• Wistar rat
• acute kidney injury (AKI)
• ischemia/reperfusion injuries (IRI)
• omentum

• IL-1
• IL-10
• IL-6
• brain death
• ischemia-reperfusion
• liver transplantation
• nitric oxide
• steatotic liver grafts

• Animals
• Rats
• Brain
• Brain Death
• Fatty Liver
• Inflammation
• Interleukin-6
• Nitric Oxide
• Nitric Oxide Donors

Background. Brain death (BD) and steatosis are key risk factors to predict adverse post-transplant outcomes. We investigated the role of Neuregulin-1 (NRG1) in rat steatotic and non-steatotic liver transplantation (LT) from brain death donors (DBD). Methods: NRG1 pathways were characterized after surgery. Results: NRG1 and p21-activated kinase 1 (PAK1) levels increased in steatotic and non-steatotic grafts from DBDs. The abolishment of NRG1 effects reduced PAK1. When the effect of either NRG1 nor PAK1 was inhibited, injury and regenerative failure were exacerbated. The benefits of the NRG-1-PAK1 axis in liver grafts from DBDs were associated with increased vascular endothelial growth factor-A (VEGFA) and insulin growth factor-1 (IGF1) levels, respectively. Indeed, VEGFA administration in non-steatotic livers and IGF1 treatment in steatotic grafts prevented damage and regenerative failure resulting from the inhibition of either NRG1 or PAK-1 activity in each type of liver. Exogenous NRG1 induced greater injury than BD induction. Conclusions: This study indicates the benefits of endogenous NRG1 in liver grafts from DBDs and underscores the specificity of the NRG1 signaling pathway depending on the type of liver: NRG1-PAK1-VEGFA in non-steatotic livers and NRG1-PAK1-IGF1 in steatotic livers. Exogenous NRG1 is not an appropriate strategy to apply to liver grafts from DBD.

Herein, we investigate whether: (1) the administration of glucose or a lipid emulsion is useful in liver transplantation (LT) using steatotic (induced genetically or nutritionally) or non-steatotic livers from donors after brain death (DBDs); and (2) any such benefits are due to reductions in intestinal damage and consequently to gut microbiota preservation. In recipients from DBDs, we show increased hepatic damage and failure in the maintenance of ATP, glycogen, phospholipid and growth factor (HGF, IGF1 and VEGFA) levels, compared to recipients from non-DBDs. In recipients of non-steatotic grafts from DBDs, the administration of glucose or lipids did not protect against hepatic damage. This was associated with unchanged ATP, glycogen, phospholipid and growth factor levels. However, the administration of lipids in steatotic grafts from DBDs protected against damage and ATP and glycogen drop and increased phospholipid levels. This was associated with increases in growth factors. In all recipients from DBDs, intestinal inflammation and damage (evaluated by LPS, vascular permeability, mucosal damage, TLR4, TNF, IL1, IL-10, MPO, MDA and edema formation) was not shown. In such cases, potential changes in gut microbiota would not be relevant since neither inflammation nor damage was evidenced in the intestine following LT in any of the groups evaluated. In conclusion, lipid treatment is the preferable nutritional support to protect against hepatic damage in steatotic LT from DBDs; the benefits were independent of alterations in the recipient intestine.

• brain death
• glucose
• gut microbiota
• intestinal inflammation
• ischemia-reperfusion
• lipid emulsion
• liver transplantation
• polysaccharides
• steatotic liver grafts

• acute myocardial infarction
• experimental models
• ischaemia/reperfusion injury
• oxidative stress
• pharmacological treatment

• BPC 157
• Caval hypertension
• Ischemia
• Portal hypertension
• Pringle maneuver
• Rats

• BPC 157
• Budd Chiari syndrome
• Portal/caval hypertension

• Ischemic stroke
• Neuron
• Neurovascular unit
• Vascular endothelial cell

• Kidney
• ischaemic preconditioning
• reperfusion injury

• complement
• extended criteria donor
• liver transplantation
• steatosis

• Animals
• Complement Activation
• Delayed Graft Function/immunology
• Delayed Graft Function/prevention & control
• Donor Selection/standards
• Fatty Liver/immunology
• Humans
• Liver Transplantation/adverse effects
• Liver Transplantation/methods
• Liver Transplantation/standards
• Tissue Donors

