• Ischemia/reperfusion injury
• Ischemic preconditioning
• MicroRNAs

• MicroRNAs/genetics
• MicroRNAs/metabolism
• Humans
• Reperfusion Injury/metabolism
• Reperfusion Injury/pathology
• Reperfusion Injury/genetics
• Ischemic Preconditioning
• Animals
• Oxidative Stress

• 4020122 Yasuj University of Medical Sciences

• Fatty liver
• Ischemia–reperfusion injury
• Ischemic postconditioning
• Liver transplantation

• Ischemia reperfusion injury
• Kidney
• Liver
• Transplantation
• microRNAs

Despite the ongoing decades-long controversy, Pringle maneuver (PM) is still frequently used by hepatobiliary surgeons during hepatectomy. The aim of this study was to investigate the effect of PM on intraoperative blood loss, morbidity, and posthepatectomy hemorrhage (PHH). A series of 209 consecutive patients underwent extended hepatectomy (EH) (≥5 segment resection). The association of PM with perioperative outcomes was evaluated using multivariate analysis with a propensity score method to control for confounding. Fifty patients underwent PM with a median duration of 19 minutes. Multivariate analysis revealed that risk of excessive intraoperative bleeding (≥1500 ml; odds ratio [OR] 0.27, 95%-confidence interval [CI] 0.10–0.70, p = 0.007), major morbidity (OR 0.41, 95%-CI 0.18–0.97, p = 0.041), and PHH (OR 0.22, 95%-CI 0.06–0.79, p = 0.021) were significantly lower in PM group after EH. Furthermore, there was no significant difference in 3-year recurrence-free-survival between groups. PM is associated with lower intraoperative bleeding, PHH, and major morbidity risk after EH. Performing PM does not increase posthepatectomy liver failure and does not affect recurrence rate. Therefore, PM seems to be justified in EH.

We analyzed the participation of mitogen-activated protein kinases (MAPKs), namely p38, JNK and ERK 1/2 in steatotic and non-steatotic livers undergoing ischemia-reperfusion (I-R), an unresolved problem in clinical practice. Hepatic steatosis is a major risk factor in liver surgery because these types of liver tolerate poorly to I-R injury. Also, a further increase in the prevalence of steatosis in liver surgery is to be expected. The possible therapies based on MAPK regulation aimed at reducing hepatic I-R injury will be discussed. Moreover, we reviewed the relevance of MAPK in ischemic preconditioning (PC) and evaluated whether MAPK regulators could mimic its benefits. Clinical studies indicated that this surgical strategy could be appropriate for liver surgery in both steatotic and non-steatotic livers undergoing I-R. The data presented herein suggest that further investigations are required to elucidate more extensively the mechanisms by which these kinases work in hepatic I-R. Also, further researchers based in the development of drugs that regulate MAPKs selectively are required before such approaches can be translated into clinical liver surgery.

• ischemic-reperfusion injury
• mitogen activated protein kinases
• non-alcoholic fatty liver disease
• steatosis

• Animals
• Fatty Liver/metabolism
• Fatty Liver/pathology
• Fatty Liver/physiopathology
• Fatty Liver/therapy
• Humans
• Ischemic Preconditioning
• Liver/metabolism
• Liver/pathology
• Liver/physiopathology
• MAP Kinase Signaling System
• Mitogen-Activated Protein Kinases/metabolism
• Reperfusion Injury/metabolism
• Reperfusion Injury/pathology
• Reperfusion Injury/physiopathology
• Reperfusion Injury/prevention & control

• NAD+
• bioenergetics
• hepatic steatosis
• indirubin-3′-oxime
• mitochondrial dysfunction
• permeability transition

