Markers of Allograft Viability in the Rat Relationship Between Transplantation Viability and Liver Function in the Isolated Perfused Liver

Iu, S.; Harvey, P. R. C.; Makowka, Leonard; Petrunka, C. N.; Ilson, R. G.; Strasberg, Steven M.

doi:10.1097/00007890-198710000-00021

Cited by 126 publications

(39 citation statements)

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“…Transaminase levels in the IPRL are the best surrogate markers for posttransplantation function in the rat. 27 Notably, dantrolene did not improve results when UW solution was used, suggesting that UW has ingredients that maintain calcium levels in the normal range or oppose calpain activity. We have previously found that lactobionate, a major ingredient of UW, solution chelates calcium down to the millimolar level (unpublished observations).…”

Section: Discussionmentioning

confidence: 98%

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Effect of cold preservation on intracellular calcium concentration and calpain activity in rat sinusoidal endothelial cells

et al. 2003

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I n the past several years, we have examined intracellular events that occur in sinusoidal endothelial cells (SEC) when they are placed in the cold. 1-4 SEC are the main targets of cold preservation injury, 5,6 and understanding the mechanisms by which they are injured might provide an avenue to development of improved preservation solutions. Our studies show that cold causes actin disassembly 2 and that this is associated with rounding of the cells 2 and release of matrix metalloproteases (MMPs) into the supernatants of SEC cell cultures. 1,3 Actin disassembly and MMP secretion lead to activation of the cell surface, as shown by increased expression of von Willebrand factor and increased adhesiveness for platelets. 4 Platelet adhesion is one of the key events that leads to allograft injury on reperfusion. 7,8 To date, the cause of cold-induced actin disassembly is unclear, but there are suggestions that abnormalities of calpain and calcium metabolism are important. There is a sharp rise in intracellular calcium when SECs are placed in the cold in the presence of extracellular calcium. 9 Calpain is a calcium-dependent intracellular protease the activity of which is increased in whole rat livers preserved in the cold 10 and in human allografts that show poor function after reperfusion. 11 Calpain activity has been shown to be associated with remodeling of actin. 12-14 Therefore, we hypothesized that exposure of SEC to cold results in the following sequence: elevated intracellular calcium concentration, increased calpain activity, and actin disassembly.

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Section: Discussionmentioning

confidence: 98%

“…The design of the apparatus was that of Miller et al 26 with modifications as previously described. 27,28 The perfusate consisted of Sprague-Dawley rat blood added to Krebs-Henseleit solution, supplemented with 0.2% BSA and 0.1 g dextrose. The final hematocrit was approximately 14%.…”

Section: Effect Of Addition Of Dantrolene To Uw and Ec Solutions On Tmentioning

confidence: 99%

Effect of cold preservation on intracellular calcium concentration and calpain activity in rat sinusoidal endothelial cells

et al. 2003

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“…36 Blood samples were obtained from the inferior vena cava using a 24G catheter via a midline incision. The samples were collected in serum separator tubes (Becton Dickinson, Franklin Lakes, NJ) and immediately centrifuged at 11,000 rpm for 5 minutes.…”

Section: Serum Markers Of Reperfusion Injurymentioning

confidence: 99%

P–Selectin Mediates Reperfusion Injury Through Neutrophil and Platelet Sequestration in the Warm Ischemic Mouse Liver

Yadav¹,

et al. 1999

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Hepatic damage following ischemia-reperfusion injury involves polymorphonuclear leukocytes (PMN) and platelet sequestration, however the mechanisms of adhesion remain elusive. In this study, using gene-targeted deficient mice, we evaluated P-selectin and its contribution to PMN and platelet adhesion in hepatic damage. In an in vivo warm ischemia model, hepatic injury was assessed by serum transaminase levels, survival, PMN adhesion by histological analysis, and platelet sequestration by immunostaining. Serum transaminase levels were strikingly reduced (by up to threefold) in the P-selectin deficient mice, particularly at 90 minutes of ischemia, when compared with wild-type controls. PMN adhesion and platelet sequestration was also significantly decreased in P-selectin deficient mice following 90 minutes of partial ischemia. Animal survival was significantly improved after 75 minutes of total hepatic ischemia in P-selectin deficient mice when compared with wild-type mice. Survival was also achieved after 90 minutes of ischemia in the mutant mice whereas none of the wild-type animals survived. These data show that P-selectin plays a critical role in PMN and platelet adhesion following ischemia-reperfusion injury to the liver. (HEPATOLOGY 1999; 29:1494-1502.)The pathogenesis of cell damage following reperfusion of ischemic tissue is an incompletely understood series of events. 1,2 Various mechanisms have been proposed including enhanced production of inflammatory mediators, 3-5 recruitment of polymorphonuclear leukocytes (PMN), 6,7 and blockage of blood flow. 7-9 The leukocyte-endothelial interaction that occurs following ischemia/reperfusion (I/Rp) injury has been shown to be important for microvascular dysfunction and release of cytotoxic mediators such as reactive oxygen intermediates and a variety of proteases. 10-12 We 13 and others 5,6,9,14,15 have shown leukocyte accumulation to be a critical determinant of hepatic I/Rp injury. Other blood elements including platelets adhere to the hepatic sinusoids in conditions of ischemia, 16,17 but little is known about their contribution to the injury.The adhesion of PMN and platelets to the vascular endothelium involves a variety of adhesion receptors. [18][19][20][21] The selectin family (P-, E-, and L-selectin) are the first to be engaged in the process, 19 with P-selectin acting at the earliest stage of interaction between PMN and the endothelium. P-selectin is found in the ␣ granules of resting platelets and Weibel-Palade bodies of endothelial cells, 18 and expression of P-selectin on the cell surface can occur within minutes under stimulation by mediators of inflammation such as thrombin, histamine, complement, and peroxide. 22 P-selectin is able to tether leukocytes to the endothelial surface through its ligand P-selectin glycoprotein ligand-1 (PSGL-1), which leads to their activation. 23 Once leukocytes attach, they can interact with flowing PMN and platelets through the action of P-and L-selectin, 23 which may lead to further adhesion of PMN and platelets as we...

