Liver Ischemia-reperfusion Injury Research Articles

Liraglutide Attenuates Hepatic Ischemia-Reperfusion Injury by Modulating Macrophage Polarization.

Ischemia-reperfusion injury (IRI) is a common complication associated with liver surgery, and macrophages play an important role in hepatic IRI. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog primarily used to treat type 2 diabetes and obesity, regulates intracellular calcium homeostasis and protects the cardiomyocytes from injury; however, its role in hepatic IRI is not yet fully understood. This study aimed to investigate whether liraglutide can protect the liver from IRI and determine the possible underlying mechanisms. Our results showed that liraglutide pretreatment significantly alleviated the liver damage caused by ischemia-reperfusion (I/R), as evidenced by H&E staining, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and TUNEL staining. Furthermore, the levels of inflammatory cytokines elicited by I/R were distinctly suppressed by liraglutide pretreatment, accompanied by significant reduction in TNF-α, IL-1β, and IL-6 levels. Furthermore, pretreatment with liraglutide markedly inhibited macrophage type I (M1) polarization during hepatic IRI, as revealed by the significant reduction in CD68+ levels in Kupffer cells (KCs) detected via flow cytometry. However, the protective effects of liraglutide on hepatic IRI were partly diminished in GLP-1 receptor-knockout (GLP-1R-/-) mice. Furthermore, in an in vitro study, we assessed the role of liraglutide in macrophage polarization by examining the expression profiles of M1 in bone marrow-derived macrophages (BMDMs) from GLP-1R-/- and C57BL/6J mice. Consistent with the results of the in vivo study, liraglutide treatment attenuated the LPS-induced M1 polarization and reduced the expression of M1 markers. However, the inhibitory effect of liraglutide on LPS-induced M1 polarization was largely abolished in BMDMs from GLP-1R-/- mice. Collectively, our study indicates that liraglutide can ameliorate hepatic IRI by inhibiting macrophage polarization towards an inflammatory phenotype via GLP-1R. Its protective effect against liver IRI suggests that liraglutide may serve as a potential drug for the clinical treatment of liver IRI.

Extracellular vesicles derived from mesenchymal stromal cells as nanotherapeutics for liver ischaemia–reperfusion injury by transferring mitochondria to modulate the formation of neutrophil extracellular traps

As nanotherapeutics, mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are considered a potent alternative for whole-cell therapy and are gradually entering the clinical field of liver diseases. In this study, neutrophil extracellular traps (NETs) formation in liver tissue was verified as a critical factor for liver ischaemia–reperfusion injury (IRI) in both clinical samples and animal models. Human umbilical cord-derived MSC-EVs (hUC-MSC-EVs) might function to reduce the NETs formation and subsequently improve liver IRI. Mechanistically, we showed that hUC-MSC-EVs contain functional mitochondria that are transferred to intrahepatic neutrophils. This effect triggers mitochondrial fusion and subsequently restores the mitochondrial status and functions in neutrophils to reduce NETs formation. Collectively, our findings suggest that MSC-EVs exert a nanotherapeutic effect on inhibiting local NETs formation by transferring functional mitochondria to intrahepatic neutrophils and repairing their mitochondrial function, which highlights the therapeutic value of hUC-MSC-EVs for liver IRI.

Natural Killer Cells in Hepatic Ischemia-Reperfusion Injury

Ischemia-reperfusion injury can be divided into two phases, including insufficient supply of oxygen and nutrients in the first stage and then organ injury caused by immune inflammation after blood flow recovery. Hepatic ischemia-reperfusion is an important cause of liver injury post-surgery, consisting of partial hepatectomy and liver transplantation, and a central driver of graft dysfunction, which greatly leads to complications and mortality after liver transplantation. Natural killer (NK) cells are the lymphocyte population mainly involved in innate immune response in the human liver. In addition to their well-known role in anti-virus and anti-tumor defense, NK cells are also considered to regulate the pathogenesis of liver ischemia-reperfusion injury under the support of more and more evidence recently. The infiltration of NK cells into the liver exacerbates the hepatic ischemia-reperfusion injury, which could be significantly alleviated after depletion of NK cells. Interestingly, NK cells may contribute to both liver graft rejection and tolerance according to their origins. In this article, we discussed the development of liver NK cells, their role in ischemia-reperfusion injury, and strategies of inhibiting NK cell activation in order to provide potential possibilities for translation application in future clinical practice.