• Adenosine Triphosphate/metabolism
• Animals
• Antibiotics, Antineoplastic/pharmacology
• Calcium/metabolism
• Peptidyl-Prolyl Isomerase F
• Cyclophilins/drug effects
• Cyclophilins/metabolism
• Cytochromes c/drug effects
• Cytochromes c/metabolism
• Fatty Liver/metabolism
• Fatty Liver/pathology
• Glycogen Synthase Kinase 3 beta/antagonists & inhibitors
• Hepatic Artery
• Indoles/pharmacology
• Liver/drug effects
• Liver/metabolism
• Liver/pathology
• Mitochondria, Liver/drug effects
• Mitochondria, Liver/metabolism
• Mitochondrial ADP, ATP Translocases/metabolism
• NAD/pharmacology
• Oximes/pharmacology
• Rats
• Rats, Zucker
• Reactive Oxygen Species/metabolism
• Reperfusion Injury/metabolism
• Sirtuins/metabolism
• Warm Ischemia

A rat HIRI model was constructed and treated with an intraperitoneal injection of agomir-miR-494 or agomir-NC (negative control) for 7 days after the surgery. The pathophysiological changes in sham-operated rats, HIRI, HIRI + agomir-miR-494, and HIRI + agomir-NC were compared. The effect of miR-494 was also assessed in an H₂O₂-induced apoptosis model. Hepatic AML12 cells were transfected with mimics NC or miR-494 mimics, followed by 6-h H₂O₂ treatment. Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry, respectively. Further, the miR-494 target gene was identified by luciferase reporter assay, and verified both in vitro and in vivo experiments. The activity of AKT pathway was further analyzed in vivo by Western blot. HIRI + agomir-miR-494 rats exhibited significantly higher miR-494 expression, lower serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and glutamate dehydrogenase (GLDH) level, lower hepatic MDA, TOA, and OSI, alleviated hepatic necrosis, reduced hepatocyte apoptosis, and decreased expression of apoptosis-related proteins, when compared with HIRI + agomir-NC rats (P<0.05 or 0.01). After H₂O₂ treatment, AML-12 cells transfected with miR-494 mimics had significantly higher proliferation and lower apoptosis rate compared with mimics NC group (P<0.01). PTEN was identified as an miR-494 target gene. PTEN expression was significantly down-regulated in AML12 cells transfected with miR-494 mimics, and was up-regulated by treatment of miR-494 inhibitor (P<0.01). Moreover, HIRI + agomir-miR-494 rats exhibited significantly lower PTEN expression, and higher p-AKT, p-mTOR, and p-p70S6K levels compared with HIRI + agomir-NC rats. Therefore, miR-494 protected rats against hepatic ischemia/reperfusion (I/R) injury through down-regulating its downstream target gene PTEN, leading to the activation of PI3K/AKT signaling pathway.

• AML12 cells
• MicroRNA-494
• PI3K/Akt
• apoptosis
• hepatic ischemia/reperfusion injury

IRI results from the interruption then reinstatement of an organ's blood supply, and this poses a significant problem in liver transplantation and resectional surgery.

In this paper, we explore the role T cells play in the pathogenesis of this injury.

We used an in vivo murine model of warm partial hepatic IRI, genetically-modified mice, in vivo antibody depletion, adoptive cell transfer and flow cytometry to determine which lymphocyte subsets contribute to pathology. Injury was assessed by measuring serum alanine aminotransfersase (ALT) and by histological examination of liver tissue sections.

The absence of T cells (CD3εKO) is associated with significant protection from injury (p = 0.010). Through a strategy of antibody depletion it appears that NKT cells (p = 0.0025), rather than conventional T (CD4 + or CD8 +) (p = 0.11) cells that are the key mediators of injury.

Our results indicate that tissue-resident NKT cells, but not other lymphocyte populations are responsible for the injury in hepatic IRI. Targeting the activation of NKT cells and/or their effector apparatus would be a novel approach in protecting the liver during transplantation and resection surgery; this may allow us to expand our current criteria for surgery.

•

Hepatic IRI worsens outcome in liver transplantation.

