Hepatic Ischemia Injury Research Articles

Assessing Liver Viability: Insights From Mitochondrial Bioenergetics in Ischemia-Reperfusion Injury

Orthotopic liver transplantation remains the definitive treatment for patients with end-stage liver disease. Unfortunately, the increasing demand for donor livers and the limited supply of viable organs have both led to a critical need for innovative strategies to expand the pool of transplantable organs. The mitochondrion, central to hepatic cellular function, plays a pivotal role in hepatic ischemic injury, with impaired mitochondrial function and oxidative stress leading to cell death. Mitochondrial protection strategies have shown promise in mitigating IRI and resuscitating marginal organs for transplant. Machine perfusion (MP) has been proven a valuable tool for reviving marginal organs with very promising results. Evaluation of liver viability during perfusion traditionally relies on parameters including lactate clearance, bile production, and transaminase levels. Nevertheless, the quest for more comprehensive and universally applicable viability markers persists. Normothermic regional perfusion has gained robust attention, offering extended recovery time for organs from donation after cardiac death donors. This approach has shown remarkable success in improving organ quality and reducing ischemic injury using the body's physiological conditions. The current challenge lies in the absence of a reliable assessment tool for predicting graft viability and post-transplant outcomes. To address this, exploring insights from mitochondrial function in the context of ischemia-reperfusion injury could offer a promising path toward better patient outcomes and graft longevity. Indeed, hypoxia-induced mitochondrial injury may serve as a surrogate marker of organ viability following oxygenated resuscitation techniques in the future.

Mitochondrial Lipid Peroxidation and Microsomal Drug-metabolizing Enzyme Activity of Rat Hepatotoxicity under Heavy Metals from Slag Waste Exposure

Heavy metals from slag waste (HMSWs) have attracted much attention because of their serious toxicity to the environment and human organs, especially hepatotoxicity. The aim of this study was to explore the effects of different HMSWs exposure on mitochondrial lipid peroxidation, microsomal drug metabolizing enzyme activities as well as their relationship in the rat liver injury. Based on toxicogenomic analysis, heavy metals including iron, copper, cobalt, nickel and manganese, might interfere with pathophysiological processes such as oxidative stress, cell death, and energy metabolism regulation in vivo, and participate in the regulation of HIF-1 signaling pathway, peroxisomes, drug metabolism-cytochrome P450, ferroptosis, and other signaling pathways. HMSWs exposure caused weight loss, and significantly increased lactate dehydrogenase (LDH), malondialdehyde (MDA), alanine transaminase (ALT), and aspartate transaminase (AST) in different groups of rat liver, suggesting the presence of mitochondrial lipid peroxidation damage. In addition, the ratios of AST/ALT and ALT/LDH were down-regulated, especially the ALT/LDH ratios were less than 1, indicating that hepatic ischemic injury occurred in the process of liver injury. The superoxide dismutase (SOD) and mitochondrial membrane potential (MMP) activities in rats also showed significant decreases, indicating the occurrence of hepatic oxidative/antioxidant dysfunction imbalance. Further decision tree analysis of live biochemical abnormalities suggested that AST > 58.78 U/gprot and MDA > 173.2 nmol/mgprot could be used for hepatotoxicity warning. Liver microsomal cytochrome P4501A2 (CYP1A2) and 3A1 (CYP3A1) enzymes were also involved in the hepatotoxic process of heavy metals. These results suggest that lipid peroxidation damage and metabolic damage in liver mitochondria and peroxisomes, may be one of the key events in heavy metal-induced liver injury.

O120 A functional assessment of hepatic ischaemic injury on hepatocellular carcinoma behaviour

