Protection by Cyclosporine A against Normothermic Liver Ischemia-Reperfusion in Pigs

Travis, Denise L.; Fabia, Renata; Netto, George J.; Husberg, Bo S.; Goldstein, Robert M.; Klintmalm, Göran B.; Levy, Marlon F.

doi:10.1006/jsre.1998.5297

Cited by 20 publications

(16 citation statements)

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“…In addition, AIF-1 levels were significantly decreased in allografted animals receiving immunosuppression (44). Interestingly animals treated with immunosuppression before ischemia/reperfusion showed ameliorated organ injury (45)(46)(47). The increased concentrations that we found are an indicator of the up-regulation of Kupffer cells after warm ischemic liver injury and a potential involvement of interferon-␥-mediated protein cascades and provide further evidence that ischemia/reperfusion injury may contribute to allograft rejection.…”

Section: Table III Proteins Of the Arachidonic Acid Metabolismsupporting

confidence: 53%

Warm Ischemia-induced Alterations in Oxidative and Inflammatory Proteins in Hepatic Kupffer Cells in Rats

Hirsch

Hansen

Choi

et al. 2006

Molecular & Cellular Proteomics

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The aim of the study was to investigate the impact of ischemia/reperfusion injury on the proteome of Kupffer cells. Lean Zucker rats (n ‫؍‬ 6 each group) were randomized to 75 min of warm ischemia or sham operation. After reperfusion for 8 h, Kupffer cells were isolated by enzymatic perfusion and density gradient centrifugation. Proteins were tryptically digested into peptides and differentially labeled with iTRAQ (isobaric tags for relative and absolute quantitation) reagent. After fractionation by cation exchange chromatography, peptides were identified by mass spectrometry (ESI-LC-MS/MS). Spectra were interrogated against the Swiss-Prot database and quantified using ProteinProspectorா. The results for heat shock protein 70 and myeloperoxidase were validated by ELISA. There is substantial evidence that indicates that Kupffer cells play a central role in the pathogenesis of liver parenchymal cell damage as seen during ischemia/reperfusion injury (1). The activation of Kupffer cells that occurs during ischemia results in the production of oxygen radicals and the modulation of proinflammatory and anti-inflammatory cytokines (2). These mediators are implicated in hepatic cell injury and sinusoidal function. It has been demonstrated that modulation of Kupffer cells can protect the liver (3, 4). The mechanisms that have been postulated include a decreased production of oxygen radicals and neutrophil infiltration. However, little is known about the differential effects of protein expression and changes in post-translational modifications in Kupffer cells that are exposed to warm ischemia. One objective of proteome research is to identify and describe the complex responses of an organism to different stimuli (5, 6). Rapid progress in both protein separation and identification techniques has made mass spectrometry a powerful tool for characterizing the protein content of a biological system (7-13).Isotope ratio mass spectrometry with isobaric tags for relative and absolute quantitation (iTRAQ) 1 allows for the quantification and identification of the protein content of up to four samples in one experiment by labeling all peptides in a given sample (14). Peptides of the samples are modified by incorporating the four different reagents. The derivatized peptides are indistinguishable in MS but exhibit intense low mass MS/MS signature ions that support quantitation.To our knowledge there have been no studies to date that have used a proteomic approach to study the effects of warm ischemia on protein expression in Kupffer cells. We hypothe- The abbreviations used are: iTRAQ, isobaric tags for relative and absolute quantitation; AIF-1, allograft inflammatory factor-1; C3, complement factor 3; C3a, activated C3; FDR, false discovery rate; IL, interleukin. Research

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Section: Table III Proteins Of the Arachidonic Acid Metabolismsupporting

confidence: 53%

Warm Ischemia-induced Alterations in Oxidative and Inflammatory Proteins in Hepatic Kupffer Cells in Rats

Hirsch

Hansen

Choi

et al. 2006

Molecular & Cellular Proteomics

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“…This lack of protective CsA effect on CI-WR injury using the ex vivo IPRL model was unexpected and contrasted with previous data reporting amelioration of warm ischemic injury to the liver [9][10][11][12][13]. In some studies, the amelioration was found using very high oral CsA dosages (20 to 30 mg/Kg) and, although blood levels were not reported, toxic levels would have been attained not applicable for human studies [11,12]. We therefore used the in vivo ORLT model in order to determine if our data were not model-dependent.…”

