Ischemia impairs liver regeneration after major tissue loss in rodents: Protective effects of interleukin-6

Selzner, Markus; Camargo, Carlos A.; Clavien, Pierre‐Alain

doi:10.1002/hep.510300215

Cited by 139 publications

(124 citation statements)

References 20 publications

(45 reference statements)

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“…The increase of IL-6 production (5-fold) in TNFR-1(Ϫ͞Ϫ) mice may also explain the high regeneration observed in these animals after partial OLT. We also previously demonstrated the protective effects of IL-6 in restoring regeneration in liver subjected to warm (36) and cold (37) ischemia. Similar data are emerging for IL-10 (38), and in cold ischemiareperfusion injury pretreatment of the donor with IL-10 decreased liver injury and the release of T cell and macrophagedependent cytokines (39).…”

Section: Discussionmentioning

confidence: 81%

Kupffer cell-dependent TNF-α signaling mediates injury in the arterialized small-for-size liver transplantation in the mouse

Tian¹,

Jochum

Georgiev³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Implantation of small liver grafts causes liver injury and defective regeneration leading to graft failure. We investigated whether Kupffer cell-dependent TNF-␣ signaling contributes to this poor outcome. Partial 30% liver transplantation was performed in C57BL͞6 wild-type mice (control group), and in three groups with down-regulation of the TNF-␣ pathway: (i) TNF receptor 1 knockout [TNFR-1(؊͞؊)] mice, and mice pretreated with (ii) gadolinium chloride or (iii) pentoxifylline (PTX). Fifty-percent partial liver transplantation, a model associated with full recovery, and transplantation in IL-6 knockout [IL-6(؊͞؊)] mice were performed in some experiments. Graft injury, regeneration, portal flow, liver microcirculation, leukocyte adhesion, and animal survival were assessed. Animal survival rates were 14% in the control group vs. 43% in the gadolinium chloride group, 57% for the TNFR-1(؊͞؊) group, and 86% in the PTX group (P < 0.001). Markers of liver injury were reduced in all treated groups when compared with controls. Each treated group disclosed better portal flow and sinusoid perfusion, decreased leukocyte adherence, particularly in the PTX group. Liver regeneration occurred only in the treated groups. IL-6 and IL-10 levels were dramatically up-regulated (50؋) in the PTX group, and at lower levels in other experimental groups. The protective effect of PTX was lost in IL-6(؊͞؊) mice and protection was restored by a single dose of r-IL-6. In conclusion, interruption of TNF-␣ signaling or depletion of Kupffer cells improves survival after 30% liver transplantation, reduces liver injury, and enhances regeneration. The superior effects of PTX are mediated by IL-6.

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Section: Discussionmentioning

confidence: 81%

Kupffer cell-dependent TNF-α signaling mediates injury in the arterialized small-for-size liver transplantation in the mouse

Tian¹,

Jochum

Georgiev³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…16 As demonstrated herein, exogenous IL-6 may accelerate recovery of liver mass in vivo, consistent with findings that IL-6 may have therapeutic application in the prevention of ischemic injury during organ preservation before transplantation and in amelioration of hepatic steatosis. [32][33][34][35] The role and effects of the persistently increased IL-6 present in a wide variety of disease states, however, remains poorly defined. Several reports suggest that this chronic signaling may be protective against injury.…”

Section: Discussionmentioning

confidence: 99%

Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair

et al. 2006

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Interleukin-6 (IL-6) is an important mediator of liver regeneration and repair that is also elevated in chronic liver diseases, including fatty liver of obesity and cirrhosis. IL-6 has been reported both to delay and accelerate liver regeneration. We examined the effects on liver injury and regeneration of a continuous administration of exogenous IL-6 to mice by injection of an IL-6 -expressing CHO-cell line in athymic nude mice and by osmotic mini-pump delivery of recombinant murine IL-6. Short-term IL-6 administration (1-2 days) accelerated early recovery of liver mass, whereas more long-term administration (5-7 days) markedly impaired liver regeneration. Similarly, short-term IL-6 treatment increased hepatic resistance to the lethal effects of the Fas agonist Jo-2, but on more prolonged IL-6 exposure the Jo-2 resistance vanished. IL-6 administration initially induced expression of the anti-apoptotic proteins Bcl-2 and Bcl-x L , correlating with protection against Fas-mediated cell death. More prolonged IL-6 administration, however, resulted in marked induction of the proapoptotic protein Bax. This result coincided with increased activation of the type II or intrinsic, mitochondrial path to cell death, manifested by increased caspase-9 activation and increased cytochrome c release after Jo-2 exposure. These data demonstrate that IL-6 can function acutely to improve hepatic regeneration and repair, but that more chronic exposure not only abolishes the protective effects of IL-6, but actually sensitizes the liver to injury and death. In conclusion, elevated IL-6 in certain chronic liver diseases contributes to an increased likelihood of liver failure after injury. (HEPATOLOGY 2006;43:474-484.)

