Tumor Necrosis Factor and Endotoxin in the Pathogenesis of Liver and Pulmonary Injuries After Orthotopic Liver Transplantation in the Rat

Goto, Minoru; Takei, Yoshiyuki; Kawano, Seiji; Tsuji, S.; Fukui, Hirokazu; Fushimi, Hiroaki; Nishimura, Y; Kashiwagi, Toru; Fusamoto, Hideyuki; Kamada, Takenobu

doi:10.1002/hep.1840160230

Cited by 76 publications

(45 citation statements)

References 23 publications

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“…36,37 After ORLT following 24-hour cold ischemia in UW solution, a marked increase in TNF levels was found during reperfusion with a delayed increase in NO levels (as evaluated by nitrate/nitrite levels), and finally an increased pulmonary neutrophil sequestration, as reported during endotoxemia 38,39 and after warm intestinal ischemia/reperfusion. 40,41 Similar findings have been reported by Goto et al 42 after ORLT following extended preservation in Euro-Collins solution and using long PVCTs (18 to 22 minutes). In the present study, these alterations were significantly more pronounced with long PVCTs, particularly 12 hours after surgery when nonsurvivors became lethargic and died within the next hours.…”

Section: Discussionsupporting

confidence: 67%

Decreased survival in rat liver transplantation with extended cold preservation: Role of portal vein clamping time

Urata¹,

Nguyen²,

Brault³

et al. 1998

Hepatology

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Primary liver graft dysfunction is currently related to cold ischemia-reperfusion injury, although a wide survival range has been reported using 24-hour preservation in cold University of Wisconsin (UW) solution. We hypothesized that the portal vein clamping time (PVCT) played a more important role than cold preservation injury in the postoperative outcome. Rat liver transplantation was performed using different clamping times after 24-hour cold ischemia in the UW solution. Survival rates, plasma tumor necrosis factor (TNF), and nitrate/nitrite levels were examined. Subsequently, the effect of clamping time was evaluated on hepatocyte and sinusoidal endothelial cell (SEC) function using isolated perfused livers. Survival rate was directly related to clamping time length. Marked increases in TNF and nitrate/nitrite levels were found after surgery, particularly after long clamping times. In perfusion studies, the SEC function was already markedly altered after preservation alone and was not further modified by transplantation. By contrast, the hepatocyte function was moderately altered after transplantation, irrespective of clamping times, even when rats operated with long clamping times were in terminal conditions. In rats, 24-hour preservation in cold UW solution is not a severely compromising condition leading to primary liver nonfunction. Long PVCTs are associated with an endotoxemia-like syndrome more related to a warm intestinal ischemia than to cold ischemia injury of the liver. (HEPATOLOGY 1998;28:366-373.)The underlying mechanism of cold ischemia-reperfusion injury of the liver culminating in primary liver nonfunction is still poorly understood. It is currently hypothesized that Kupffer cell activation plays a causal role in cold ischemiareperfusion injury of the liver, precipitating sinusoidal endothelial cell (SEC) death, and leading to microcirculatory disturbances. [1][2][3][4][5][6][7] This hypothesis is based on experimental findings using mainly the orthotopic rat liver transplantation (ORLT) model, first described by Lee et al. 8 and subsequently modified by Kamada and Calne. 9 However, recent experimental reports have shown that, after ORLT following extended cold ischemia, the mortality of animals could not be related to the severity of SEC dysfunction. 10 Moreover, Imamura et al. 11 and Reinders et al. 12 have reported that the presence or absence of Kupffer cells did not modify the effect of 24-hour cold ischemia/ reperfusion using the isolated perfused rat liver model and/or the ORLT model.Indeed, the ORLT model has been widely used for studying cold ischemia-reperfusion injury of the liver, particularly the effects of various solutions and of different biochemical strategies aimed at protecting the transplanted liver. A large number of these studies used cold University of Wisconsin (UW) solution as the preservation solution and 24 hours as the preservation time, conditions considered severely compromising for the grafted rat liver. However, under these preservation conditions, reported su...

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Section: Discussionsupporting

confidence: 67%

Decreased survival in rat liver transplantation with extended cold preservation: Role of portal vein clamping time

Urata¹,

Nguyen²,

Brault³

et al. 1998

Hepatology

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“…The veno-venous bypass system could, in part, be a source of ,B-glucan because similar levels of ,B-glucan were measured in both groups during the anhepatic phase. ,B-Glucan-like substance was reported to increase also during cardiopulmonary bypass [7]. However, bypass system origin cannot explain the entire profile of ,B-glucan in this experiment, in particular marked elevation of ,B-glucan in Group II after reperfusion.…”