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“…After a midline laparot-marker of hepatic reperfusion injury. 21 Liver biopsies for histological assessment of tissue necrosis, PMN infiltration, and expression omy, the portal triad was exposed. In mice, the median lobe of the liver (Ç45% of liver mass) was clamped at its base using a of TNF-a messenger RNA (mRNA) were obtained after 1 and 6 hours following reperfusion.…”

Section: Fig 1 Serum Ast Levels Following Reperfusion Of Rat Liversmentioning

confidence: 99%

Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent

et al. 1997

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Interleukin-6 (IL-6) is an acute reactant cytokine with anti-thought to be the most important risk factor for postoperative inflammatory properties, which has been found to prevent complications in patients undergoing liver resection 1,2 and it injury in a model of acute hepatitis in mice through downregu-is an important cause of primary nonfunction of liver allolation of tumor necrosis factor alpha (TNF-a); to correlate grafts. [3][4][5] The potential mediators involved in WI/Rp injury inversely with markers of hepatocellular injury in patients are numerous, 6-8 and include acute phase reactant cytokines with liver ischemia; and to initiate liver regeneration in mice. and polymorphonuclear neutrophils (PMN). 3,9 Better underIn this study, we investigated the role of IL-6 in rodent models standing of the pathogenesis of WI/Rp injury of the liver and of hepatic warm ischemia/reperfusion (WI/Rp) injury. IL-6-the availability of an agent that could alleviate Rp injury deficient mice (0/0) were subjected to hepatic WI and com-would have important clinical implications. pared with C57BL/6 mice, as well as IL-6 0/0 mice pretreated Interleukin-6 (IL-6) is an acute phase reactant cytokine with recombinant IL-6 (rIL-6). The effects of rIL-6 following with pleiotropic biological effects. This cytokine plays a cenvarious periods of ischemia were further studied in models of tral role in hematopoiesis, host defense, and inflammation. 10 hepatic ischemia in rats. IL-6 0/0 mice had increased reperfu-IL-6 has been found to have potent anti-inflammatory propsion injury as assessed by transaminase levels and a tissue erties, particularly in preventing injuries related to endotoxenecrosis scoring system when compared with controls, an ef-mia. 11,12 In a rat model of endotoxin-induced tracheal injury, fect prevented by pretreatment with rIL-6. Similarly, rats pre-recombinant IL-6 (rIL-6) was found to significantly prevent treated with rIL-6 had reduced reperfusion injury and better neutrophil infiltration and reduce other markers of inflamsurvival than controls in each respective WI group. Tissue mation. 11 TNF-a expression measured by Northern blot analysis andAlthough the liver is an important source of IL-6 and the serum C-reactive protein (CRP) levels, a marker of inflamma-primary site for its clearance, 13 the role of IL-6 in liver disease tion, were significantly reduced in animals pretreated with is unclear. In an acute hepatitis model in mice, rIL-6 was rIL-6. Administration of antibodies to TNF-a reproduced the found to confer a high degree of hepatoprotection when given beneficial effect of rIL-6. Hepatocyte proliferation, as assessed before the induction of the injury. 14 This effect was thought by a scoring method for mitotic index and proliferating nuclear to be related to downregulation of tumor necrosis factor cell antigen staining, was markedly increased in rIL-6-treated alpha (TNF-a) production. In a recent prospective randomrats when compared with controls. In conclusion, this study ized study of hepatic vascular...

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Markers of Allograft Viability in the Rat Relationship Between Transplantation Viability and Liver Function in the Isolated Perfused Liver

Cited by 126 publications

References 0 publications

Effect of cold preservation on intracellular calcium concentration and calpain activity in rat sinusoidal endothelial cells

Effect of cold preservation on intracellular calcium concentration and calpain activity in rat sinusoidal endothelial cells

P–Selectin Mediates Reperfusion Injury Through Neutrophil and Platelet Sequestration in the Warm Ischemic Mouse Liver

Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent

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