Role of Cytokines and Cytokine-Producing Cells in Reperfusion Injury to the Liver

Lichtman, Steven N.; Lemasters, John J.

doi:10.1055/s-2007-1007108

Cited by 91 publications

(68 citation statements)

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“…In morphology, changes of hepatocytes included swelling, ballooning and vacuolization. Although little loss of cell viability occurred after 24 h of storage in UW solution, the cellular functions were already injured [22] . In this study, histological results showed that hepatocytes were apparently damaged in control group after cold storage for 36 to 48 h. In contrast, the shapes of hepatocytes were normal in DXR group.…”

Section: Discussionmentioning

confidence: 98%

“…Male Sprague-Dawley rats weighing 200-300 g were purchased from Sino-British Sippr/BK Lab Animal Ltd. All rats were kept in animal quarters with controlled temperature (18)(19)(20)(21)(22)(23)(24)(25) and light (light on from 7 a.m. to 7 p.m.) and were fed with a standard laboratory chow and water in accordance with institutional animal care policies. Prior to the experimental procedure, the rats were fasted for 12 hours but allowed free access to water.…”

Section: Animalsmentioning

confidence: 99%

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Protective effect of doxorubicin induced heat shock protein 72 on cold preservation injury of rat livers

Chen

Yu²,

Zhang³

et al. 2004

WJG

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AIM:To observe the protective effect of heat shock protein 72 (HSP 72) induced by pretreatment of doxorubicin (DXR) on long-term cold preservation injury of rat livers. METHODS:Sprague-Dawley rats were administered intravenously DXR at a dose of 1 mg/kg body mass in DXR group and saline in control group. After 48 h, the rat liver was perfused with cold Linger's and University of Wisconsin (UW) solutions and then was preserved in UW solution at 4 for 24, 36 and 48 h. AST, ALT, LDH and hyaluronic acid in preservative solution were determined. Routine HE, immunohistochemical staining for HSP 72 and electron microscopic examination of hepatic tissues were performed. RESULTS:After 24, 36 and 48 h, the levels of AST, ALT and hyaluronic acid in preservative solution were significantly higher in control group than in DXR group (P<0.05), while LDH level was not significantly different between the 2 groups (P>0.05). Hepatic tissues in DXR group were morphologically normal and significantly injured in control group. HSP 72 was expressed in hepatocytes and sinusoidal endothelial cells in DXR group but not in control group.CONCLUSION: Pretreatment of DXR may extend the time of rat liver cold preservation and keep liver alive. The expression of HSP 72 in liver can prevent hepatocytes and sinusoidal endothelial cells from long-term cold preservation injury.

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Section: Discussionmentioning

confidence: 98%

Section: Animalsmentioning

confidence: 99%

Protective effect of doxorubicin induced heat shock protein 72 on cold preservation injury of rat livers

Chen

Yu²,

Zhang³

et al. 2004

WJG

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“…Ischemia-reperfusion injury is responsible for primary liver dysfunction and failure after transplantation, [1][2][3][4][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.…”

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confidence: 99%

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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“…[5][6][7] During the cascade leading to activation of Kupffer cells, DNA binding activity of NFkB, a key regulator of genes encoding inflammatory cytokines, acute phase response proteins, and cell adhesion molecules, 36 37 is upregulated through several mechanisms, including pathways dependent on oxidative stress or endotoxin. 14-16 18 In the present study, we demonstrated that inactivation of NFkB in the liver using adenoviral gene transfer of IkBa SR effectively blocked a short term warm ischaemia/reperfusion injury that was transient and sublethal, showing a good resemblance to liver injury observed clinically after an intraoperative manipulation, Pringle's manoeuvre.…”

Section: Discussionmentioning

confidence: 99%

Nuclear factor B inactivation in the rat liver ameliorates short term total warm ischaemia/reperfusion injury

Suetsugu

2005

Gut

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Background: In hepatic ischaemia/reperfusion injury, activated liver macrophages (Kupffer cells) are dominantly regulated by a transcription factor, nuclear factor kB (NFkB), with respect to expression of inflammatory cytokines, acute phase response proteins, and cell adhesion molecules. Aims: We assessed whether inactivation of NFkB in the liver could attenuate total hepatic warm ischaemia/reperfusion injury. Methods: We studied rats with hepatic overexpression of inhibitor kBa super-repressor (IkBa SR) caused by a transgene introduced using an adenoviral vector. Hepatic ischaemia/reperfusion injury was induced under warm conditions by total occlusion of hepatoduodenal ligament structures for 20 minutes, followed by reperfusion. Controls included uninfected and control virus (AdLacZ) infected rats. Results: IkBa SR was overexpressed in Kupffer cells as well as in hepatocytes, blocking nuclear translocation of NFkB (p65) into the nucleus after reperfusion. Gene transfection with IkBa SR, but not with LacZ, markedly attenuated ischaemia/reperfusion injury, suppressing inducible nitric oxide synthase and nitrotyrosine expression in the liver. Moreover, no remarkable hepatocyte apoptosis was detected under IkBa SR overexpression. Conclusions: Adenoviral transfer of the IkBa SR gene in the liver ameliorates short term warm ischaemia/ reperfusion injury, possibly through attenuation of hepatic macrophage activation.

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Role of Cytokines and Cytokine-Producing Cells in Reperfusion Injury to the Liver

Cited by 91 publications

References 1 publication

Protective effect of doxorubicin induced heat shock protein 72 on cold preservation injury of rat livers

Protective effect of doxorubicin induced heat shock protein 72 on cold preservation injury of rat livers

Mechanism of cell death during warm hepatic ischemia-reperfusion in rats: Apoptosis or necrosis?

Nuclear factor B inactivation in the rat liver ameliorates short term total warm ischaemia/reperfusion injury

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