Effects of Three Superoxide Dismutase Genes Delivered With an Adenovirus on Graft Function After Transplantation of Fatty Livers in the Rat1

Lehmann, Thorsten G.; Wheeler, Michael D.; Froh, Matthias; Schwabe, Robert F.; Bunzendahl, H.; Samulski, R. Jude; Lemasters, John J.; Brenner, David A.; Thurman, Ronald G.

doi:10.1097/01.tp.0000065299.29900.17

Cited by 53 publications

(39 citation statements)

References 26 publications

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“…Experimental studies have previously shown that upregulation of HO-1 protects liver grafts against ischemia/reperfusion injury and improves graft survival (2,3,37-39). Especially, steatotic livers, which are highly sensitive to ischemic injury, seem effectively protected against this type of injury by induction of HO-1 (37,40). The inferior outcomes of livers with the unfavorable TT genotype (associated with a reduced HO-1 promoter activity) in the current study supports these previous findings.…”

Section: Ho-1 Polymorphisms and Outcome After Liver Transplantationsupporting

confidence: 82%

Heme Oxygenase-1 Genotype of the Donor Is Associated With Graft Survival After Liver Transplantation

Buis

Steege

Visser

et al. 2008

American Journal of Transplantation

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Heme oxygenase-1 (HO-1) has been suggested as a cytoprotective gene during liver transplantation. Inducibility of HO-1 is modulated by a (GT) n polymorphism and a single nucleotide polymorphism (SNP) A(-413)T in the promoter. Both a short (GT) n allele and the A-allele have been associated with increased HO-1 promoter activity. In 308 liver transplantations, we assessed donor HO-1 genotype and correlated this with outcome variables. For (GT) n genotype, livers were divided into two classes: short alleles (<25 repeats; class S) and long alleles (≥25 repeats; class L). In a subset, hepatic messenger ribonucleic acid (mRNA) expression was correlated with genotypes. Graft survival at 1 year was significantly better for A-allele genotype compared to TT-genotype (84% vs. 63%, p = 0.004). Graft loss due to primary dysfunction (PDF) occurred more frequently in TT-genotype compared to A-receivers (p = 0.03). Recipients of a liver with TT-genotype had significantly higher serum transaminases after transplantation and hepatic HO-1 mRNA levels were significantly lower compared to the A-allele livers (p = 0.03). No differences were found for any outcome variable between class S and LL-variant of the (GT) n polymorphism. Haplotype analysis confirmed dominance of the A(-413)T SNP over the (GT) n polymorphism. In conclusion, HO-1 genotype is associated with outcome after liver transplantation. These findings suggest that HO-1 mediates graft survival after liver transplantation.

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Section: Ho-1 Polymorphisms and Outcome After Liver Transplantationsupporting

confidence: 82%

Heme Oxygenase-1 Genotype of the Donor Is Associated With Graft Survival After Liver Transplantation

Buis

Steege

Visser

et al. 2008

American Journal of Transplantation

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“…However, baseline levels of antioxidants were not measured between steatotic and lean livers but have been previously reported to be similar [111]. These results further confirm that steatotic livers have a predisposition for increased ROS production rather than lacking antioxidants.…”

Section: Troloxsupporting

confidence: 75%

Effect of Hepatic Steatosis on Bioenergetic Function During Hepatic Ischemia-reperfusion: A Systematic Review

