Role of Reactive Metabolites of Oxygen and Nitrogen in Partial Liver Transplantation: Lessons Learned From Reduced‐size Liver Ischaemia and Reperfusion Injury

Urakami, Hidejiro; Abe, Yuta; Grisham, Matthew B.

doi:10.1111/j.1440-1681.2007.04640.x

Cited by 31 publications

(31 citation statements)

References 80 publications

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“…1, 3, 4, 23 Therefore, inhibition of ROS production and scavenging ROS have been expected as therapeutic approaches. Nrf2— a transcription factor mediating the expression of many endogenous antioxidants—is known to play an important role in the cytoprotection against oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Nrf2 Activation Protects the Liver From Ischemia/Reperfusion Injury in Mice

et al. 2014

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Objective To investigate the role of Nrf2 in the pathogenesis of hepatic ischemia-reperfusion (I/R) injury. Summary Background Data Hepatic I/R injury is a serious complication that leads to liver failure after liver surgery. NF-E2-related factor 2 (Nrf2) is a transcription factor that plays a critical role in protecting cells against oxidative stress. Therefore, it is suggested that Nrf2 activation protects the liver from I/R injury. Methods Wild-type (WT) and Nrf2-deficient mice were treated with 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2), or a vehicle. Subsequently, these mice were subjected to 60 min hepatic 70% ischemia followed by reperfusion. Liver and blood samples were collected to evaluate liver injury and mRNA expressions. Results After hepatic I/R, Nrf2-deficient livers exhibited enhanced tissue damage, impaired GSTm1, NQO1, and GCLc inductions, disturbed redox state, and aggravated TNF-α mRNA expression in comparison to WT livers. 15d-PGJ2 treatment protected the livers of WT mice from I/R injury via increased expressions of GSTm1, NQO1 and GCLc, maintained redox status, and decreased TNF-α induction. These effects induced by 15d-PGJ2 were not seen in the livers of Nrf2−/− mice and were not annulled by PPARγ antagonist in Nrf2+/+ mice, suggesting that the protective effect of 15d-PGJ2 is mediated by Nrf2-dependent antioxidant response. Conclusions Nrf2 plays a critical role in the mechanism of hepatic I/R injury and would be a new therapeutic target for preventing hepatic I/R injury during liver surgery.

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Section: Discussionmentioning

confidence: 99%

Nrf2 Activation Protects the Liver From Ischemia/Reperfusion Injury in Mice

et al. 2014

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“…Here we investigated whether overproduction of RNS plays a role. Effects of NO production on liver injury in hepatic ischemia/reperfusion (IR) and LT have been controversial (18,39). Although iNOS is required for liver regeneration after partial hepatectomy in mice (40), excessive NO causes DNA damage, leading to accumulation of p53 and p21Cip1 and cell cycle arrest (41).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Inducible Nitric Oxide Synthase Prevents Mitochondrial Damage and Improves Survival of Steatotic Partial Liver Grafts

Rehman

Wright

et al. 2010

Transplantation

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Background Steatotic liver grafts are excluded for partial liver transplantation due to increased risk of primary non-function. Mechanisms underlying the failure of fatty partial liver grafts (FPG) remain unknown. This study investigated whether inducible nitric oxide synthase (iNOS) plays a role in failure of FPG. Methods Fatty livers were induced by feeding rats a high-fat high-fructose (HFFr) diet for 2-weeks. Hepatic triglyceride was ~9-fold higher in rats fed the HFFr diet than those fed a low-fat low-fructose diet. Lean and fatty liver explants were reduced in size ex vivo to ~1/3, stored in the UW solution for 2 h, and implanted. Results Post-transplantational hepatic iNOS expression and reactive nitrogen species (RNS) formation (nitrite/nitrate levels and 3-nitrotyrosine adducts) increased more profoundly in FPG than in lean partial grafts (LPG). Serum alanine aminotransferase (ALT) and bilirubin were 2-and 5.5-fold higher after transplantation of FPG than LPG. 5-Bromo-2′-deoxyuridine incorporation was 25% in LPG but only 5% in FPG, and graft weight increased by 64% in LPG while remaining unchanged in FPG. All rats that received FPG died, whereas all those receiving LPG survived. 1400W (5 μM), a specific iNOS inhibitor, largely blunted the production of RNS, prevented the elevation of ALT and bilirubin, restored liver regeneration and improved survival of FPG. Mitochondrial cytochrome c oxidase-IV, ATP synthase-β and NADH dehydrogenase-3 decreased markedly in FPG, and these effects were blocked by 1400W. Conclusion Thus, hepatic steatosis causes failure of partial liver grafts, most likely by increasing RNS that leads to mitochondrial damage and dysfunction.

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“…Indeed, the pathophysiological mechanisms responsible for warm I/R-induced liver injury may be significantly different than those that occur with the cold ischemia (4°C) associated with liver storage prior to transplantation. (1,2) Nevertheless, a great deal of mechanistic information has been derived from in situ I/R studies. (3) These studies demonstrate that reperfusion of ischemic tissue initiates a cascade of molecular and cellular events that culminate in the superoxide anion radical (O 2 •− ) dependent, nuclear transcription factor-κB (NF-κB)-mediated expression of both injurious and protective mediators in favor of the former (Fig.…”

Section: Introductionmentioning

confidence: 99%

Divergent roles of superoxide and nitric oxide in liver ischemia and reperfusion injury

Hines¹,

Grisham

2010

J. Clin. Biochem. Nutr.

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Liver ischemia and reperfusion-induced injury is a major clinical complication associated with hemorrhagic or endotoxin shock and thermal injury as well as liver transplantation and resectional surgery. Data obtained from several different studies suggest that an important initiating event in the pathophysiology of ischemia and reperfusion-induced tissue injury is enhanced production of superoxide concomitant with a decrease in the bioavailability of endothelial cell-derived nitric oxide. This review will summarize the evidence supporting the hypothesis that the redox imbalance induced by alterations in superoxide and nitric oxide generation creates a more oxidative environment within the different cells of the liver that enhances the nuclear transcription factor-κB-dependent expression of a variety of different cytokines and mediators that may promote as well as limit ischemia and reperfusion-induced hepatocellular injury. In addition, the evidence implicating endothelial cell nitric oxide synthase-dependent and -independent generation of nitric oxide as important regulatory pathways that act to limit ischemia and reperfusion-induced liver injury and inflammation is also presented.

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Role of Reactive Metabolites of Oxygen and Nitrogen in Partial Liver Transplantation: Lessons Learned From Reduced‐size Liver Ischaemia and Reperfusion Injury

Cited by 31 publications

References 80 publications

Nrf2 Activation Protects the Liver From Ischemia/Reperfusion Injury in Mice

Nrf2 Activation Protects the Liver From Ischemia/Reperfusion Injury in Mice

Inhibition of Inducible Nitric Oxide Synthase Prevents Mitochondrial Damage and Improves Survival of Steatotic Partial Liver Grafts

Divergent roles of superoxide and nitric oxide in liver ischemia and reperfusion injury

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