Apoptosis after ischemia-reperfusion in human liver allografts

Borghi-Scoazec, G; Scoazec, Jean‐Yves; Durand, François; Bernuau, Jacques; Belghiti, Jacques; Feldmann, Gérard; Hénin, Dominique; Degott, Claude

doi:10.1002/lt.500030408

Cited by 112 publications

(33 citation statements)

References 13 publications

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“…These microcirculatory abnormalities were accompanied by significant hepatic injury, as demonstrated by marked increments in: hepatic enzymes release, inflammation, apoptosis, oxidative stress, histological injury, and significant reduction in bile production. Our results are in agreement with previous reports describing increased vascular tone, apoptosis, and inflammation following cold storage and warm reperfusion, 8,[28][29][30][31][32] further supporting the concept that both the endothelium and the liver parenchyma are negatively affected by cold storage and warm reperfusion.…”

Section: Discussionsupporting

confidence: 93%

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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Section: Discussionsupporting

confidence: 93%

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

et al. 2012

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“…During the last 2 years, an increasing number of publications suggested that SEC and hepatocytes undergo apoptosis during reperfusion after cold 29,[32][33][34] or warm ischemia. 28,30,31 However, our investigation could not confirm these findings.…”

Section: Discussionmentioning

confidence: 99%

“…Most investigators use the TUNEL assay to quantify apoptotic cells. [28][29][30][31][32][33][34] However, this assay detects DNA strand breaks, which occur during apoptosis but also during necrosis. 39,48 Thus, if the mode of cell death is in question, the TUNEL assay cannot be used to quantify apoptotic cells without supporting morphological evidence, which, incidentally, is regarded as the gold standard for apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…30,31 A high percentage of apoptotic hepatocytes were also identified in human liver allografts. 32 Although there is morphological evidence of apoptosis for individual cells, the quantitation of apoptosis in the tissue was mainly based on the TUNEL assay. [29][30][31][32][33] In addition to these parameters, DNA laddering 29,31 and moderate caspase-3 activation 30 were reported.…”

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confidence: 99%

“…32 Although there is morphological evidence of apoptosis for individual cells, the quantitation of apoptosis in the tissue was mainly based on the TUNEL assay. [29][30][31][32][33] In addition to these parameters, DNA laddering 29,31 and moderate caspase-3 activation 30 were reported. Moreover, inhibitors of caspases reduced endothelial cell injury during cold storage and reperfusion 34 and attenuated hepatocyte damage during warm ischemia.…”

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confidence: 99%

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Mechanism of Cell Death During Warm Hepatic Ischemia–Reperfusion in Rats: Apoptosis or Necrosis?

2001

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Reperfusion injury can cause liver dysfunction after cold storage and warm ischemia. Recently it has been suggested that more than 50% of hepatocytes and sinusoidal endothelial cells (SEC) are undergoing apoptosis during the first 24 hours of reperfusion. The aim of our study was to quantify apoptotic and necrotic hepatocytes and apoptotic SEC after 60 or 120 minutes of warm, partial no-flow ischemia and 0 to 24 hours reperfusion in male SD rats. Apoptotic cells were identified by TUNEL assay in combination with morphological criteria. After 60 minutes of ischemia and 1 hour of reperfusion there was a significant increase of apoptotic hepatocytes (0.7 ؎ 0.1% vs. 0.3 ؎ 0.1% in controls) and SEC (1.5 ؎ 0.6% vs. 0.3 ؎ 0.1% in controls). The number of apoptotic SEC and hepatocytes was not different from controls at 6 hours or 24 hours of reperfusion. In contrast, the number of necrotic hepatocytes was quantified as 12 ؎ 2% at 1 hour, 34 ؎ 6% at 6 hours, and 57 ؎ 11% at 24 hours. These results correlated with the increase in plasma ALT levels at these time points. Longer (120 min) ischemia times did not affect the number of apoptotic cells but increased hepatocellular necrosis to 58 ؎ 4% at 6 hours reperfusion. No significant increase in caspase-3 activity and processing was detectable in any of these livers. Moreover, the caspase inhibitor Z-Asp-cmk (2 mg/kg IV) had no significant effect on reperfusion injury. Our results suggest that only a small minority of SEC and hepatocytes undergo apoptosis after 60 to 120 minutes of warm ischemia followed by 0 to 24 hours of reperfusion. Oncotic necrosis appears to be the principal mechanism of cell death for both cell types. (HEPATOLOGY 2001;33:397-405.)Ischemia-reperfusion injury is responsible for primary liver dysfunction and failure after transplantation, 1-5 after liver resection (Pringle maneuver), 6 or after hemorrhagic shock. 7 Cold storage appears to cause injury mainly to sinusoidal endothelial cells (SEC), 8,9 whereas warm ischemia affects hepatocytes and endothelial cells. 10 In addition, Kupffer cells are activated and primed, 11-13 which causes a substantial aggravation of the injury during the early reperfusion period. At the same time, activation of complement 14 and the formation of cytokines 15 and chemokines 16,17 lead to hepatic neutrophil sequestration and a neutrophil-dependent injury 18 several hours later. Injury by Kupffer cells and neutrophils is largely dependent on reactive oxygen species 19-21 and proteases. [22][23][24] Although the postischemic oxidant stress is not sufficient to kill hepatocytes by lipid peroxidation, 25 there is evidence that reactive oxygen species and proteases cause hepatocellular necrosis. 22,26,27 In recent years, several laboratories reported evidence for apoptotic cell death during hepatic ischemia and reperfusion. [28][29][30][31] According to these studies, 50% to 70% of endothelial cells and 40% to 60% of hepatocytes undergo apoptosis during reperfusion. 30,31 A high percentage of apoptotic hepatocytes were also ide...

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Apoptosis and Necrosis in the Liver

Guicciardi

Malhi

Mott

et al. 2013

Comprehensive Physiology

324

248

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Because of its unique function and anatomical location, the liver is exposed to a multitude of toxins and xenobiotics, including medications and alcohol, as well as to infection by hepatotropic viruses, and therefore, is highly susceptible to tissue injury. Cell death in the liver occurs mainly by apoptosis or necrosis, with apoptosis also being the physiologic route to eliminate damaged or infected cells and to maintain tissue homeostasis. Liver cells, especially hepatocytes and cholangiocytes, are particularly susceptible to death receptor-mediated apoptosis, given the ubiquitous expression of the death receptors in the organ. In a quite unique way, death receptor-induced apoptosis in these cells is mediated by both mitochondrial and lysosomal permeabilization. Signaling between the endoplasmic reticulum and the mitochondria promotes hepatocyte apoptosis in response to excessive free fatty acid generation during the metabolic syndrome. These cell death pathways are partially regulated by microRNAs. Necrosis in the liver is generally associated with acute injury (i.e., ischemia/reperfusion injury) and has been long considered an unregulated process. Recently, a new form of “programmed” necrosis (named necroptosis) has been described: the role of necroptosis in the liver has yet to be explored. However, the minimal expression of a key player in this process in the liver suggests this form of cell death may be uncommon in liver diseases. Because apoptosis is a key feature of so many diseases of the liver, therapeutic modulation of liver cell death holds promise. An updated overview of these concepts is given in this article.

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Apoptosis after ischemia-reperfusion in human liver allografts

Cited by 112 publications

References 13 publications

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

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

Mechanism of Cell Death During Warm Hepatic Ischemia–Reperfusion in Rats: Apoptosis or Necrosis?

Apoptosis and Necrosis in the Liver

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