Improvement of Normothermic Rat Liver Ischemia/Reperfusion by Muramyl Dipeptide

doi:10.1006/jsre.1998.5445

Journal of Surgical Research

Volume 80, Issue 2, December 1998, Pages 339-344

https://doi.org/10.1006/jsre.1998.5445 Get rights and content

Abstract

Normothermic ischemia and reperfusion (I/R) of the liver remains a major problem after liver surgery and transplantation. Activation of Kupffer cells (KCs) after normothermic I/R is responsible for a massive release of various monokines such as tumor necrosis factor α (TNF-α) and a decrease in phagocytic activity. Muramyl dipeptide (MDP) is an immunostimulant that increases phagocytic activity of KCs. The aim of this study was to demonstrate that MDP pretreatment might protect the liver against I/R injury by a modification of KC functions. Rats were divided into three groups: group 1, control, Ringer's lactate administration; group 2, MDP (N-acetyl-muramyl-d-alanyl-d-isoglutamine) treatment; group 3, sham-operated control animals. MDP (500 μg/250 g) was injected intravenously 5 min before the induction of 90 min ischemia. Survival rates were compared and serum activities of TNF-α, aspartate aminotransferase, and alanine aminotransferase were assessed in the blood collected from the suprahepatic vena cava. Histology of the liver and KC activity were assessed 6 and 9 h after the end of ischemia, respectively. MDP treatment significantly increased 7-day survival (86.6%) compared with nontreated rats (40%,P< 0.001). Serum activities of TNF-α and aminotransferases were significantly decreased after MDP treatment, whereas phagocytic capacity of KCs was partially restored. The extent of liver necrosis was decreased after MDP administration. A significant difference was observed for other histological parameters studied, except for steatosis. Our findings have demonstrated that MDP is able to protect the liver from ischemic insult by modulation of KC activity (TNF-α release and phagocytic capacity). Control of macrophage activity may offer a new strategy to reduce ischemic injury of the liver.

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Hepatic ischemia-reperfusion injury is commonplace in liver surgery, particularly in hepatic transplantation, hepatic resection, and trauma. The signaling events contributing to local hepatocellular damage are diverse and complex and involve the interaction between hepatocytes, sinusoidal endothelial cells, Kupffer cells, as well as infiltrating neutrophils, macrophages, and platelets. Signaling mediators include cytokines, reactive oxygen and nitrogen species, calcium, complement, and several transcription factors. The purpose of this review article was to summarize the factors that contribute to the pathophysiology of hepatic ischemia-reperfusion injury.
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Specimens fixed in 10% formalin were stained with hematoxylin and eosin (4-μm sections) for light microscopic examination. The degree of damage to the liver was determined as percentage of total area that exhibited hepatocellular necrosis as previously described.9 Results were expressed as mean values ± SEM.
Pentoxifylline (PTX) has been shown to protect the liver against normothermic ischemia-reperfusion (I-R) injury. The aims of this study were to investigate the action of PTX on tumor necrosis factor alpha (TNFα) gene transcription following normothermic liver I-R as well as to evaluate the resulting effects on liver function and survival. A segmental normothermic liver ischemia was induced for 90 minutes. Rats were divided into three groups: group 1, control, Ringer lactate administration; group 2, PTX treatment; group 3, sham-operated control rats. PTX (50 mg/kg) was injected intravenously 30 minutes before induction of ischemia and 30 minutes before reperfusion. The nonischemic liver lobes were resected at the end of ischemia. Survival rates were compared and serum activities of TNFα, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase were measured. Liver histology was assessed 6 hours after reperfusion. Liver TNFα mRNA was assessed by polymerase chain reaction amplification at different times after reperfusion. PTX treatment significantly decreased serum activities of TNFα and inhibited liver expression of TNFα mRNA. The extent of liver necrosis and serum levels of liver enzymes were significantly decreased by PTX treatment, resulting in a significant increase in 7-day survival compared with nontreated control rats. In conclusion, PTX inhibits liver TNFα gene transcription, decreases serum TNFα levels, and reduces liver injury following normothermic I-R.
Pentoxifylline inhibits liver expression of tumor necrosis factor alpha mRNA following normothermic ischemia-reperfusion
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In this study, in the control group, 90 min lobar normothermic liver ischemia followed by reperfusion and 30% hepatectomy (involving the nonischemic lobes) resulted in post-hepatic (suprahepatic vena cava) blood release of TNFα. This effect is in line with a previous study [13]. PTX treatment decreased TNFα serum levels at each time interval studied.
Background: Pentoxifylline (PTX) has been shown to reduce hepatic injury after normothermic ischemia and reperfusion (I-R) in rat liver. Aim: The aim of this study was to evaluate the effects of PTX on liver expression of tumor necrosis factor alpha (TNFα) mRNA following normothermic liver I-R. Materials and methods: A segmental normothermic ischemia of the liver was induced in male Lewis rats by occluding the blood vessels including the bile duct to the median and left lateral lobes for 90 min. At the end of ischemia the nonischemic liver lobes were resected. Rats were divided into three groups: group 1, control Ringer lactate administration; group 2, PTX treatment; group 3, sham-operated control rats. PTX (50 mg/kg) was injected intravenously 30 min before and 60 min after induction of ischemia. Survival rates were compared and the serum activities of TNFα, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) were measured. Histology of the liver was assessed 6 h after reperfusion. Liver TNFα mRNA was assessed by PCR amplification at 0, 60, 120, and 210 min after reperfusion. Results: PTX treatment significantly increased 7 day survival (93.3%) compared with nontreated control rats (46.6%, p<0.007). The extent of liver necrosis and the release of liver enzymes were significantly decreased after PTX treatment. Serum activities of TNFα were significantly decreased and liver expression of TNFα mRNA was inhibited after PTX treatment. Conclusion: PTX protects the liver from ischemic injury and inhibits liver expression of TNFα mRNA.
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This article summarizes strategies to protect the liver from injuries caused by ischemia and reperfusion. Three different sections (i.e., surgical and pharmacologic strategies and gene therapy) present approaches to enhance the survival and viability of the liver in various surgical procedures including liver transplantation. The first section reviews approaches using surgical interventions such as ischemic preconditioning and intermittent clamping. Their protective effects are discussed with respect to the mechanism of injury. In the second section, pharmacologic agents targeting microcirculation, oxidative stress, proteases, and inflammation are described. Mechanisms of injury and their suppression by a wide variety of drugs are discussed. The third section focuses on gene therapy. Potential target genes have been identified (e.g., superoxide dismutase or heme oxygenase). Animal experiments in which the liver injury is reduced successfully may pave the way to novel strategies applied to different liver diseases in humans.
Microvascular dysfunction induced by reperfusion injury and protective effect of ischemic preconditioning
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Hepatic ischemia/reperfusion injury has immediate and deleterious effects on the outcome of patients after liver surgery. The precise mechanisms leading to the damage have not been completely elucidated. However, there is substantial evidence that the generation of oxygen free radicals and disturbances of the hepatic microcirculation are involved in this clinical syndrome. Microcirculatory dysfunction of the liver seems to be mediated by sinusoidal endothelial cell damage and by the imbalance of vasoconstrictor and vasodilator molecules, such as endothelin (ET), reactive oxygen species (ROS), and nitric oxide (NO). This may lead to no-reflow phenomenon with release of proinflammatory cytokines, sinusoidal plugging of neutrophils, oxidative stress, and as an ultimate consequence, hypoxic cell injury and parenchymal failure. An inducible potent endogenous mechanism against ischemia/reperfusion injury has been termed ischemic preconditioning. It has been suggested that preconditioning could inhibit the effects of different mediators involved in the microcirculatory dysfunction, including endothelin, tumor necrosis factor-α, and oxygen free radicals. In this review, we address the mechanisms of liver microcirculatory dysfunction and how ischemic preconditioning could help to provide new surgical and/or pharmacological strategies to protect the liver against reperfusion damage.
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^☆: G. L. MandellR. G. DouglasJ. E. Bennett