FOXO1 Alleviates Liver Ischemia-reperfusion Injury by Regulating the Th17/Treg Ratio through the AKT/Stat3/FOXO1 Pathway.

Hepatic ischemic reperfusion injury (IRI) occurring during surgery seriously affects patient prognosis. The specific mechanism of IRI has not been fully elucidated. The study aim was to explore the changes of inflammatory environment, and the relationship of the Th17/Treg cell ratio and FOXO1 expression in hepatic IRI. Liver samples at different ischemic times were collected from patients and mice. The expression of inflammatory markers and FOXO1 in the liver was detected by western blotting and qPCR. Phenotypic changes of liver lymphocytes were analyzed by flow cytometry. The AKT/Stat3/FOXO1 pathway was verified by targeting AKT with GSK2141795. The role of FOXO1 in liver inflammation and changes in lymphocyte phenotype was confirmed by upregulating FOXO1 with resveratrol. Prolonged ischemic time aggravates liver injury in both humans and mouse models of hepatic IRI. IR-stress caused Th17/Treg imbalance and FOXO1 down-regulation by activating the AKT/Stat3/FOXO1 signaling pathway. Upregulation of FOXO1 reversed the Th17/Treg cytokine imbalance and altered the inflammation environment in the liver. Liver IRI induced Th17/Treg imbalance. Upregulation of FOXO1 reversed the imbalance and alleviated liver inflammation.

Human Amnion-Derived Mesenchymal Stromal/Stem Cells Pre-Conditioning Inhibits Inflammation and Apoptosis of Immune and Parenchymal Cells in an In Vitro Model of Liver Ischemia/Reperfusion.

Ischemia/reperfusion injury (IRI) represents one of the leading causes of primary non-function acute liver transplantation failure. IRI, generated by an interruption of organ blood flow and the subsequent restoration upon transplant, i.e., reperfusion, generates the activation of an inflammatory cascade from the resident Kupffer cells, leading first to neutrophils recruitment and second to apoptosis of the parenchyma. Recently, human mesenchymal stromal/stem cells (hMSCs) and derivatives have been implemented for reducing the damage induced by IRI. Interestingly, sparse data in the literature have described the use of human amnion-derived MSCs (hAMSCs) and, more importantly, no evidence regarding hMSCs priming on liver IRI have been described yet. Thus, our study focused on the definition of an in vitro model of liver IRI to test the effect of primed hAMSCs to reduce IRI damage on immune and hepatic cells. We found that the IFNγ pre-treatment and 3D culture of hAMSCs strongly reduced inflammation induced by M1-differentiated macrophages. Furthermore, primed hAMSCs significantly inhibited parenchymal apoptosis at early timepoints of reperfusion by blocking the activation of caspase 3/7. All together, these data demonstrate that hAMSCs priming significantly overcomes IRI effects in vitro by engaging the possibility of defining the molecular pathways involved in this process.

Sulforaphane Exerts Beneficial Immunomodulatory Effects on Liver Tissue via a Nrf2 Pathway-Related Mechanism in a Murine Model of Hemorrhagic Shock and Resuscitation.

Our research explores the immunomodulatory effects of sulforaphane (SFN), a well-known nuclear factor erythroid 2-related factor 2 (Nrf2) pathway agonist, on the sterile inflammation of and ischemia-reperfusion injuries to the liver after hemorrhagic shock (HS) followed by resuscitation (R). Male C57/BL6 wild-type and transgenic ARE-luc mice were exposed to mean arterial pressure-controlled HS. Fluid resuscitation was performed after 90 min of HS, and SFN was administrated intraperitoneally after that. The animals were sacrificed at 6 h, 24 h, and 72 h after resuscitation, and their livers were extracted to perform H&E staining and myeloperoxidase (MPO) activity analysis. The Kupffer cells were isolated for cytokines profile measurements and Nrf2 immunofluorescence staining. Further, the ARE-luc mice were used to assess hepatic Nrf2 activity in vivo. We identified that SFN-activated Kupffer cells’ Nrf2 pathway and modulated its cytokines expression, including TNF-α, MCP-1, KC/CXCL1, IL-6, and IL-10. Furthermore, SFN mitigated liver ischemia-reperfusion injury, as evidenced by the downregulation of the Suzuki score and the enhanced hepatic Nrf2 activity. The in vivo SFN treatment decreased neutrophils infiltration, as shown by the decreased MPO levels. Our study shows that SFN can decrease HS/R-induced hepatic ischemia-reperfusion injury and modulate the activity of Kupffer cells via an Nrf2-dependent pathway.