Liver Ischaemia Reperfusion (IR) injury is a major cause of post-operative liver dysfunction, morbidity and mortality following liver resection surgery and transplantation. There are no proven therapies for IR injury in clinical practice and new approaches are required. Ischaemic Preconditioning (IPC) can be applied in both a direct and remote fashion and has been shown to ameliorate IR injury in small animal models. Its translation into clinical practice has been difficult, primarily by a lack of knowledge regarding the dominant protective mechanisms that it employs. A review of all current studies would suggest that IPC/RIPC relies on creating a small tissue injury resulting in the release of adenosine and l-arginine which act through the Adenosine receptors and the haem-oxygenase and endothelial nitric oxide synthase systems to reduce hepatocyte necrosis and improve the hepatic microcirculation post reperfusion. The next key step is to determine how long the stimulus requires to precondition humans to allow sufficient injury to occur to release the potential mediators. This would open the door to a new therapeutic chapter in this field.

• Ischaemic Preconditioning
• Ischaemic Reperfusion injury
• Remote Ischaemic Preconditioning

• 10/4001/11 Department of Health

• extensive hepatectomy
• fatty liver disease
• intermittent ischemic preconditioning
• ischemia-reperfusion injury
• simple ischemic preconditioning
• steatotic liver

Ischemia reperfusion (IR) injury is a significant cause of morbidity and mortality in liver transplantation. When oxygen is reintroduced to the liver graft it initiates a cascade of molecular reactions leading to the release of reactive oxygen species (ROS) and pro-inflammatory cytokines. These soluble mediators propagate a sterile immune response to cause significant tissue damage. Ischemic preconditioning (IPC) is one method that reduces hepatocellular injury by altering the immune response and inhibiting the production of ROS. Studies quantifying the effects of IPC in humans have demonstrated an improved liver enzyme panel in patients receiving grafts pretreated with IPC as compared to patients receiving the standard of care. In our review, we explore current literature in the field in order to describe the mechanism through which IPC regulates the production of ROS and improves IR injury.

• ischemia
• liver
• oxidative stress
• preconditioning
• reactive oxygen species
• reperfusion injury

• GSK-3β
• cardioprotection
• liver ischemic conditioning
• myocardial ischemia and reperfusion injury

• Animals
• Death, Sudden, Cardiac/prevention & control
• Extracellular Signal-Regulated MAP Kinases/metabolism
• Glycogen Synthase Kinase 3 beta/metabolism
• Ischemic Preconditioning
• Liver/blood supply
• Male
• Rats
• Rats, Sprague-Dawley

• R01 HL079275 NHLBI NIH HHS
• National Natural Science Foundation of China
• National Institutes of Health

Liver ischemia/reperfusion injury has been extensively studied during the last decades and has been implicated in the pathophysiology of many clinical entities following hepatic surgery and transplantation. Apart from its pivotal role in the pathogenesis of the organ's post reperfusion injury, it has also been proposed as an underlying mechanism responsible for the dysfunction and injury of other organs as well. It seems that liver ischemia and reperfusion represent an event with “global” consequences that influence the function of many remote organs including the lung, kidney, intestine, pancreas, adrenals, and myocardium among others. The molecular and clinical manifestation of these remote organs injury may lead to the multiple organ dysfunction syndrome, frequently encountered in these patients. Remote organ injury seems to be in part the result of the oxidative burst and the inflammatory response following reperfusion. The present paper aims to review the existing literature regarding the proposed mechanisms of remote organ injury after liver ischemia and reperfusion.