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Regular ArticleImprovement of Normothermic Rat Liver Ischemia/Reperfusion by Muramyl Dipeptide☆

Abstract

J. Hepatol.

J. Hepatol.

J. Immunol. Methods

J. Biol. Chem.

Hepatic reperfusion injury following orthotopic liver transplantation in the rat

Transplantation

Sinusoidal lining cell damage: The critical injury in cold preservation of liver allografts in the rat

Transplantation

Reperfusion injury to endothelial cells following cold ischemic storage of rat liver

Hepatology

Transhepatic metabolism of TNF-alpha, IL-6, and endotoxin in the early hepatic reperfusion period after human liver transplantation

Transplantation

Pathogenic role of Kupffer cell activation in the reperfusion injury of cold-preserved liver

Transplantation

Kupffer cell activation and endothelial cell damage after storage of rat livers: Effects of reperfusion

Hepatology

Assessment of hepatic phagocytic activity by in vivo microscopy after liver transplantation in the rat

Hepatology

Role of tumor necrosis factor-α in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat

J. Clin. Invest.

Evidence that FK506 alleviates ischemia/reperfusion injury to the rat liver: In vivo demonstration for suppression of TNF-α production in response to endotoxemia

Eur. Surg. Res.

Role of non-parenchymal liver cells in ischaemia–reperfusion liver injury: Protective effects of muramyl dipeptide

Transplant. Int.

Effect of ischemia on hepatic parenchymal and reticuloendothelial function in the baboon

Surgery

Ischemic injury in liver transplantation: Difference in injury between warm and cold ischemia in rats

Hepatology

Protective effect of prostaglandin E1 (PgE1) on energy metabolism and reticuloendothelial function in the ischemically damaged canine liver

Liver

Protective properties of anti-IFNα/β antibodies in normothermic hepatic ischemia in the rat

Transplant. Proc

Biologic properties of a new synthetic adjuvant, muramyl dipeptide (MDP)

Springer Semin Immunopathol

Induction of tumoricidal activity in isolated rat liver macrophages by liposomes containing recombinant rat gamma-interferon supplemented with lipopolysaccharide or muramyl dipeptide

Cancer Res.

Stimulation of the reticuloendothelial system of mice by muramyl dipeptide

Infect. Immun.

Regular Article
Improvement of Normothermic Rat Liver Ischemia/Reperfusion by Muramyl Dipeptide☆