Role of the PI3K/Akt signaling pathway in liver ischemia reperfusion injury: a narrative review.

To explore the role of phosphatidylinositol-3-kinase/protein kinase B and alpha serine/threonine protein kinase PI3K/PKB (also known as PI3K/Akt) signaling pathway in liver ischemia reperfusion injury. The PI3K/Akt signaling pathway is one of the major signal transduction pathways that regulates numerous cellular activities in vivo. The main functions of this pathway include induction of stem cell differentiation and metastasis, promotion of cell proliferation, inhibition of apoptosis, and regulation of tissue inflammation, tumor growth, and invasion. Liver ischemia reperfusion injury is an inevitable clinical problem that can occur during liver transplantation, liver resection, and various circulatory shock events, and it is one of the primary reasons for postoperative liver dysfunction, and poor disease outcome and patient prognosis. In recent years, it has been found that PI3K/Akt signaling pathway is closely related to liver ischemia reperfusion injury. In this review, a large number of relevant literatures were collected to explain the biological basis of PI3K/Akt signaling pathway and its role in liver ischemia reperfusion injury. The review was based on a PubMed search using the terms "liver ischemia reperfusion injury", "PI3K/Akt signaling pathway", and "PI3K/Akt signaling pathway AND liver ischemia reperfusion injury", so as to understand the complex interaction between them. Activated PI3K/Akt signaling pathway can exert anti-inflammatory, antioxidant stress, anti-apoptosis and autophagy regulation effects through downstream related targeted pathways and proteins, thus alleviating liver ischemia-reperfusion injury. Therefore, the regulation of PI3K/Akt signaling pathway is expected to become an effective targeted pathway for clinical prevention and alleviation of liver ischemia reperfusion injury.

Caspase-3/Treg and PI3K/AKT/mTOR pathway is involved in Liver Ischemia Reperfusion Injury (IRI) protection by everolimus

Ischemia-reperfusion injury (IRI) of the liver is a severe complication that can follow hemorrhagic shock and liver surgery. Regulatory T cells (Treg) show the potential of improving outcomes of IRI. Everolimus is an mTOR inhibitor used in liver transplantation and the treatment of tumor patients through PI3K/AKT/mTOR pathway. The present study was designed to investigate the efficacy and mechanism of everolimus on Treg for the treatment of IRI. Hepatocytes were exposed to H2O2 and hypoxic conditions to investigate the effects of everolimus on reactive oxygen species ROS-induced and H/R-induced injury in vitro. The effects of everolimus on liver IRI were investigated in a warm ischemia liver model in vivo. Our results indicate that everolimus markedly protected liver IRI in vivo and vitro. Furthermore, everolimus increased the levels of phospho- (p-)AKT, p-mTOR but not p-GSK following IRI. Taken together, our data showed that everolimus protected against IRI via regulation of caspase-3/Treg and the PI3K/AKT/mTOR signalling pathway, which provides new insight into the treatment of liver IRI.

STING Induces Liver Ischemia-Reperfusion Injury by Promoting Calcium-Dependent Caspase 1-GSDMD Processing in Macrophages.

Objectives Although a recent study reported that stimulator of interferon genes (STING) in macrophages has an important regulatory effect on liver ischemia-reperfusion injury (IRI), the underlying mechanism of STING-dependent innate immune activation in liver macrophages (Kupffer cells, KCs) remains unclear. Here, we investigated the effect of STING on liver macrophage pyroptosis and the associated regulatory mechanism of liver IRI. Methods Clodronate liposomes were used to block liver macrophages. AAV-STING-RNAi-F4/80-EGFP, an adenoassociated virus (AAV), was transfected into the portal vein of mice in vivo, and the liver IRI model was established 14 days later. In vitro, liver macrophages were treated with STING-specific siRNA, and a hypoxia-reoxygenation (H/R) model was established. The level of STING was detected via Western blotting (WB), RT-PCR, and immunostaining. Liver tissue and blood samples were collected. Pathological changes in liver tissue were detected by hematoxylin and eosin (H&E) staining. Macrophage pyroptosis was detected by WB, confocal laser scanning microscopy (CLSM), transmission electron microscopy (TEM), and enzyme-linked immunosorbent assay (ELISA). The calcium concentration was measured by immunofluorescence and analyzed with a fluorescence microplate reader. Results The expression of STING increased with liver IRI but decreased significantly after the clodronate liposome blockade of liver macrophages. After knockdown of STING, the activation of caspase 1-GSDMD in macrophages and liver IRI was alleviated. More interestingly, hypoxia/reoxygenation (H/R) increased the calcium concentration in liver macrophages, but the calcium concentration was decreased after STING knockdown. Furthermore, after the inhibition of calcium in H/R-induced liver macrophages by BAPTA-AM, pyroptosis was significantly reduced, but the expression of STING was not significantlydecreased. Conclusions Knockdown of STING reduces calcium-dependent macrophage caspase 1-GSDMD-mediated liver IRI, representing a potential therapeutic approach in the clinic.