Abstract Introduction Hypothermic oxygenated perfusion (HOPE) preservation improves outcomes after donation after cardiac death (DCD) liver transplantation. Database analysis has also suggested significantly lower hepatocellular carcinoma (HCC) recurrence rates in recipients with HOPE-DCD livers compared to non-perfused livers. Whilst HOPE may protect against severe hepatic ischaemia-reperfusion injury, the exact mechanisms for lower recurrence rates are not fully understood. As HOPE preservation fluid, or perfusate, dynamically flushes out many inflammatory and ischaemic markers from the donor liver, the effect of these contents on in-vitro HCC cell behaviour was investigated. Methods An HCC cell line, HepG2, was functionally assessed following treatment with HOPE perfusate samples from 3 human livers declined for transplant. In-vitro HepG2 proliferation, stemness and initiation were assessed by an MTS assay, cytokeratin-19 (K-19) immunocytochemistry, and a colony-forming assay respectively. All experiments were conducted with approval by an ethical committee. Results All 3 HOPE perfusate samples resulted in significant HepG2 proliferation and increased aggressive behaviour potential. At 24 hours, HepG2 proliferation was significantly greater after treatment with 1:2 perfusate dilution compared to blank perfusate (p<0.05). Membrane invadopodia development, signifying an increased invasive potential, was also noted at 24 hours with treatments of 1:2 and 1:20, without observed differences in K-19 expression compared to untreated controls. Conclusion End-timepoint HOPE perfusate from declined livers facilitate increased HepG2 proliferation and aggression. HOPE may reduce early tumour recurrence in HCC patients by dynamically flushing out these liver-secreted trophic factors.

Exogenous melatonin alleviates hemorrhagic shock‑induced hepatic ischemic injury in rats by inhibiting the NF‑κB/IκBα signaling pathway.

Melatonin (MT) is an indoleamine hormone that can counteract ischemia-induced organ injury through its antioxidant effects. The aim of the present study was to investigate the protective effects of exogenous MT against hemorrhagic shock (HS)-induced hepatic ischemic injury in rats, and the role of the nuclear factor (NF)-κB signaling pathway in this process. A rat model of HS-induced hepatic ischemic injury was established. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), glutamate dehydrogenase (GDH), tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-6 and IL-1β were measured every 6 h, and the 24-h survival rate of the rats was analyzed. All surviving rats were sacrificed after 24 h. Pathological changes in the liver and the hepatocyte apoptosis rate were observed by hematoxylin and eosin staining and TUNEL assay, respectively, and the expression levels of NF-κB p65 and NF-κB inhibitor α (IκBα) were analyzed by reverse transcription-quantitative PCR analysis and western blotting. The results demonstrated that the serum levels of ALT, AST, LDH, GDH, TNF-α, IFN-γ, IL-6 and IL-1β gradually increased after HS compared with those in rats subjected to a sham procedure, but this increase was attenuated by MT. Furthermore, the survival rate of the MT group was significantly higher compared with that of the HS group. The degree of pathological hepatic injury, the hepatocyte apoptosis rate, and the hepatic levels of TNF-α, IFN-γ, IL-6 and IL-1β were significantly decreased in the MT group compared with the HS group. In addition, the mRNA expression of NF-κB p65 was significantly decreased and the mRNA expression of IκBα was significantly increased in the MT group compared with the sham group. Furthermore, the NF-κB p65 protein levels in the MT group were significantly increased in the cytosol but decreased in the nucleus, and the IκBα protein levels were increased while those of phosphorylated IκBα were decreased compared with those in the HS group. Therefore, it may be inferred that exogenous MT alleviates HS-induced hepatic ischemic injury in rats via the inhibition of NF-κB activation and IκBα phosphorylation.

A Preconditioning Strategy to Augment Retention and Engraftment Rate of Donor Cells During Hepatocyte Transplantation.

Hepatocyte transplantation has been extensively investigated as an alternative to orthotopic liver transplantation. However, its application in routine clinical practice has been restricted because of low initial engraftment and subsequent repopulation. Using mice as a model, we have developed a minimally invasive and nontoxic preconditioning strategy based on preadministration of antibodies against hepsin to increase donor hepatocyte retention and engraftment rate. Liver sinusoid diameters decreased significantly with antihepsin pretreatment, and graft cell numbers increased nearly 2-fold in the recipients' liver parenchyma for 20 days after hepatocyte transplantation. Postoperative complications such as hepatic ischemia injury or apparent immune cell accumulation were not observed in recipients. In a hemophilia B mouse model, antihepsin preconditioning enhanced the expression and clotting activity of coagulation factor IX (FIX) to nearly 2-fold that of immunoglobulin G-treated controls and maintained higher plasma FIX clotting activity relative to the prophylactic range for 50 days after hepatocyte transplantation. Antihepsin pretreatment combined with adeno-associated virus-transduced donor hepatocytes expressing human FIX-Triple, a hyperfunctional FIX variant, resulted in plasma FIX levels similar to those associated with mild hemophilia, which protected hemophilia B mice from major bleeding episodes for 50 days after transplantation. Furthermore, antihepsin pretreatment and repeated transplantation resulted in extending the therapeutic period by 30 days relative to the immunoglobulin G control. Thus, this antihepsin strategy improved the therapeutic effect of hepatocyte transplantation in mice with tremendous safety and minimal invasion. Taken together, we suggest that preconditioning with antihepsin may have clinical applications for liver cell therapy.

