scholarly journals Cardiotrophin-1 defends the liver against ischemia-reperfusion injury and mediates the protective effect of ischemic preconditioning

2006 ◽  
Vol 203 (13) ◽  
pp. 2809-2815 ◽  
Author(s):  
Maria Iñiguez ◽  
Carmen Berasain ◽  
Eduardo Martinez-Ansó ◽  
Matilde Bustos ◽  
Puri Fortes ◽  
...  
Keyword(s):  
Blood Flow ◽  
Liver Injury ◽  
Protective Effect ◽  
Ischemic Preconditioning ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Isolated Hepatocytes ◽  
Survival Pathways ◽  
Stat3 Phosphorylation ◽  
Deficient Mice

Ischemia-reperfusion (I/R) liver injury occurs when blood flow is restored after prolonged ischemia. A short interruption of blood flow (ischemic preconditioning [IP]) induces tolerance to subsequent prolonged ischemia through ill-defined mechanisms. Cardiotrophin (CT)-1, a cytokine of the interleukin-6 family, exerts hepatoprotective effects and activates key survival pathways like JAK/STAT3. Here we show that administration of CT-1 to rats or mice protects against I/R liver injury and that CT-1–deficient mice are exceedingly sensitive to this type of damage. IP markedly reduced transaminase levels and abrogated caspase-3 and c-Jun–NH2-terminal kinase activation after I/R in normal mice but not in CT-1–null mice. Moreover, the protective effect afforded by IP was reduced by previous administration of neutralizing anti–CT-1 antibody. Prominent STAT3 phosphorylation in liver tissue was observed after IP plus I/R in normal mice but not in CT-1–null mice. Oxidative stress, a process involved in IP-induced hepatoprotection, was found to stimulate CT-1 release from isolated hepatocytes. Interestingly, brief ischemia followed by short reperfusion caused mild serum transaminase elevation and strong STAT3 activation in normal and IL-6–deficient mice, but failed to activate STAT3 and provoked marked hypertransaminasemia in CT-1–null animals. In conclusion, CT-1 is an essential endogenous defense of the liver against I/R and is a key mediator of the protective effect induced by IP.

scholarly journals Postconditioning ameliorates lipid peroxidation in liver ischemia-reperfusion injury in rats

2009 ◽  
Vol 24 (1) ◽  
pp. 52-56 ◽  
Author(s):  
Antonio Roberto Franchi Teixeira ◽  
Nilza T. Molan ◽  
Márcia Saldanha Kubrusly ◽  
Marta Bellodi-Privato ◽  
Ana Maria Coelho ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Blood Flow ◽  
Protective Effect ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Control Group ◽  
Liver Ischemia ◽  
Glutathione S Transferase ◽  
Ischemic Event

PURPOSE: Liver ischemia-reperfusion injury is a phenomenon presents in events like liver resections and transplantation. The restoration of blood flow may leads to local and systemic injury. Several techniques have been developed in order to avoid or ameliorate ischemia-reperfusion injury in clinical situations. The application of a sttuter reperfusion after the ischemic event (postconditioning) could alters the hydrodynamics and stimulates endogenous mechanisms that attenuate the reperfusion injury. The present study was designed to evaluate the potential protective effect of postconditioning in a model of ischemia-reperfusion in rats. METHODS: Hepatic anterior pedicle of median and left anterolateral segments were exposed and clamped for 1 hour. Two hours later, clamp was released in two different ways: Control Group (n=7): clamp was release straightforward; Postconditioning Group (n=7): clamp was released intermittently. Lipid peroxidation (malondialdehyde) and expression of the glutathione-s-transferase-α-3 gene were studied. RESULTS: Lipid peroxidation was significantly decreased in ischemic and non-ischemic liver by postconditioning. GST- α3 gene was overexpressed in postconditioned group, but not significantly. CONCLUSION: Postconditioning induced hepatoprotection by reducing lipid peroxidation in the ischemic and non-ischemic liver.

scholarly journals Role of Remote Ischemic Preconditioning in Hepatic Ischemic Reperfusion Injury

Dose-Response ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 155932582094692
Author(s):  
Eun Kyung Choi ◽  
Hoon Jung ◽  
Sungmin Jeon ◽  
Jung A. Lim ◽  
Jungwon Lee ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protective Effect ◽  
Reperfusion Injury ◽  
Inflammatory Cytokines ◽  
Ischemic Preconditioning ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Remote Ischemic Preconditioning ◽  
Hepatic Tissue ◽  
Hepatic Ischemia