Literature review of the mechanisms of acute kidney injury secondary to acute liver injury.

People exposed to liver ischaemia reperfusion (IR) injury often develop acute kidney injury and the combination is associated with significant morbidity and mortality. Molecular mediators released by the liver in response to IR injury are the likely cause of acute kidney injury (AKI) in this setting, but the mediators have not yet been identified. Identifying the mechanism of injury will allow the identification of therapeutic targets which may modulate both liver IR injury and AKI following liver IR injury.

Nrf2 and oxidative stress in liver ischemia/reperfusion injury.

In response to stress signal, nuclear factor-erythroid 2-related factor 2 (Nrf2) induces the expression of target genes involved in antioxidant defense and detoxification. Nrf2 activity is strictly regulated through a variety of mechanisms, including regulation of Keap1-Nrf2 stability, transcriptional regulation (NF-ĸB, ATF3, ATF4), and post-transcriptional regulation (miRNA), evidencing that transcriptional responses of Nrf2 are critical for the maintenance of homeostasis. Ischemia-reperfusion (IR) injury is a major cause of graft loss and dysfunction in clinical transplantation and organ resection. During the IR process, the generation of reactive oxygen species (ROS) leads to damage from oxidative stress, oxidation of biomolecules, and mitochondrial dysfunction. Oxidative stress can trigger apoptotic and necrotic cell death. Stress factors also result in the assembly of the inflammasome protein complex and the subsequent activation and secretion of proinflammatory cytokines. After Nrf2 activation, the downstream antioxidant upregulation can act as a primary cellular defense against the cytotoxic effects of oxidative stress and help to promote hepatic recovery during IR. The complex crosstalk between Nrf2 and cellular pathways in liver IR injury and the potential therapeutic target of the Nrf2 inducers will be discussed in the present review.

Hypothermic oxygenated perfusion combined with TJ-M2010-5 alleviates hepatic ischemia-reperfusion injury in donation after circulatory death

Ischemia-reperfusion injury (IRI) is an inevitable pathological process during donation after circulatory death (DCD) liver transplantation, which contributes to serious damage to the graft. Oxidative stress, inflammation and apoptosis are all fatal causes of IRI of the liver. Hypothermic oxygenated perfusion (HOPE), as an emerging dynamic preservation technology, has a more significant effect on reducing DCD liver IRI than static cold storage (CS) mainly by regulating oxidative stress and inflammation. To further enhance the effect of HOPE and reveal its underlying mechanisms, investigators have recently combined HOPE with various methods. Excessive activation of the TLR/MyD88 signaling pathway can lead to severe immune inflammatory response. TJ-M2010-5 (TJ-5), a novel thiazaol-aminoramification MyD88 inhibitor, plays an essential role in the treatment of various diseases or pathological injuries in mice, such as hepatocellular carcinoma, acute liver injury and myocardial IRI. However, little is known about the role of TJ-5 in HOPE alleviating DCD liver IRI. Herein, we sought to investigate the role of HOPE combined with TJ-5 in reducing DCD liver IRI. We found that HOPE combined with TJ-5 significantly reduced oxidative stress, lessened inflammation, and decreased apoptosis during DCD liver IRI. Furthermore, HOPE combined with TJ-5 exerted their effects by inhibiting the TLR/MyD88 signaling pathway. Overall, these results demonstrated that HOPE combined with TJ-5 has a significant effect on alleviating DCD liver IRI. Therefore, the combined application of HOPE and TJ-5 may be an available and valid treatment option for DCD liver IRI.

PEG35 and Glutathione Improve Mitochondrial Function and Reduce Oxidative Stress in Cold Fatty Liver Graft Preservation.