Section: Discussioncontrasting

confidence: 60%

“…These complications may be related to inflammatory mediators stimulated by endotoxin (ET) escaping hepatic filtration. We [2][3][4] and others [5][6][7] have previously reported postoperative endotoxemia, in which ET levels correlated with the severity of liver injury and clinical outcome. However, endotoxemia after liver transplantation was not always seen in some studies [8][9][10].…”

mentioning

confidence: 99%

beta-Glucan Reflects Liver Injury After Preservation and Transplantation in Dogs

Kimura

Suzuki²,

Zhu³

et al. 1999

Journal of Investigative Surgery

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Graft failure and extrahepatic organ complications, which frequently develop after transplantation, may be related to inflammatory mediators stimulated by endotoxin (ET). The role of endotoxemia after liver transplantation is controversial and may depend upon differences in the ET assay method used in the various contradicting studies. While the standard Limulus amebocyte lysate (LAL) is reactive for ET and tJ-glucan, a novel turbidimetric assay method enables separate determinations of ET and tJ-glucan. Beagle dogs undergoing orthotopjc liver transplantation were divided into two groups. In Group I (n = 6) the grafts were transplanted immediately and in Group II (n = 6) grafts were preserved for 48 h in University of Wisconsin (UW) solution. Animals received cyclosporine immunosuppression and were followed for 14 days. Daily measurements of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) were performed. Samples for ET and tJ-glucan measurement were collected serially and processed using the turbidimetric assay method. While no graft failure was seen in Group I, three of six Group II animals died from graft failure within 1 day after transplantation. Preservation and reperfusion injury was much more severe in the Group II grafts than in Group I grafts. While endotoxemia could not be detected, postoperative tJ-glucan levels (undetectable pretransplant) were seen in both groups. tJ-Glucan levels were much higher in Group II grafts than in Group I grafts, and correlated with the severity ofliver damage. In conclusion, this study shows that tJ-glucann, instead of ET, appears during the early posttransplant period. We believe that posttransplant elevation of ~-glucan is related to liver damage, especially endothelial damage by preservation and reperfusion.

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“…42,43 Anti-TNF-␣ antibodies reduce liver injury in models of warm and cold ischemia and reperfusion. 44,45 A variety of agents that suppress lipopolysaccharide-stimulated TNF-␣ formation by Kupffer cells also decrease graft failure from storage-reperfusion injury. 46 Accordingly, TNF-␣ appears to be an important factor in graft failure after liver transplantation.…”

Section: Discussionmentioning

confidence: 99%

Ischemic preconditioning of rat livers against cold storage-reperfusion injury: Role of nonparenchymal cells and the phenomenon of heterologous preconditioning

2001

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Brief periods of ischemia followed by reperfusion render tissues resistant against subsequent prolonged ischemia, a phenomenon called ischemic preconditioning. The effect of ischemic preconditioning on liver transplantation was investigated in relation to sinusoidal endothelial cell injury and Kupffer-cell activation, which are prominent features of storage and reperfusion injury leading to liver graft failure. Rat livers were preconditioned by 5 or 10 minutes of ischemia and 5 minutes of reperfusion and stored in University of Wisconsin (UW) solution for 30 hours. Livers were then reperfused for 15 minutes with physiological buffer containing trypan blue. Under these conditions, injury occurs predominantly to sinusoidal endothelial cells, reflected by trypan blue staining of nonparenchymal cells in histological sections. Ischemic preconditioning decreased nonparenchymal cell killing by more than 50%. When half the liver was preconditioned, sinusoidal endothelial cells were also protected in the contralateral half. Other stored livers were reperfused with nitroblue tetrazolium, which is converted to insoluble formazan by superoxide radicals. Ischemic preconditioning decreased the intensity of formazan deposition over Kupffer cells. Finally, stored livers were transplanted into nontreated rats. Ischemic preconditioning improved recipient long-term survival after 30 hours of cold ischemic storage in UW solution from 30% to 80% and decreased serum tumor necrosis factor-␣ levels in posthepatic blood 4 hours postoperatively from 98 to 54 pg/mL. In conclusion, ischemic preconditioning protects sinusoidal endothelial cells and suppresses Kupffer-cell activation after storage and reperfusion. As a result, graft survival improves after liver transplantation. Moreover, ischemia to half the liver confers protection to the other half. Such heterologous preconditioning provides a new means to protect liver tissue against ischemia-reperfusion injury without imposing ischemia on the target tissue. (Liver Transpl 2001;7:292-299.)

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Tumor Necrosis Factor and Endotoxin in the Pathogenesis of Liver and Pulmonary Injuries After Orthotopic Liver Transplantation in the Rat

Cited by 76 publications

References 23 publications

Decreased survival in rat liver transplantation with extended cold preservation: Role of portal vein clamping time

Decreased survival in rat liver transplantation with extended cold preservation: Role of portal vein clamping time

beta-Glucan Reflects Liver Injury After Preservation and Transplantation in Dogs

Ischemic preconditioning of rat livers against cold storage-reperfusion injury: Role of nonparenchymal cells and the phenomenon of heterologous preconditioning

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