Optimization of 5′ Untranslated Region of Modified mRNA for Use in Cardiac or Hepatic Ischemic Injury

Modified mRNA (modRNA) is a gene-delivery platform for transiently introducing a single gene or several genes of interest to different cell types and tissues. modRNA is considered to be a safe vector for gene transfer, as it negligibly activates the innate immune system and does not compromise the genome integrity. The use of modRNA in basic and translational science is rising, due to the clinical potential of modRNA. We are currently using modRNA to induce cardiac regeneration post-ischemic injury. Major obstacles in using modRNA for cardiac ischemic disease include the need for the direct and single administration of modRNA to the heart and the inefficient translation of modRNA due to its short half-life. Modulation of the 5′ untranslated region (5′ UTR) to enhance translation efficiency in ischemic cardiac disease has great value, as it can reduce the amount of modRNA needed per delivery and will achieve higher and longer protein production post-single delivery. Here, we identified that 5′ UTR, from the fatty acid metabolism gene carboxylesterase 1D (Ces1d), enhanced the translation of firefly luciferase (Luc) modRNA by 2-fold in the heart post-myocardial infarction (MI). Moreover, we identified, in the Ces1d, a specific RNA element (element D) that is responsible for the improvement of modRNA translation and leads to a 2.5-fold translation increment over Luc modRNA carrying artificial 5′ UTR, post-MI. Importantly, we were able to show that 5′ UTR Ces1d also enhances modRNA translation in the liver, but not in the kidney, post-ischemic injury, indicating that Ces1d 5′ UTR and element D may play a wider role in translation of protein under an ischemic condition.

Remote Ischemic Preconditioning and Diazoxide Protect from Hepatic Ischemic Reperfusion Injury by Inhibiting HMGB1-Induced TLR4/MyD88/NF-κB Signaling.

Remote ischemic preconditioning (RIPC) is known to have a protective effect against hepatic ischemia-reperfusion (IR) injury in animal models. However, the underlying mechanism of action is not clearly understood. This study examined the effectiveness of RIPC in a mouse model of hepatic IR and aimed to clarify the mechanism and relationship of the ATP-sensitive potassium channel (KATP) and HMGB1-induced TLR4/MyD88/NF-κB signaling. C57BL/6 male mice were separated into six groups: (i) sham-operated control, (ii) IR, (iii) RIPC+IR, (iv) RIPC+IR+glyburide (KATP blocker), (v) RIPC+IR+diazoxide (KATP opener), and (vi) RIPC+IR+diazoxide+glyburide groups. Histological changes, including hepatic ischemia injury, were assessed. The levels of circulating liver enzymes and inflammatory cytokines were measured. Levels of apoptotic proteins, proinflammatory factors (TLR4, HMGB1, MyD88, and NF-κB), and IκBα were measured by Western blot and mRNA levels of proinflammatory cytokine factors were determined by RT-PCR. RIPC significantly decreased hepatic ischemic injury, inflammatory cytokine levels, and liver enzymes compared to the corresponding values observed in the IR mouse model. The KATP opener diazoxide + RIPC significantly reduced hepatic IR injury demonstrating an additive effect on protection against hepatic IR injury. The protective effect appeared to be related to the opening of KATP, which inhibited HMGB1-induced TRL4/MyD88/NF-kB signaling.

Dexmedetomidine exerts a protective effect on ischemia-reperfusion injury after hepatectomy: A prospective, randomized, controlled study.