• Acute liver injury
• Ischemia-reperfusion injury (IRI)
• Liver surgery
• NKT cells
• Natural killer cells
• T cells
• Transplantation

• hemo-dynamics
• ischemia-reperfusion injury
• liver function
• remifentanil

• Blood loss
• Liver resection
• Pringle maneuver

• Animals
• Antioxidants/therapeutic use
• Complement System Proteins
• Cytokines/immunology
• Cytokines/physiology
• Endothelium, Vascular/immunology
• Endothelium, Vascular/physiopathology
• Humans
• Immunotherapy
• Ischemia/immunology
• Ischemia/physiopathology
• Ischemia/therapy
• Ischemic Preconditioning
• Neutrophils
• Reactive Oxygen Species/immunology
• Reperfusion
• Reperfusion Injury/immunology
• Reperfusion Injury/physiopathology
• Reperfusion Injury/therapy

Hepatic ischemia-reperfusion injury is a dynamic process consisting of two stages: ischemia and reperfusion, and triggers a cascade of physiological and biochemical events. Given the important role of microRNAs in regulating gene expression, we analyzed gene expression changes in mouse livers at sham control, ischemia stage, and reperfusion stage. We generated global expression profiles of microRNA and mRNA genes in mouse livers subjected to ischemia-reperfusion injury at the three stages, respectively. Comparison analysis showed that reperfusion injury had a distinct expression profile whereas the ischemia sample and the sham control were clustered together. Consistently, there are 69 differentially expressed microRNAs between the reperfusion sample and the sham control whereas 28 differentially expressed microRNAs between the ischemia sample and the sham control. We further identified two modes of microRNA expression changes in ischemia-reperfusion injury. Functional analysis of both the differentially expressed microRNAs in the two modes and their target mRNAs revealed that ischemia injury impaired mitochondrial function, nutrient consumption, and metabolism process. In contrast, reperfusion injury led to severe tissue inflammation that is predominantly an innate-immune response in the ischemia-reperfusion process. Our staged analysis of gene expression profiles provides new insights into regulatory mechanisms of microRNAs in mouse hepatic IR injury.

Introduction. Ischemia/reperfusion (IR) injury, often associated with liver surgery, is an unresolved problem in the clinical practice. Spironolactone is an antagonist of aldosterone that has shown benefits over IR injury in several tissues, but its effects in hepatic IR are unknown. Objective. To evaluate the effect of spironolactone on IR-induced damage in liver. Materials and Methods. Total hepatic ischemia was induced in rats for 20 min followed by 60 min of reperfusion. Spironolactone was administered and hepatic injury, cytokine production, and oxidative stress were assessed. Results. After IR, increased transaminases levels and widespread acute inflammatory infiltrate, disorganization of hepatic hemorrhage trabeculae, and presence of apoptotic bodies were observed. Administration of SPI reduced biochemical and histological parameters of liver injury. SPI treatment increased IL-6 levels when compared with IR group but did not modify either IL-1β or TNF-α with respect to IR group. Regarding oxidative stress, increased levels of catalase activity were recorded in IR + SPI group in comparison with group without treatment, whereas MDA levels were similar in IR + SPI and IR groups. Conclusions. Spironolactone reduced the liver damage induced by IR, and this was associated with an increase in IL-6 production and catalase activity.

• desferoxamine
• hepatectomy
• hepatoprotective modalities
• intracranial pressure
• iron chelation
• ischemic preconditioning
• swine

• TβRII
• ischaemia-reperfusion injury
• liver
• microRNA-370

Ischemia-reperfusion (I/R) injury is a multifactorial process that affects graft function after liver transplantation. An understanding of the mechanisms involved in I/R injury is essential for the design of therapeutic strategies to improve the outcome of liver transplantation. The generation of reactive oxygen species subsequent to reoxygenation inflicts tissue damage and initiates a cascade of deleterious cellular responses, leading to inflammation, cell death, and ultimate organ failure. Increasing experimental evidence has suggested that Kupffer cells and T-cells mediate activation of neutrophil inflammatory responses. Activated neutrophils infiltrate the injured liver in parallel with increased expression of adhesion molecules on endothelial cells. The heme oxygenase system is among the most critical of the cytoprotective mechanisms activated during cellular stress, exerting antioxidant and anti-inflammatory functions, modulating the cell cycle, and maintaining the microcirculation. Finally, the activation of toll-like receptors on Kupffer cells may play a fundamental role in exploring new therapeutic strategies based on the concept that hepatic I/R injury represents a case for host “innate” immunity. In the present study, there was a significant decrease in hepatic activity of glycogen in the I/R group as compared with corresponding values in the control group. On the other hand, there was a significant increase in the hepatic activity of glycogen in the I/R-IP (ischemic preconditioning) group as compared with corresponding values in the I/R group.

