantation (orthotopic liver transplantation (OLT)) using an anti-PSGL-1 Ab with diminished Fc-mediated effector function. In the ex vivo hepatic cold ischemia and reperfusion model, pretreatment with anti-PSGL-1 Ab improved portal venous flow, increased bile production, and decreased hepatocellular damage. Rat pretreatment with anti-PSGL-1 Ab prevented hepatic insult in a model of cold ischemia, followed by OLT, as assessed by 1) decreased hepatocellular damage (serum glutamic oxaloacetic transaminase/glutamic-pyruvic transaminase levels), and ameliorated histological features of ischemia/reperfusion injury, consistent with extended OLT survival; 2) reduced intrahepatic leukocyte infiltration, as evidenced by decreased expression of P-selectin, ED-1, CD3, and OX-62 cells; 3) inhibited expression of proinflammatory cytokine genes (TNF-α, IL-1β, IL-6, IFN-γ, and IL-2); and 4) prevented hepatic apoptosis accompanied by up-regulation of antiapoptotic Bcl-2/Bcl-xL protective genes. Thus, targeting PSGL-1 with a blocking Ab that has diminished Fc-mediated effector function is a simple and effective strategy that provides the rationale for novel therapeutic approaches to maximize the organ donor pool through the safer use of liver transplants despite prolonged periods of cold ischemia.

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Section: Discussionmentioning

confidence: 99%

Molecular Characterization of Rat Leukocyte P-Selectin Glycoprotein Ligand-1 and Effect of Its Blockade: Protection from Ischemia-Reperfusion Injury in Liver Transplantation

Tsuchihashi

Fondevila

Shaw³

et al. 2006

The Journal of Immunology

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“…Although apoptosis of graft parenchymal cells is documented in I/R injury, it is unclear whether apoptosis is the primary event associated with I/R injury in organ transplantation or if it is induced secondarily following the inflammatory response of I/R injury. Thus, the role of apoptosis during I/R injury needs to be studied further; however, inhibition of the cell death pathway has been shown to be an important strategy for the prevention of I/R injury [116,117], suggesting that apoptosis could be equally important as necrosis in the development of graft injury and dysfunction following I/R injury.…”

Section: Co Inhibits Apoptosismentioning

confidence: 99%

Protective effect of carbon monoxide in transplantation

Nakao¹

2006

J Cell Mol Med

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During the last decades due to the development of new immunosuppressive agents and improvements in organ preservation methods, surgical techniques, and postoperative care, organ transplantation has become an ultimate therapeutic option for irreversible organ failure. Early graft survival has significantly improved; however, the long-term outcome remains unsatisfactory. Multiple factors, both immunogenic and non-immunogenic etiologies, are involved in the deterioration of the allografts, and the recent use of expanded criteria donors to overcome the organ shortage may also contribute to the graft losses. Carbon monoxide (CO) is commonly viewed as a poison in high concentrations due to its ability to interfere with oxygen delivery. However, CO is endogenously produced in the body as a byproduct of heme degradation by the heme oxygenase (HO) and has recently received notable attention as a gaseous regulatory molecule. In fact, an augmentation of endogenous CO by induction of HO-1 or exogenously added CO is known to have potent cytoprotective effects in various disease models. Several recent reports have demonstrated that CO provides potent cytoprotective effects in the field of organ and cell transplantation. CO is able to prevent ischemia/reperfusion injury, allograft rejection, and xenograft rejection via its anti-inflammatory, anti-apoptotic and anti-proliferation effects, suggesting that CO might be a valuable therapeutic option in the field of transplantation. Based on the recent advancement of our understanding of CO as a new therapeutic molecule, this review attempts to summarize the functional roles as well as biological and molecular mechanisms of CO in transplantation and discusses potential CO application to the clinical transplant setting.

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“…Caspase-3 in particular is the main effector molecule of apoptosis and a selective inhibitor in the IR process that effectively reduces hepatic IRI. 38 Intrahepatic caspase-3-like activity was measured after IR, as caspase-3 activation plays a pivotal role in tissue damage. The hepatic caspase activity in IRtreated animals was significantly increased in comparison to nonischemic animals.…”

Section: Effect Of Xanthohumol (1) On Expression Of Antiapoptoticmentioning

confidence: 99%

Antioxidant Effects of Xanthohumol and Functional Impact on Hepatic Ischemia−Reperfusion Injury

et al. 2009

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Therapeutic effects of dietary flavonoids have been attributed mainly to their antioxidant capacity. Xanthohumol (1), a prominent flavonoid of the hop plant, Humulus lupulus, was investigated for its antioxidant potential and for its effect on NF-κB activation. To examine the biological relevance of 1, a hepatic ischemia/reperfusion model was chosen as a widely accepted model of oxidative stress generation. The impact of 1 on endogenous antioxidant systems, on the NF-κB signal transduction pathway as well as on apoptotic parameters, and on hepatic tissue damage was evaluated. Compound 1 markedly decreased the level of reactive oxygen species in vitro. Furthermore, levels of enzymatic and nonenzymatic antioxidants were restored after pretreatment in postischemic hepatic tissue, and lipid peroxidation was attenuated. NF-κB activity was reduced in vitro as well as in hepatic tissue after ischemia/reperfusion upon pretreatment with 1. In addition, the phosphorylation of Akt was markedly inhibited. Surprisingly, 1 decreased the expression of the antiapoptotic protein Bcl-X and increased caspase-3 like-activity, a proapoptotic parameter. Moreover, hepatic tissue damage as well as TNF-α levels increased in xanthohumol-pretreated liver tissue after ischemia/reperfusion. In summary, xanthohumol did not protect against ischemia/reperfusion injury in rat liver, despite its antioxidant and NF-κB inhibitory properties.

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Caspase 3 Inhibition Improves Survival and Reduces Early Graft Injury After Ischemia and Reperfusion in Rat Liver Transplantation

Cited by 49 publications

References 42 publications

Molecular Characterization of Rat Leukocyte P-Selectin Glycoprotein Ligand-1 and Effect of Its Blockade: Protection from Ischemia-Reperfusion Injury in Liver Transplantation

Molecular Characterization of Rat Leukocyte P-Selectin Glycoprotein Ligand-1 and Effect of Its Blockade: Protection from Ischemia-Reperfusion Injury in Liver Transplantation

Protective effect of carbon monoxide in transplantation

Antioxidant Effects of Xanthohumol and Functional Impact on Hepatic Ischemia−Reperfusion Injury

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