Dexmedetomidine, a highly selective α2-receptor agonist, has been widely used for protection against ischemia-reperfusion (IR) injury. We hypothesized that dexmedetomidine might exert a protective effect on IR injury after hepatectomy. A prospective, randomized, single-blind study was conducted in 58 patients undergoing hepatectomy who were randomly assigned to two study groups. The dexmedetomidine group (D group) received a loading dose of 0.5 μg/kg for 10 min, and maintained it with 0.5 μg/kg/h until resection of the liver lobes. The control group (C group), received 0.9% sodium chloride administered in the same volume and infusion rate as D group. Eleven patients had hepatic inflow occlusion in D group as did 14 patients in C group. The primary outcome was the serum concentration of α-glutathione S-transferase (α-GST), which reflects hepatic ischemic injury. Secondary outcomes included laboratory variables reflecting inflammatory responses, liver and kidney function, and blood coagulation, as well as hemodynamic changes, recovery variables, and complications related to anesthesia and surgery. The concentration of α-GST at 0.5 h after resection was significantly lower in the dexmedetomidine group than the control group (9.1 ± 3.4 ng/mL vs 15.8 ± 6.5 ng/mL; p < .01), and was also significantly lower in the dexmedetomidine group in subgroup analyses of patients with and without hepatic inflow occlusion. While the concentrations of α-GST at 0.5 h after resection in patients with or without occlusion in D group were comparable, in C group the α-GST concentration without occlusion was significantly higher than that with occlusion. There was an interaction between dexmedetomidine and no occlusion (p < .01), and its concentration in D group without occlusion was the lowest of all subgroups. In addition, there were significant differences in interleukin (IL)-6 and tumor necrosis (TNF)-α concentrations at 24 h after hepatectomy between the two groups, and mean arterial pressure, heart rate, and the bispectral index were also significantly lower in D group than in C group (p < .05). There were significant differences between the two groups in ALT and AST at 2 h and 24 h after the resection of the liver lobe. However, there were no significant differences in renal function, recovery variables, blood coagulation. No severe complications related surgeries and anesthesia were found in both groups. Dexmedetomidine exerts a protective effect on ischemia-reperfusion injury after hepatectomy.

Hypothermic Perfusion Hepatectomy for Unresectable Liver Cancer: A Single-Center Experience

Introduction: Despite technical advancements in liver surgery, resection of liver tumors that involve the hepatic veins adjacent to the vena cava or hepatic hilum remains technically challenging. We present our surgical techniques and the long-term outcome of 5 patients with conventionally unresectable tumors. Method: Between September 1999 and March 2016, we encountered 5 patients with conventionally unresectable tumors that were successfully treated by “ex-situ liver resection” and “in-situ & ante -situm hypothermic liver perfusion” under total vascular exclusion and venovenous bypass. Result: These approaches allowed complete tumor removal with vascular reconstruction under a bloodless operation field, while minimizing hepatic ischemic injury and preserving liver function. No perioperative mortalities occurred and postoperative complications were minimal. The postoperative survival periods were limited due to the advanced malignancies in our patients, but the survival benefit was encouraging. The median postoperative survival time was 29.1 months, with the longest survival period being nearly 10 years. Furthermore, these approaches improved the quality of life and provided our patients with an opportunity for additional treatment. Conclusion: Hypothermic perfusion hepatectomy is a realistic option for achieving surgical cure or significantly improved survival and quality of life in patients with tumors deemed unresectable using conventional normothermic hepatectomy. These approaches can overcome the limitations of the liver’s restricted normothermic ischemia tolerance or inaccessible tumor locations.

Short fasting does not protect perfused ex vivo rat liver against ischemia-reperfusion. On the importance of a minimal cell energy charge

ObjectiveDietary restriction or reduced food intake was supported to protect against renal and hepatic ischemic injury. In this vein, short fasting was recently shown to protect in situ rat liver against ischemia-reperfusion. Here, perfused ex vivo instead of in situ livers were exposed to ischemia-reperfusion to study the impact of disconnecting liver from extrahepatic supply in energetic substrates on the protection given by short-term fasting. MethodsPerfused ex vivo livers using short (18 h) fasted compared with fed rats were submitted to ischemia-reperfusion and studied for release of cytolysis markers in the perfusate. Energetic stores are differently available in time and cell energetic charges (ratio of adenosine triphosphate plus half of the adenosine diphosphate concentrations to the sum of adenosine triphosphate + adenosine diphosphate + adenosine monophosphate concentrations), adenosine phosphates, and glycogen, which were further measured at different time points in livers. ResultsShort fasting versus feeding failed to protect perfused ex vivo rat livers against ischemia/reperfusion, increasing the release of cytolysis markers (potassium, cytochrome c, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase) in the perfusate during reoxygenation phase. Toxicity of short fasting versus feeding was associated with lower glycogen and energetic charges in livers and lower lactate levels in the perfusate. ConclusionHigh energetic charge, intracellular content in glycogen, and glycolytic activity may protect liver against ischemia/reperfusion injury. This work does not question how much the protective role previously demonstrated in the literature for dietary restriction and short fasting. In fact, it suggests that exceeding the energy charge threshold value of 0.3 might trigger the effectiveness of this protective role.