Chu¹

2013

TOTRANSJ

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Abstract:Background: The impact of hepatic steatosis on bioenergetics following hepatic ischemia-reperfusion injury (IRI) remains controversial and is associated with variable reports on its outcome. Large numbers of studies have been published examining the relationship between hepatic steatosis and cellular bioenergetics following hepatic IRI. This systematic review evaluates these studies.Methods: An electronic search of the Medline and Embase databases (January 1946 to June 2012) was performed to select studies that reported relevant outcomes in animal models or patients with hepatic steatosis subjected to IRI.Results: A total of 489 articles were identified, of which 63 animal studies met the predefined criteria and were included in the study. There was large variation in the type of animal model, duration and type of IRI utilized and histological description of hepatic steatosis. Bioenergetic impairments appear to increase the susceptibility of steatotic livers to IRI. The most common impairment was decreased adenosine triphosphate recovery with increased oxidative stress following IRI. Impaired mitochondrial function play a key role in the susceptibility of steatotic livers to IRI.Conclusions: Animals with >30% hepatic steatosis have been shown to have poor outcome following IRI. Despite limitations of different experimental models and inconsistency in histological description, impaired mitochondrial function and bioenergetics appear to be important mediators in the decreased tolerance of steatotic livers to IRI. Future studies need to be consistent and clinically relevant to further improve our understanding of this issue.

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“…However, our results obtained with the pharmacological modulation of MAPKs, are in line with those reported in a study in transplantation from steatotic liver grafts indicating that JNK activation might be harmful to hepatocytes after reperfusion. 54 In addition, under the conditions reported here, the levels of both p38 and JNK fell in both liver types following preconditioning. These apparently contradictory data on MAPKs in liver preconditioning have also been reported for the heart.…”

Section: 34mentioning

confidence: 80%

Heat Shock Proteins and Mitogen-activated Protein Kinases in Steatotic Livers Undergoing Ischemia-Reperfusion: Some Answers

Massip-Salcedo

Casillas-Ramírez

Franco-Gou

et al. 2006

The American Journal of Pathology

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Ischemic preconditioning protects steatotic livers against ischemia-reperfusion (I/R) injury, but just how this is achieved is poorly understood. Here, I/R or preconditioning plus I/R was induced in steatotic and nonsteatotic livers followed by investigating the effect of pharmacological treatments that modulate heat shock proteins (HSPs) and mitogen-activated protein kinases (MAPKs). MAPKs, HSPs, protein kinase C, and transaminase levels were measured after reperfusion. We report that preconditioning increased HSP72 and heme-oxygenase-1 (HO-1) at 6 and 24 hours of reperfusion, respectively. Unlike nonsteatotic livers, steatotic livers benefited from HSP72 activators (geranylgeranylacetone) throughout reperfusion. This protection seemed attributable to HO-1 induction. In steatotic livers, preconditioning and geranylgeranylacetone treatment (which are responsible for HO-1 induction) increased protein kinase C activity. HO-1 activators (cobalt(III) protoporphyrin IX) protected both liver types. Preconditioning reduced p38 MAPK and c-Jun N-terminal kinase (JNK), resulting in HSP72 induction though HO-1 remained unmodified. Like HSP72, both p38 and JNK appeared not to be crucial in preconditioning, and inhibitors of p38 (SB203580) and JNK (SP600125) were less effective against hepatic injury than HO-1 activators. These results provide new data regarding the mechanisms of preconditioning and may pave the way to the development of new pharmacological strategies in liver surgery.

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Effects of Three Superoxide Dismutase Genes Delivered With an Adenovirus on Graft Function After Transplantation of Fatty Livers in the Rat1

Abstract: This study demonstrates that cytosolic SOD represents the most effective isoform of SOD to protect transplanted livers from failure; this may be related to lowered NF-kappaB and JNK activities because of reduced oxygen-derived radical production.

Cited by 53 publications

References 26 publications

Heme Oxygenase-1 Genotype of the Donor Is Associated With Graft Survival After Liver Transplantation

Heme Oxygenase-1 Genotype of the Donor Is Associated With Graft Survival After Liver Transplantation

Effect of Hepatic Steatosis on Bioenergetic Function During Hepatic Ischemia-reperfusion: A Systematic Review

Heat Shock Proteins and Mitogen-activated Protein Kinases in Steatotic Livers Undergoing Ischemia-Reperfusion: Some Answers

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