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“…30 Recent studies have shown a narrow balance between cell death during preservation and reperfusion, followed by cell proliferation through regeneration. 22,31 Accumulating data have suggested that the impact of ischemic rewarming on liver injury is more critical than injuries related to hypothermia. 32 Whether the mechanisms of injury related to cold versus normothermic ischemia are similar remains controversial.…”

Section: Discussionmentioning

confidence: 99%

“…[21][22][23] Our hypothesis is that this process of hepatocyte proliferation could enhance HCV incorporation into the new hepatocyte within the allograft. Although no correlation was found in 1 study between the duration of cold preservation and severity of post-OLT HCV infection, 5 other types of injury related to organ preservation, such as the duration of graft rewarming during implantation surgery, could be important.…”

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confidence: 99%

Prolonged Rewarming Time During Allograft Implantation Predisposes to Recurrent Hepatitis C Infection After Liver Transplantation

Baron

Sindram

Higdon

et al. 2000

Liver Transplantation

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The majority of patients undergoing orthotopic liver transplantation (OLT) have end-stage liver disease secondary to hepatitis C virus (HCV) infection. Although OLT does not cure the disease and recurrent virus is present in all patients, relatively few patients with recurrent viremia develop clinical disease. When the disease recurs, however, the results can be devastating. Factors associated with increased risk for recurrent HCV disease remain controversial. We hypothesized that preservation injury may predispose to the severity of HCV disease after OLT. We reviewed our series of OLTs performed for HCV cirrhosis between January 1994 and December 1998 (n ‫؍‬ 56; 62 transplants). Patients were grouped according to the severity of recurrent hepatitis C. Group 1 had no or mild HCV disease (n ‫؍‬ 36), and group 2 had moderate to severe HCV disease (n ‫؍‬ 20). The duration of ischemic rewarming during graft implantation was significantly associated with the severity of recurrent hepatitis C (P F .04). The estimated chances of severe disease within the first year post-OLT after 30, 60, or 90 minutes of ischemic rewarming time were 19%, 40%, and 65%, respectively. Cold ischemia time, transaminase levels, and prothrombin time did not correlate with the severity of hepatitis C. In conclusion, our data suggest that the duration of ischemic rewarming predisposes to severe recurrent hepatitis C. This finding warrants the investigation of the pathogenesis of recurrent HCV disease after ischemic injury. Reduction of rewarming time should be stressed in OLT, particularly in patients with HCV cirrhosis. (Liver Transpl 2000;6:407-412.)A pproximately 1% of Americans (2.7 million individuals) are currently infected with the hepatitis C virus (HCV). 1 Although the natural history of the viral infection is unknown, it is estimated that chronic hepatitis caused by HCV infection develops in approximately 20% of infected individuals 20 years after initial exposure. 2-4 Patients with chronic HCV have an increased risk for hepatocellular carcinoma (1% to 4% per year) and the complications of end-stage liver disease. In these patients, the survival rate with decompensated cirrhosis is 50% at 5 years without transplantation. Orthotopic liver transplantation (OLT) for these patients leads to 5-year survival rates between 73% and 81%. 5,6 As a result of these data, patients with decompensated HCV cirrhosis should be considered for liver replacement therapy, as well as medical treatment, for better long-term survival. HCV-associated cirrhosis was the predominant indication for OLT in patients who underwent transplantation in the United States between 1987 and 1995. 7 Currently, hepatitis C is the indication for transplantation in more than 30% of adults, making it the most common indication for OLT. 8 Although several studies have suggested that the long-term survival rate after OLT in patients with HCV cirrhosis is not different from those who undergo OLT for other indications, 5,6,9,10 all patients have recurrent HCV infection at 1 year ...

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Ischemia impairs liver regeneration after major tissue loss in rodents: Protective effects of interleukin-6

Cited by 139 publications

References 20 publications

Kupffer cell-dependent TNF-α signaling mediates injury in the arterialized small-for-size liver transplantation in the mouse

Kupffer cell-dependent TNF-α signaling mediates injury in the arterialized small-for-size liver transplantation in the mouse

Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair

Prolonged Rewarming Time During Allograft Implantation Predisposes to Recurrent Hepatitis C Infection After Liver Transplantation

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