• Congestion
• Ischemia reperfusion injury
• Ischemic precondition
• Living donor liver transplantation

Background. Remote ischemic preconditioning (RIP) and pharmacological preconditioning are the effective methods that can be used to prevent ischemia reperfusion (IR) injury. The aim of this study was to evaluate the effects of RIP and N-Acetylcysteine (NAC) with RIP in the rat hepatic IR injury model. Materials and Methods. 28 rats were divided into 4 groups. Group I (sham): only laparotomy was performed. Group II (IR): following 30 minutes of hepatic pedicle occlusion, 4 hours of reperfusion was performed. Group III (RIP + IR): following 3 cycles of RIP, hepatic IR was performed. Group IV (RIP + NAC + IR): following RIP and intraperitoneal administration of NAC (150 mg/kg), hepatic IR was performed. All the rats were sacrificed after blood samples were taken for the measurements of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and liver was processed for conventional histopathology. Results. The hepatic histopathological injury scores of RIP + IR and RIP + NAC + IR groups were significantly lower than IR group (P = 0.006, P = 0.003, resp.). There were no significant differences in AST and ALT values between the IR, RIP + IR, and RIP + NAC + IR groups. Conclusions. In the present study, it was demonstrated histopathologically that RIP and RIP + NAC decreased hepatic IR injury significantly.

The shortage of donor livers has led to an increased use of organs from expanded criteria donors. Included are livers with steatosis, a metabolic abnormality that increases the likelihood of graft complications post-transplantation. After a brief introduction on the etiology, pathophysiology, categories and experimental models of hepatic steatosis, we herein review the methods to rescue steatotic donor livers before transplantation applied in clinical and experimental studies. The methods span the spectrum of encouraging donor weight loss, employing drug therapy, heat shock preconditioning, ischemia preconditioning and selective anesthesia on donors, and the treatment on isolated grafts during preservation. These methods work at different stages of transplantation process, although share similar molecular mechanisms including lipid metabolism stimulation through enzymes or nuclear receptor e.g., peroxisomal proliferator-activated receptor, or anti-inflammation through suppressing cytokines e.g., tumor necrosis factor-α, or antioxidant therapies to alleviate oxidative stress. This similarity of molecular mechanisms implies possible future attempts to reinforce each approach by repeating the same treatment approach at several stages of procurement and preservation, as well as utilizing these alternative approaches in tandem.

• Liver transplantation
• Steatosis
• Donor liver
• Clinical
• Experimental

• Animals
• Disease Models, Animal
• Donor Selection
• Fatty Liver/diagnosis
• Fatty Liver/therapy
• Humans
• Liver Transplantation/adverse effects
• Liver Transplantation/methods
• Risk Factors
• Tissue Donors/supply & distribution
• Treatment Outcome

Pulmonary complications after liver transplantation (LT) often cause mortality. This study investigated whether small-for-size LT increases acute pulmonary injury and whether NIM811 which improves small-for-size liver graft survival attenuates LT-associated lung injury. Rat livers were reduced to 50% of original size, stored in UW-solution with and without NIM811 (5 μM) for 6 h, and implanted into recipients of the same or about twice the donor weight, resulting in half-size (HSG) and quarter-size grafts (QSG), respectively. Liver injury increased and regeneration was suppressed after QSG transplantation as expected. NIM811 blunted these alterations >75%. Pulmonary histological alterations were minimal at 5–18 h after LT. At 38 h, neutrophils and monocytes/macrophage infiltration, alveolar space exudation, alveolar septal thickening, oxidative/nitrosative protein adduct formation, and alveolar epithelial cell/capillary endothelial apoptosis became overt in the lungs of QSG recipients, but these alterations were mild in full-size and HSG recipients. Liver pretreatment with NIM811 markedly decreased pulmonary injury in QSG recipients. Hepatic TNFα and IL-1β mRNAs and pulmonary ICAM-1 expression were markedly higher after QSG transplantation, which were all decreased by NIM811. Together, dysfunctional small-for-size grafts produce toxic cytokines, leading to lung inflammation and injury. NIM811 decreased toxic cytokine formation, thus attenuating pulmonary injury after small-for-size LT.

