Protective strategies against ischemic injury of the liver

Selzner, Nazia; Rüdiger, Hannes A.; Graf, Rolf; Clavien, Pierre‐Alain

doi:10.1016/s0016-5085(03)01048-5

Cited by 503 publications

(473 citation statements)

References 239 publications

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“…Some of the process that participate both directly and indirectly in IR injury by ROS include the formation of xantine oxidase from xantine dehydrogenase (an oxygendependent process that releases ROS, hydrogen peroxide, and superoxide and produces uric acid) [52], induction of NADPH oxidase by activated KC and neutrophils (ROS production is blocked when NADPH oxidase is inhibited), and NO formation and its conversion to peroxynitrite (both are RNS) [53]. The cytotoxic effects of ROS and RNS in the liver translate into tyrosine residues, lipid peroxidation, inactivation of the heme group, and nitrosylation of ironsulfur group [44,53].…”

Section: Ischemia/reperfusion Liver Injury and Free Radicalsmentioning

confidence: 99%

“…The cytotoxic effects of ROS and RNS in the liver translate into tyrosine residues, lipid peroxidation, inactivation of the heme group, and nitrosylation of ironsulfur group [44,53].…”

Section: Ischemia/reperfusion Liver Injury and Free Radicalsmentioning

confidence: 99%

“…Ischemia activates KC, which are the main source of ROS during the reperfusion period [53]. Various studies show that newly recruited nonocytes and leukocytes are partially responsible for the ischemic damage.…”

Section: Ischemia/reperfusion Liver Injury and Free Radicalsmentioning

confidence: 99%

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Role of free radicals in liver diseases

2009

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Reactive oxygen and nitrogen species (ROS and RNS) are produced by metabolism of normal cells. However, in liver diseases, redox is increased thereby damaging the hepatic tissue; the capability of ethanol to increase both ROS/RNS and peroxidation of lipids, DNA, and proteins was demonstrated in a variety of systems, cells, and species, including humans. ROS/RNS can activate hepatic stellate cells, which are characterized by the enhanced production of extracellular matrix and accelerated proliferation. Cross-talk between parenchymal and nonparenchymal cells is one of the most important events in liver injury and fibrogenesis; ROS play an important role in fibrogenesis throughout increasing platelet-derived growth factor. Most hepatocellular carcinomas occur in cirrhotic livers, and the common mechanism for hepatocarcinogenesis is chronic inflammation associated with severe oxidative stress; other risk factors are dietary aflatoxin B 1 consumption, cigarette smoking, and heavy drinking. Ischemia-reperfusion injury affects directly on hepatocyte viability, particularly during transplantation and hepatic surgery; ischemia activates Kupffer cells which are the main source of ROS during the reperfusion period. The toxic action mechanism of paracetamol is focused on metabolic activation of the drug, depletion of glutathione, and covalent binding of the reactive metabolite N-acetyl-pbenzoquinone imine to cellular proteins as the main cause of hepatic cell death; intracellular steps critical for cell death include mitochondrial dysfunction and, importantly, the formation of ROS and peroxynitrite. Infection with hepatitis C is associated with increased levels of ROS/RNS and decreased antioxidant levels. As a consequence, antioxidants have been proposed as an adjunct therapy for various liver diseases.

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Section: Ischemia/reperfusion Liver Injury and Free Radicalsmentioning

confidence: 99%

“…The cytotoxic effects of ROS and RNS in the liver translate into tyrosine residues, lipid peroxidation, inactivation of the heme group, and nitrosylation of ironsulfur group [44,53].…”

Section: Ischemia/reperfusion Liver Injury and Free Radicalsmentioning

confidence: 99%

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Role of free radicals in liver diseases

2009

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“…Transient episodes of hepatic ischemia occur during solid organ transplantation, trauma, hypovolemic shock, and elective liver resection, when inflow occlusion or total vascular exclusion is used to minimize blood loss. The pathophysiology of liver I/R injury includes both direct cellular damage as the result of the ischemic insult as well as delayed dysfunction and damage resulting from activation of inflammatory pathways [1][2][3][4]. There is evidence that the L-arginine-nitric oxide pathway plays an important role in mediating this injury [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Arginase blockade protects against hepatic damage in warm ischemia-reperfusion

et al. 2008

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Background-Liver ischemia reperfusion (I/R) injury is associated with profound arginine depletion due to arginase release from injured hepatocytes. Nitric oxide (NO), shown to have protective effects in I/R, is produced by nitric oxide synthase (NOS) from the substrate arginine. The purpose of this study was to determine if nor-NOHA, a novel arginase inhibitor, would be able to increase circulating arginine levels and decrease hepatic damage following warm I/R.

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“…2 Hepatic ischemia/reperfusion (I/ R) injury is considered one of the main determinants of the outcome after liver transplantation. 3,4 The process of hepatic I/R injury is a sequence of events involving many interconnected factors occurring in a variety of cell types. Liver endothelial cells are particularly vulnerable to I/R injury and develop serious alterations during cold storage, such as retraction, cell body detachment, and apoptosis, which are magnified upon warm reperfusion.…”

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confidence: 99%

Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers

et al. 2012

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Pathophysiological alterations in the endothelial phenotype result in endothelial dysfunction. Flow cessation, occurring during organ procurement for transplantation, triggers the endothelial dysfunction characteristic of ischemia/reperfusion injury, partly due to a reduction in the expression of the vasoprotective transcription factor Kruppel-like Factor 2 (KLF2). We aimed at (1) characterizing the effects of flow cessation and cold storage on hepatic endothelial phenotype, and (2) ascertaining if the consequences of cold stasis on the hepatic endothelium can be pharmacologically modulated, improving liver graft function. Expression of KLF2 and its vasoprotective programs was determined in (i) hepatic endothelial cells (HEC) incubated under cold storage conditions with or without the KLF2-inducer simvastatin, and (ii) rat livers not cold stored or preserved in cold University of Wisconsin solution (UWS) supplemented with simvastatin or its vehicle. In addition, upon warm reperfusion hepatic vascular resistance, endothelial function, nitric oxide vasodilator pathway, apoptosis, inflammation, and liver injury were evaluated in not cold stored livers or livers preserved in cold UWS supplemented with simvastatin or vehicle. Expression of KLF2 and its vasoprotective programs decrease in HEC incubated under cold storage conditions. Cold-stored rat livers exhibit a time-dependent decrease in KLF2 and its target genes, liver injury, increased hepatic vascular resistance, and endothelial dysfunction. The addition of simvastatin to the storage solution, maintained KLF2-dependent vasoprotective programs, prevented liver damage, inflammation, and oxidative stress and improved endothelial dysfunction. Conclusion: Our results provide a rationale to evaluate the beneficial effects of a vasoprotective preservation solution on human liver procurement for transplantation. (HEPATOLOGY 2012;55:921-930)

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Protective strategies against ischemic injury of the liver

Cited by 503 publications

References 239 publications

Role of free radicals in liver diseases

Role of free radicals in liver diseases

Arginase blockade protects against hepatic damage in warm ischemia-reperfusion

Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers

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