• caspase
• glycogen
• ischemic preconditioning
• liver
• nitric oxide
• oxidative stress
• reperfusion injury

• L02 cells
• Liver ischemia reperfusion injury
• MiR-124
• Rab38

• Animals
• Apoptosis/drug effects
• Apoptosis/genetics
• Cell Line
• Cytoprotection/drug effects
• Drug Interactions
• Gene Targeting/methods
• Hepatocytes/cytology
• Hepatocytes/drug effects
• Hepatocytes/physiology
• Humans
• Hydrogen Peroxide/pharmacology
• Liver Diseases/genetics
• Liver Diseases/prevention & control
• Male
• MicroRNAs/pharmacology
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury/genetics
• Reperfusion Injury/prevention & control
• Treatment Outcome
• rab GTP-Binding Proteins/antagonists & inhibitors
• rab GTP-Binding Proteins/genetics

Ischemia-reperfusion injury is a fascinating topic which has drawn a lot of interest in the last several years. Hepatic ischemia reperfusion injury may occur in a variety of clinical situations. These include transplantation, liver resection, trauma, and vascular surgery.

The purpose of this review was to outline the molecular mechanisms underlying hepatic I/R injury and present the latest approaches, both surgical and pharmacological, regarding the prevention of it. A comprehensive electronic literature search in MEDLINE/PubMed was performed to identify relative articles published within the last 2 years.

The basic mechanism of hepatic ischemia – reperfusion injury is one of blood deprivation during ischemia, followed by the return of flow during reperfusion. It involves a complex series of events, such as mitochondrial deenergization, adenosine-5'-triphosphate depletion, alterations of electrolyte homeostasis, as well as Kupffer cell activation, oxidative stress changes and upregulation of proinflammatory cytokine signaling. The great number of variable pathways, with several mediators interacting with each other, leads to a high number of candidates for potential therapeutic intervention. As far as surgical approaches are concerned, the modification of existing clamping techniques and the ischemic preconditioning are the most promising techniques till recently. In the search for novel techniques of protecting against hepatic ischemia reperfusion injury, many different strategies have been used in experimental models. The biggest part of this research lies around antioxidant therapy, but other potential solutions have been explored as well.

The management of hepatic trauma, in spite of the fact that it has become increasingly nonoperative, there still remains the possibility of hepatic resection in the hepatic trauma setting, especially in severe injuries. Hence, clinicians should be familiar with the concept of hepatic ischemia-reperfusion injury and respond appropriately and timely.

• Ischemia
• Pathophysiology
• Prevention
• Reperfusion Injury

• Biliary stricture
• Hepatocyte transplantation
• Liver transplant
• NHBD
• Organ donor
• Preservation

• Apoptosis
• Ischemic preconditioning
• Microarray analysis
• Necrosis
• Reperfusion injury

• Iron
• Liver preconditioning
• Thyroid hormone
• n-3 polyunsaturated fatty acids

Ischemia-reperfusion injury associated with liver transplantation remains a serious complication in clinical practice. In the present study the effect of intake of α-tocopherol or β-carotene to limit liver injury by oxidative stress in ischemia and reperfusion was explored. Wistar rats were fed with diets enriched with α-tocopherol (20 mg/day) or β-carotene (3 mg/day) for 21 days. After 21 days, their livers were subjected to 15 and 30 min of ischemia and afterwards were reperfused for 60 min. The recovery of levels of ATP during reperfusion was better in the group of rats whose diets were supplemented with α-tocopherol or β-carotene than in the group control. The supplementation of the diet induced changes in the profile of enzymatic antioxidants. The supplementation with α-tocopherol and β-carotene resulted in a decreased of superoxide dismutase during the ischemia and a recovery was observed after reperfusion. Not changes were observed for the enzymes catalase and glutathione peroxidase and glutathione but their values were higher to those of the group control. In conclusion, the supplementation with α-tocopherol and β-carotene improve the antioxidant and energetic state of liver after ischemia and reperfusion injury.