• ischaemia reperfusion
• transplant

• Animals
• Blood Flow Velocity
• Cell Adhesion
• Cell Death
• Chemokine CXCL1/blood
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Hindlimb/blood supply
• Ischemic Preconditioning
• Liver/blood supply
• Liver/metabolism
• Liver/pathology
• Liver Circulation
• Male
• Microcirculation
• Neutrophils/metabolism
• Neutrophils/pathology
• Rats
• Rats, Sprague-Dawley
• Regional Blood Flow
• Reperfusion Injury/blood
• Reperfusion Injury/pathology
• Reperfusion Injury/physiopathology
• Reperfusion Injury/prevention & control
• Time Factors
• Tourniquets

• emulsified isoflurane
• inflammation
• intercellular adhesion molecule-1
• neutrophils
• nuclear factor-κB
• rats
• tumor necrosis factor-α

AIM: To investigate the benefits of insulin like growth factor-1 (IGF-1) supplementation to serum-free institut georges lopez-1 (IGL-1)^® solution to protect fatty liver against cold ischemia reperfusion injury.

METHODS: Steatotic livers were preserved for 24 h in IGL-1^® solution supplemented with or without IGF-1 and then perfused “ex vivo” for 2 h at 37°C. We examined the effects of IGF-1 on hepatic damage and function (transaminases, percentage of sulfobromophthalein clearance in bile and vascular resistance). We also studied other factors associated with the poor tolerance of fatty livers to cold ischemia reperfusion injury such as mitochondrial damage, oxidative stress, nitric oxide, tumor necrosis factor-α (TNF-α) and mitogen-activated protein kinases.

RESULTS: Steatotic livers preserved in IGL-1^® solution supplemented with IGF-1 showed lower transaminase levels, increased bile clearance and a reduction in vascular resistance when compared to those preserved in IGL-1^® solution alone. These benefits are mediated by activation of AKT and constitutive endothelial nitric oxide synthase (eNOS), as well as the inhibition of inflammatory cytokines such as TNF-α. Mitochondrial damage and oxidative stress were also prevented.

CONCLUSION: IGL-1^® enrichment with IGF-1 increased fatty liver graft preservation through AKT and eNOS activation, and prevented TNF-α release during normothermic reperfusion.

• AKT
• Institut georges lopez-1^® solution
• Insulin like growth factor-1
• Ischemia reperfusion injury
• Nitric oxide
• Oxidative stress
• Steatotic graft preservation

• Acute Kidney Injury/epidemiology
• Acute Kidney Injury/etiology
• Acute Kidney Injury/physiopathology
• Adult
• Body Mass Index
• Creatinine/blood
• Databases, Factual
• Female
• Glomerular Filtration Rate
• Humans
• Kidney/physiopathology
• Kidney Function Tests
• Liver Transplantation/adverse effects
• Male
• Middle Aged
• Retrospective Studies
• Risk Factors
• Time Factors

• Apoptosis/drug effects
• Apoptosis/physiology
• Caspases/physiology
• Inflammation/prevention & control
• Ischemic Preconditioning
• MAP Kinase Signaling System/physiology
• NF-kappa B/physiology
• Necrosis/pathology
• Necrosis/physiopathology
• Reactive Oxygen Species/metabolism
• Reperfusion Injury/pathology
• Reperfusion Injury/physiopathology
• bcl-2-Associated X Protein/physiology

• 1R 43 DK 61910-01 NIDDK NIH HHS

• hepatic ischemia reperfusion injury
• ischemic preconditioning
• remote ischemic preconditioning

• Animals
• Blood Gas Analysis
• Cytokines/biosynthesis
• Disease Models, Animal
• Gene Expression Regulation
• HSP70 Heat-Shock Proteins/biosynthesis
• Hemodynamics
• Hot Temperature
• Ischemic Preconditioning
• Lung/metabolism
• Lung/pathology
• Lung/physiopathology
• Oxidative Stress
• Reperfusion Injury/metabolism
• Reperfusion Injury/pathology
• Reperfusion Injury/physiopathology
• Reperfusion Injury/therapy
• Reperfusion Injury/veterinary
• Respiratory Distress Syndrome/metabolism
• Respiratory Distress Syndrome/pathology
• Respiratory Distress Syndrome/physiopathology
• Respiratory Distress Syndrome/therapy
• Respiratory Distress Syndrome/veterinary
• Swine
• Swine Diseases/metabolism
• Swine Diseases/pathology
• Swine Diseases/physiopathology
• Swine Diseases/therapy
• Swine, Miniature
• Vascular Resistance