Effects of preoperative statin on liver reperfusion injury in major hepatic resection: a pilot study.

During major liver resection, ischemia reperfusion injury occurs resulting in adverse outcome. Animal studies have demonstrated the beneficial effect of statins on hepatic ischemic injury, but no clinical studies have been performed. Twenty consecutive patients undergoing major hepatic resection were included and were randomized into two groups. The study group (n=10) patients received oral atorvastatin 40mg for 3days prior to surgery, including the day of surgery, and the control group (n=10) received a placebo. Outcomes were assessed at 4, 24, and 72h by measurement of serum liver enzymes and cytokines-IL-1, IL-6, CRP, and TNF α. The two groups were evenly matched for demographic and perioperative variables. The AST levels were significantly higher in the control group compared with the study group at 4h (909.60±222 vs. 362.6±129 U/L), 24h (215.30±86.9 vs. 605.30±186.1 U/L) and 72h (84.30±32.7 vs. 204.70±67.5) (p<0.001). Plasma IL-1 values in the study group showed significantly lower values compared with the control group (p<0.001) postoperatively. Plasma IL-6 values postoperatively showed significantly lower mean values as compared with the mean of the control population (p<0.001). TNF α values at 4, 24, and 72h postoperatively comparable in the two groups (p=0.011) (p=0.096) and (p=0.237), respectively. Statins have the potential for pharmacological prevention of IRI. Further studies would be needed to substantiate the role of statins in prevention of IRI during liver resection. PGIMER, Chandigarh-NK/1081/MS/12182-83.

Ischemic Liver Injury After Complete Occlusion of Hepatic Artery in the Treatment of Delayed Postoperative Arterial Bleeding

BackgroundDelayed postoperative arterial bleeding is rare and may be life-threatening. When the bleeding source is the hepatic artery, complete ligation or embolization from the proximal to the distal area of the ruptured lesion usually results in complete occlusion of hepatic arterial flow. MethodsTo evaluate the frequency and severity of ischemic liver injury following complete hepatic artery occlusion, a retrospective study was conducted. Patients who underwent complete hepatic artery occlusion in the treatment of delayed postoperative arterial bleeding between January 2007 and December 2014 in our institution were reviewed. Changes of hepatic function and rates of associated complications and prognosis were analyzed. ResultsA total of 24 patients experienced 26 episodes of bleeding. Nineteen experienced transient liver enzyme elevation alone. There were no signs of acute liver failure after complete hepatic artery occlusion. The rates of liver infarction and liver abscess were 23.8 % (5/21) and 19 % (4/21), respectively. The 30-day mortality rate was 8.3 % (2/24). ConclusionComplete occlusion of the hepatic artery does not always result in severe hepatic ischemic injury. As a common cause of delayed postoperative bleeding, intra-abdominal infection may be fatal when it is not controlled successfully.

Protective effect of dieckol against chemical hypoxia-induced cytotoxicity in primary cultured mouse hepatocytes