The need to meet the demand for transplants entails the use of steatotic livers, more vulnerable to ischemia-reperfusion (IR) injury. Therefore, finding the optimal composition of static cold storage (SCS) preservation solutions is crucial. Given that ROS regulation is a therapeutic strategy for liver IR injury, we have added increasing concentrations of PEG35 and glutathione (GSH) to the preservation solutions (IGL-1 and IGL-2) and evaluated the possible protection against energy depletion and oxidative stress. Fatty livers from obese Zücker rats were isolated and randomly distributed in the control (Sham) preserved (24 h at 4 °C) in IGL-0 (without PEG35 and 3 mmol/L GSH), IGL-1 (1 g/L PEG35, and 3 mmol/L GSH), and IGL-2 (5 g/L PEG35 and 9 mmol/L GSH). Energy metabolites (ATP and succinate) and the expression of mitochondrial oxidative phosphorylation complexes (OXPHOS) were determined. Mitochondrial carrier uncoupling protein 2 (UCP2), PTEN-induced kinase 1 (PINK1), nuclear factor-erythroid 2 related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and the inflammasome (NLRP3) expressions were analyzed. As biomarkers of oxidative stress, protein oxidation (AOPP) and carbonylation (DNP derivatives), and lipid peroxidation (malondialdehyde (MDA)–thiobarbituric acid (TBA) adducts) were measured. In addition, the reduced and oxidized glutathione (GSH and GSSG) and enzymatic (Cu–Zn superoxide dismutase (SOD), CAT, GSH S-T, GSH-Px, and GSH-R) antioxidant capacities were determined. Our results showed that the cold preservation of fatty liver graft depleted ATP, accumulated succinate and increased oxidative stress. In contrast, the preservation with IGL-2 solution maintained ATP production, decreased succinate levels and increased OXPHOS complexes I and II, UCP2, and PINK-1 expression, therefore maintaining mitochondrial integrity. IGL-2 also protected against oxidative stress by increasing Nrf2 and HO-1 expression and GSH levels. Therefore, the presence of PEG35 in storage solutions may be a valuable option as an antioxidant agent for organ preservation in clinical transplantation.

Novel Targets and Therapeutic Strategies to Protect Against Hepatic Ischemia Reperfusion Injury.

Hepatic ischemia reperfusion injury (IRI), a fascinating topic that has drawn a lot of interest in the last few years, is a major complication caused by a variety of clinical situations, such as liver transplantation, severe trauma, vascular surgery, and hemorrhagic shock. The IRI process involves a series of complex events, including mitochondrial deenergization, metabolic acidosis, adenosine-5'-triphosphate depletion, Kupffer cell activation, calcium overload, oxidative stress, and the upregulation of pro-inflammatory cytokine signal transduction. A number of protective strategies have been reported to ameliorate IRI, including pharmacological therapy, ischemic pre-conditioning, ischemic post-conditioning, and machine reperfusion. However, most of these strategies are only at the stage of animal model research at present, and the potential mechanisms and exact therapeutic targets have yet to be clarified. IRI remains a main cause of postoperative liver dysfunction, often leading to postoperative morbidity or even mortality. Very recently, it was reported that the activation of peroxisome proliferator-activated receptor γ (PPARγ), a member of a superfamily of nuclear transcription factors activated by agonists, can attenuate IRI in the liver, and FAM3A has been confirmed to mediate the protective effect of PPARγ in hepatic IRI. In addition, non-coding RNAs, like LncRNAs and miRNAs, have also been reported to play a pivotal role in the liver IRI process. In this review, we presented an overview of the latest advances of treatment strategies and proposed potential mechanisms behind liver IRI. We also highlighted the role of several important molecules (PPARγ, FAM3A, and non-coding RNAs) in protecting against hepatic IRI. Only after achieving a comprehensive understanding of potential mechanisms and targets behind IRI can we effectively ameliorate IRI in the liver and achieve better therapeutic effects.

The effects of silymarin plus glutathione on the prevention of liver ischemia-reperfusion injury

Liver ischemia-reperfusion (IR) injury is a major clinical trouble encountered in clinical practice. This study aimed to examine the therapeutic effects of silymarin (SM) plus glutathione (GSH) on hepatic IR injury using a rat model of liver IR. Fifty male rats were randomly divided into five groups, each consisting of 10 rats as follows: Sham, IR, SM-IR, GSH-IR and SM plus GSH-IR. All groups except sham were subjected to 30-min ischemia and 24-h reperfusion. The treated groups received 100 mg/kg of SM, GSH and a mixture of SM plus GSH, 60 min prior to the IR. After a period of 24 h, blood and liver samples were collected for biochemical and histopathological evaluations. Pretreatment with SM, GSH and SM plus GSH before hepatic IR significantly decreased IR-induced elevations of aminotransferases, and significantly reduced the histopathological damage scores of the liver in the late phase of IR injury. Moreover, SM plus GSH treatment prior to liver IR significantly suppressed inflammatory process and oxidative stress as demonstrated by attenuations in tumor necrosis factor-α, myeloperoxidase and the thiobarbituric acid-reactive substances. These findings suggest that administration of SM plus GSH prior to liver IR may protect the liver parenchyma from the effects of an IR injury.