• GSH
• ischemia/reperfusion
• oxidative stress
• α-tocopherol
• β-carotene

During liver resection surgery for cancer or liver transplantation, the liver is subject to ischaemia (reduction in blood flow) followed by reperfusion (restoration of blood flow), which results in liver injury [ischemia-reperfusion (IR) or IR injury]. Modulation of IR injury can be achieved in various ways. These include hypothermia, ischaemic preconditioning (IPC) (brief cycles of ischaemia followed by reperfusion of the organ before the prolonged period of ischaemia i.e. a conditioning response), ischaemic postconditioning (conditioning after the prolonged period of ischaemia but before the reperfusion), pharmacological agents to decrease IR injury, genetic modulation of IR injury, and machine perfusion (pulsatile perfusion). Hypothermia decreases the metabolic functions and the oxygen consumption of organs. Static cold storage in University of Wisconsin solution reduces IR injury and has prolonged organ storage and improved the function of transplanted grafts. There is currently no evidence for any clinical advantage in the use of alternate solutions for static cold storage. Although experimental data from animal models suggest that IPC, ischaemic postconditioning, various pharmacological agents, gene therapy, and machine perfusion decrease IR injury, none of these interventions can be recommended in clinical practice. This is because of the lack of randomized controlled trials assessing the safety and efficacy of ischaemic postconditioning, gene therapy, and machine perfusion. Randomized controlled trials and systematic reviews of randomized controlled trials assessing the safety and efficacy of IPC and various pharmacological agents have demonstrated biochemical or histological improvements but this has not translated to clinical benefit. Further well designed randomized controlled trials are necessary to assess the various new protective strategies in liver resection.

• Liver
• Hepatectomy
• Liver transplantation
• Ischemia-reperfusion injury
• Hypothermia
• Ischaemic preconditioning

• Animals
• Blotting, Northern
• Blotting, Western
• Cells, Cultured
• Electrophoretic Mobility Shift Assay
• Heme Oxygenase-1/genetics
• Heme Oxygenase-1/metabolism
• Hep G2 Cells
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Humans
• Immunohistochemistry
• Kupffer Cells/metabolism
• Liver/drug effects
• Liver/enzymology
• Liver/metabolism
• Male
• Methyl Ethers/pharmacology
• Mitogen-Activated Protein Kinase 1/genetics
• Mitogen-Activated Protein Kinase 1/metabolism
• Mitogen-Activated Protein Kinase 3/genetics
• Mitogen-Activated Protein Kinase 3/metabolism
• Polymerase Chain Reaction
• Rats
• Rats, Sprague-Dawley
• Sevoflurane
• Transcription Factor AP-1/genetics
• Transcription Factor AP-1/metabolism

• Blood Loss, Surgical/prevention & control
• Constriction
• Elective Surgical Procedures/methods
• Hepatectomy/methods
• Hepatic Artery
• Hepatic Veins
• Humans
• Ischemic Preconditioning/methods
• Liver/blood supply
• Portal Vein
• Randomized Controlled Trials as Topic
• Vena Cava, Inferior

• Blood Loss, Surgical/prevention & control
• Constriction
• Hepatectomy/methods
• Hepatectomy/mortality
• Humans
• Ischemic Preconditioning
• Liver/blood supply
• Randomized Controlled Trials as Topic
• Reperfusion Injury/prevention & control

• Blood Loss, Surgical/prevention & control
• Constriction
• Elective Surgical Procedures
• Hepatectomy/methods
• Hepatic Veins
• Humans
• Liver/blood supply
• Liver/surgery
• Liver Failure/mortality
• Randomized Controlled Trials as Topic
• Vena Cava, Inferior