Hepatic ischemic injury is a major complication arising from liver surgery, transplantation, or other ischemic diseases, and both reactive oxygen species (ROS) and pro-inflammatory mediators play the role of key mediators in hepatic ischemic injury. In this study, we examined the effect of dieckol in chemical hypoxia-induced injury in mouse hepatocytes. Cell viability was significantly decreased after treatment with cobalt chloride (CoCl2), a well-known hypoxia mimetic agent in a time- and dose-dependent manner. Pretreatment with dieckol before exposure to CoCl2 significantly attenuated the CoCl2-induced decrease of cell viability. Additionally, pretreatment with dieckol potentiated the CoCl2-induced decrease of Bcl-2 expression and attenuated the CoCl2-induced increase in the expression of Bax and caspase-3. Treatment with CoCl2 resulted in an increased intracellular ROS generation, which is inhibited by dieckol or N-acetyl cysteine (NAC, a ROS scavenger), and p38 MAPK phosphorylation, which is also blocked by dieckol or NAC. In addition, dieckol and SB203580 (p38 MAPK inhibitor) increased the CoCl2-induced decrease of Bcl-2 expression and decreased the CoCl2-induced increase of Bax and caspase-3 expressions. CoCl2-induced decrease of cell viability was attenuated by pretreatment with dieckol, NAC, and SB203580. Furthermore, dieckol attenuated CoCl2-induced COX-2 expression. Similar to the effect of dieckol, NAC also blocked CoCl2-induced COX-2 expression. Additionally, CoCl2-induced decrease of cell viability was attenuated not only by dieckol and NAC but also by NS-398 (a selective COX-2 inhibitor). In conclusion, dieckol protects primary cultured mouse hepatocytes against CoCl2-induced cell injury through inhibition of ROS-activated p38 MAPK and COX-2 pathway.

Different roles of hepatic hypothermic ischemia and ischemic preconditioning in chemically induced hepatocarcinogenesis in rats

BackgroundHepatic ischemia–reperfusion (IR) injury, an unfavorable complication of hepatectomy, could be prevented by hypothermic ischemia and ischemic preconditioning (IPC). However, the effects of these two approaches on hepatocarcinogenesis have not been examined. The aim of the study was to investigate roles of hypothermic ischemia and IPC in a chemically induced rat liver tumor model. MethodsTwenty-four Sprague–Dawley rats were treated with diethylnitrosamine and phenobarbital to induce hepatocellular carcinoma. Rats underwent hepatic ischemic injury, hypothermic ischemia, and IPC. Twenty-eight-wk-old rats were sacrificed to evaluate the morbidity and growth of liver tumor. Cytokines were measured at the protein and messenger RNA level. ResultsIR injury significantly promoted liver tumor development. Intriguingly, hypothermic ischemia, but not IPC, delayed liver carcinogenesis, although both of them suppressed the hepatic IR injury. IPC-treated rats showed elevated interleukin (IL)-6 concentration in the serum and messenger RNA expression in liver. In addition, higher levels of IL-6 activated signal transducer and activator of transcription 3 in the liver of IPC-treated rats. The hepatic expression of target genes of signal transducer and activator of transcription 3 signaling, cyclin D1, c-myc, c-fos, and c-jun, all of which might participate in tumor progression, increased in IPC group, compared with that of IR group. ConclusionsThese data indicated hypothermic ischemia could ameliorate both IR injury and liver tumor development. However, IPC, another effective method to prevent hepatic IR injury, might exacerbate liver tumor growth. The elevated level of IL-6 was one of the reasons for the different effects of hypothermic ischemia and IPC on hepatocarcinogenesis in rats.

What does the liver tell us about the failing heart?

This editorial refers to ‘Liver function abnormalities, clinical profile, and outcome in acute decompensated heart failure’, by M. Nikolaou et al. , doi:10.1093/eurheartj/ehs332 The high metabolic activity of the liver results in a high perfusion rate of ∼1 mL/g/min. Under resting conditions, this is about a quarter of the bodýs total blood supply. The oxygen-rich blood of the hepatic artery contributes to about a quarter of the total liver perfusion that may rise substantially under conditions of excessive oxygen demand. The complex blood supply makes the liver extraordinarily vulnerable to acute circulatory disturbances. Both the severity and the pattern of hepatic injury depend on the relative contribution of passive congestion and diminished perfusion.1 Increased central venous pressure results in passive hepatic congestion and causes elevations of alkaline phosphatase (AP), γ-glutamyltransferase (GGT), and direct and indirect serum bilirubin. This ‘congestive hepatic injury’ is known as nutmeg liver on pathology. Decreased cardiac output with impaired organ perfusion is associated with acute centrilobular (zone 3 of the acinus) hepatocellular damage and necrosis. ‘Hepatic ischaemic injury’ results in elevations in serum aminotransferases ( Figure 1 ).2,3 Figure 1 Haemodynamic disturbances in heart failure and mechanisms resulting in different patterns of elevated liver enzymes. Congestive hepatic injury (left panel) and ischaemic hepatic injury (right panel). In contrast to acute perfusion abnormalities, prolonged and chronic haemodynamic disturbances may result in bridging fibrosis, ‘cardiac’ cirrhosis, and impaired hepatic function with decreased synthesis of coagulation factors and albumin. Hepatic congestion occurs without particular symptoms in most cases. Some patients may suffer from jaundice, stretching of the liver capsule with right upper quadrant discomfort, and ascites. Rare cases of congestive heart failure (HF) associated with fulminant hepatic failure have been reported. However, most such cases occur in the setting of superimposed cardiogenic shock and consecutive hepatic ischaemic injury.4 …