The role of MLKL in Hepatic Ischemia-Reperfusion Injury of Alcoholic Steatotic Livers.

Alcohol-related liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the primary causes of chronic liver disease in western countries. Liver transplantation is currently one of the most efficient approaches to save patients with liver failure, which is often associated with hepatic ischemia-reperfusion (IR) injury. IR injury is exacerbated by hepatic steatosis, yet the mechanism remains elusive. Necroptosis is a form of regulated cell death mediated by receptor-interacting protein kinase 1 (RIP1), RIP3 and mixed lineage kinase domain-like (MLKL) protein, which has been implicated in the pathogenesis of ALD and NAFLD. Though necroptosis plays an important role in IR injury of high fat diet - induced steatotic livers, the role of necroptosis in IR injury of ethanol - induced steototic livers has not been investigated. In the present study, we used chronic plus binge alcohol (Gao-binge) feeding followed by IR surgery to investigate IR liver injury with ethanol-associated steatosis. We found that the levels of key necroptotic proteins MLKL and RIP3 increased in alcohol-fed mouse livers. Moreover, we observed increased liver injury after IR in control diet-fed mice, which was further exacerbated by alcohol feeding based on serum alanine aminotransferase (ALT) levels and TUNEL staining of necrotic cells. Hepatic neutrophil infiltration also increased in alcohol-fed mice after IR surgery. However, deletion of Mlkl did not protect against IR liver injury in alcohol-fed mice compared with matched wild-type mice. In conclusion, alcoholic steatosis promotes IR injury, which seems to be independent of MLKL-mediated necroptosis.

The Protective Effect of a Nutraceutical Solution in an Experimental Rat Model of Liver Ischemia-Reperfusion

Introduction: Liver ischemia-reperfusion (IR) injury occurs in transplantation, liver resections, and causes important local and systemic damage. Its pathophysiology involves many signalling pathways and motivates studies that are concerned with using substances to combat this injury. Nutraceuticals (NUT) are bioactive compounds present in foods, which apart from having a nutritional role, provide health-promoting or prevention properties. There is a lack of studies that are concerned in evaluating the effects of NUT on liver IRI.

Effects of Propofol and Vitexin on Apoptosis in Rat Liver Ischemia Reperfusion Injury

Effects of Propofol and Vitexin on Apoptosis in Rat Liver Ischemia Reperfusion Injury

Conditioning with Ascorbic Acid Reduces Liver Ischemia Reperfusion Injury through Downregulation of High-Mobility Group Box 1

Conditioning with Ascorbic Acid Reduces Liver Ischemia Reperfusion Injury through Downregulation of High-Mobility Group Box 1

Description of a Recovery Model in Rabbits for the Study of the Late Phase of Liver Ischemia-Reperfusion Injury.

Description of an anesthetic recovery model with endotracheal intubation in rabbits which provides metabolic stability for the study of the late phase of liver ischemia/reperfusion (I/R) injury. Two groups of New Zealand rabbits, n=7 in each, were used: Ischemia/reperfusion (I/R) group (45 min of partial liver ischemia/reperfusion) and no intervention (sham) group. Blood alanine aminotransferase, lactate, pH values, mean arterial pressure and pCO2 were calculated at baseline, and at 2 and 24 h post reperfusion. Tissue samples from left (ischemic) and right (non-ischemic) liver lobes were examined at 2 and 24 h after reperfusion. The I/R group presented significantly higher levels of alanine aminotransferase (p=0.001) at 2 and 24 h, and of lactate (p=0.016) at 2 h post reperfusion. No differences were documented for pH, mean arterial pressure and pCO2 Histological exanimation revealed significant injury at 24 h post reperfusion for the I/R group. This anesthetic recovery model permitted avoidance of hypoxia and respiratory acidosis, allowing the study of the late phase of I/R injury.