Section: Discussioncontrasting

confidence: 77%

“…The drug exerts its effects primarily by impairing the gene expression in target cells. In addition to its protective effect on grafts, CsA has been reported to ameliorate warm ischemic injury to the liver in different animal species [9][10][11][12][13], as well as warm ischemic injury to other organs [14][15][16]. The protective effects were also reported in isolated cells [17][18][19][20].…”

Section: Introductionmentioning

confidence: 94%

Cyclosporin-A Does Not Prevent Cold Ischemia/Reperfusion Injury of Rat Livers

Tarrab

Huet

Brault

et al. 2012

Journal of Surgical Research

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“…We have also shown that only CsA analogs that block transition in isolated mitochondria can offer protection to the reperfused heart Halestrap et al, 1997a). Also, CsA offers reperfusion-injury protection to other tissues, including rat liver (Kurokawa et al, 1992;Shimizu et al, 1994;Travis et al, 1998) and brain (Folbergrova et al, 1997;Shiga et al, 1992;. Also, CsA offers reperfusion-injury protection to other tissues, including rat liver (Kurokawa et al, 1992;Shimizu et al, 1994;Travis et al, 1998) and brain (Folbergrova et al, 1997;Shiga et al, 1992;.…”

Section: Cyclosporinmentioning

confidence: 78%

Mitochondria in Pathogenesis

Lemasters¹,

Nieminen²

2002

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Preface Surprisingly, the mitochondrion has emerged as a center of attention in pathophysiology, generating both excitement and controversy. Old controversies concerning the mechanism of mitochondrial energy transduction subsided with the acceptance of Peter Mitchell's hypothesis of oxidative phosphorylation, first proposed in 1961. The chemiosmotic hypothesis elegantly described how mitochondrial respiration creates an electrochemical gradient of protons across the mitochondrial inner membrane, which in turn drives ATP synthesis through the mitochondrial ATP synthase. Tight coupling of this process requires that the mitochondrial inner membrane have an exceptionally low nonspecific permeability to protons and other charged solutions. In several pathological conditions, however, the mitochondrial permeability barrier fails, leading to cell death. Indeed, in programmed cell death (apoptosis) mitochondrial membrane failure may be a key signaling event. Moreover, the same respiratory processes that generate the proton electrochemical gradient driving oxidative phosphorylation may also lead to formation of toxic reactive oxygen species that cause cellular injury. Such oxygen radicals may contribute to the decline of bioenergetic capacity with advancing age.Among the organelles of animal cells, mitochondria are unique in that they contain their own DNA. The complete nucleotide sequence of human mtDNA is established, and it encodes genes for several hydrophobic subunits of complexes I, III, IV, and V, as well as genes for ribosomal proteins and tRNA. Mutations of mtDNA have wide-ranging consequences for mitochondrial respiration and bioenergetics. Because scores of mtDNA copies are maternally inherited, in contrast to the single maternal and paternal copies of nuclear DNA, mitochondrial diseases have unusual features of incomplete penetrance, delayed expression, and heterogeneous tissue involvement. In addition, possible links between mtDNA mutations, mitochondrial free radical generation, and several neurodegenerative diseases, including Huntington, Parkinson, and Alzheimer diseases, are under investigation by several laboratories.Toxic chemicals have long been known to disrupt mitochondrial metabolism and lead to cellular injury, but the mechanisms causing the injury are turning out to be more complex than expected. For instance, calcium, oxidant chemicals, ischemia/reperfusion, and a range of other agents promote onset of the mitochondrial permeability transition ix x Preface (MPT) in mitochondria from liver, heart, and other tissues, as first characterized by Hunter and Haworth in the mid-1970s. The significance of the MPT to pathophysiological processes, however, is only now being recognized. Besides involvement of the transition in necrotic cell death, new findings implicate it in apoptosis as well. Indeed, it may be the exceptional form of cell death that does not involve transition.This book attempts to provide an overview of recent major advances in the understanding of mitochondria's numerous roles in pathop...

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Protection by Cyclosporine A against Normothermic Liver Ischemia-Reperfusion in Pigs

Cited by 20 publications

References 14 publications

Warm Ischemia-induced Alterations in Oxidative and Inflammatory Proteins in Hepatic Kupffer Cells in Rats

Warm Ischemia-induced Alterations in Oxidative and Inflammatory Proteins in Hepatic Kupffer Cells in Rats

Cyclosporin-A Does Not Prevent Cold Ischemia/Reperfusion Injury of Rat Livers

Mitochondria in Pathogenesis

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