The effect of remote ischemic preconditioning (RIPC) has been proposed that mediates the protective response in ischemia reperfusion injury (IRI) of various organs. In this study, we investigated the effect of RIPC in hepatic IRI, by assessing biomarker of oxidative stress and inflammatory cytokines. Moreover, we intended to demonstrate any such protective effect through nitric oxide (NO). Twenty-five rats were divided into the 5 groups: (1) Sham; (2) RIPC; (3) hepatic IRI; (4) RIPC + hepatic IRI; (5) C-PTIO, 2-(4-carboxyphenyl)-4,5dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3oxide, + RIPC + hepatic IRI. RIPC downregulated the level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), histologic damage, and activity of Malondialdehyde (MDA). However, there was no significant reduction in the level of tumor necrosis factor-alpha (TNF-α) and nuclear factor kappa B (NF-κB). AST and ALT levels, and hepatic tissue morphology in the C-PTIO group showed a significant improvement compared to those of the RIPC + hepatic IRI group. The application of RIPC before hepatic ischemia downregulated the oxidative stress, not the inflammatory cytokines. Moreover, these protective effect of RIPC would be mediated through the activation of NO as well as anti-oxidant effect.

scholarly journals GGsTop, a novel and specific γ-glutamyl transpeptidase inhibitor, protects hepatic ischemia-reperfusion injury in rats

2016 ◽  
Vol 311 (2) ◽  
pp. G305-G312 ◽  
Author(s):  
Kaneto Tamura ◽  
Nobuhiko Hayashi ◽  
Joseph George ◽  
Nobuyuki Toshikuni ◽  
Tomiyasu Arisawa ◽  
...  
Keyword(s):  
Blood Flow ◽  
Liver Injury ◽  
Group Treatment ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Vena Cava ◽  
Hepatic Tissue ◽  
Protective Effects ◽  
Hepatic Ischemia ◽  
Glutamyl Transpeptidase

Ischemia-reperfusion (IR) injury is a major clinical problem and is associated with numerous adverse effects. GGsTop [2-amino-4{[3-(carboxymethyl)phenyl](methyl)phosphono}butanoic acid] is a highly specific and irreversible γ-glutamyl transpeptidase (γ-GT) inhibitor. We studied the protective effects of GGsTop on IR-induced hepatic injury in rats. Ischemia was induced by clamping the portal vein and hepatic artery of left lateral and median lobes of the liver. Before clamping, saline (IR group) or saline containing 1 mg/kg body wt of GGsTop (IR-GGsTop group) was injected into the liver through the inferior vena cava. At 90 min of ischemia, blood flow was restored. Blood was collected before induction of ischemia and prior to restoration of blood flow and at 12, 24, and 48 h after reperfusion. All the animals were euthanized at 48 h after reperfusion and the livers were harvested. Serum levels of alanine transaminase, aspartate transaminase, and γ-GT were significantly lower after reperfusion in the IR-GGsTop group compared with the IR group. Massive hepatic necrosis was present in the IR group, while only few necroses were present in the IR-GGsTop group. Treatment with GGsTop increased hepatic GSH content, which was significantly reduced in the IR group. Furthermore, GGsTop prevented increase of hepatic γ-GT, malondialdehyde, 4-hydroxynonenal, and TNF-α while all these molecules significantly increased in the IR group. In conclusion, treatment with GGsTop increased glutathione levels and prevented formation of free radicals in the hepatic tissue that led to decreased IR-induced liver injury. GGsTop could be used as a pharmacological agent to prevent IR-induced liver injury and the related adverse events.

scholarly journals Synergistic effect of the TLR5 agonist CBLB502 and its downstream effector IL-22 against liver injury

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Nicolas Melin ◽  
Daniel Sánchez-Taltavull ◽  
René Fahrner ◽  
Adrian Keogh ◽  
Michel Dosch ◽  
...  
Keyword(s):  
Liver Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Underlying Mechanism ◽  
Isolated Hepatocytes ◽  
Protective Mechanism ◽  
Mesenteric Lymph Nodes ◽  
Transcriptional Signature ◽  
Stat3 Signaling ◽  
Toll Like Receptor 5

AbstractThe toll-like receptor 5 (TLR5) agonist, CBLB502/Entolimod, is a peptide derived from bacterial flagellin and has been shown to protect against radiation-induced tissue damage in animal models. Here we investigated the protective mechanism of CBLB502 in the liver using models of ischemia-reperfusion injury and concanavalin A (ConA) induced immuno-hepatitis. We report that pretreatment of mice with CBLB502 provoked a concomitant activation of NF-κB and STAT3 signaling in the liver and reduced hepatic damage in both models. To understand the underlying mechanism, we screened for cytokines in the serum of CBLB502 treated animals and detected high levels of IL-22. There was no transcriptional upregulation of IL-22 in the liver, rather it was found in extrahepatic tissues, mainly the colon, mesenteric lymph nodes (MLN), and spleen. RNA-seq analysis on isolated hepatocytes demonstrated that the concomitant activation of NF-κB signaling by CBLB502 and STAT3 signaling by IL-22 produced a synergistic cytoprotective transcriptional signature. In IL-22 knockout mice, the loss of IL-22 resulted in a decrease of hepatic STAT3 activation, a reduction in the cytoprotective signature, and a loss of hepatoprotection following ischemia-reperfusion-induced liver injury. Taken together, these findings suggest that CBLB502 protects the liver by increasing hepatocyte resistance to acute liver injury through the cooperation of TLR5-NF-κB and IL-22-STAT3 signaling pathways.

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