The Anesthesiologist's Expanding Role in Perioperative Liver Protection

The Anesthesiologist's Expanding Role in Perioperative Liver Protection

The protective effect of liver X receptor activation on hepatic inflammation and ischemic reperfusion injury in rats

肝脏缺血再灌注损伤(reperfusion injury,RI)是肝脏缺血再灌注后肝脏功能障碍和结构损伤加重的现象.炎症反应是肝脏缺血再灌注损伤的重要机制之一[1].近年研究结果表明,肝X受体(live X receptor,LXR)除调节细胞内胆固醇平衡外,还可发挥抗炎效应[2].尽管LXR的抗炎作用业已明确,但其是否在RI后抑制肝脏炎症反应进而减轻损伤,目前仍鲜见报道.我们拟通过LXR化学激动剂T0901317诱导肝内LXR激活,观察其对肝脏RI后炎症反应及损伤情况的影响,研究其对肝脏RI损伤的保护机制,为治疗肝脏RI损伤提供新的作用靶点。

Bcl-2 expression alters the mitochondrial tri carboxyl Acid pathway in hepatic ischemic and reperfusion induced necrosis and apoptosis in rat liver.

Ischemic and reperfusion injury leads to necrosis and apoptosis. Mitochondrial enzymes and antiapoptotic gene plays an important role in necrosis and apoptosis. The aim of this study was to investigate the role of Bcl-2 expression in alternations in mitochondrial energy regulation during hepatic ischemia and reperfusion and role in necrosis and apoptosis. Total 12 Wistar rats were divided into sham-operated control group (I) and ischemia and reperfusion group (II). Mitochondrial tri carboxylic acid cycles marker enzymes, respiratory marker enzymes, apoptotic cells, necrotic cells and Bcl-2 expression was measured. Number of necrotic and apoptotic cells were increased in ischemic and reperfusion group with reducing tri carboxylic acid cycles marker enzymes, respiratory marker enzymes and decreasing of Bcl-2 expression. On the basis of our findings it may be concluded that suppression of Bcl-2 gene, inhibition of tri carboxylic acid cycles and respiration rate, adenosine tri phosphate production in mitochondria is a pathophysiological consequences which provides a clue for necrosis and apoptosis in hepatic ischemic and reperfusion injury.

The Protective Role of Steroids in Ischemia-Reperfusion Injury of the Liver

Liver ischemia-reperfusion injury occurs in a number of clinical settings, including liver surgery, transplantation, and circulatory shock, leading to significant morbidity and mortality. There is a substantial evidence that hepatic ischemia-reperfusion injury results from an intense inflammatory response initiated by oxidative stress in the liver parenchyma during reperfusion. The anti-inflammatory effects of glucocorticosteroids (GCs) have been known for decades and have found extensive therapeutic use in a wide range of clinical situations associated with organ ischemia. Based on their biological effects, routine perioperative GCs administration has been advocated to reduce hepatic ischemic injury. However, the use of GCs in hepatic surgery remains controversial and clinical benefits are still uncertain. The aim of this review is to present the experimental and clinical evidence about the role of GCs in modulating hepatic ischemia-reperfusion injury.

Effect of temperature control upon a mouse model of partial hepatic ischaemia/reperfusion injury

In vivo models of hepatic ischaemia/reperfusion injury (IRI) are widely used to study both the mechanisms of hepatic ischaemic injury and to seek means of hepatic protection. Achieving high-quality reproducible data are essential if the results of multiple studies are to be compared and reconciled. This paper presents our findings concerning the effect of intraoperative thermoregulation upon signal to noise ratios of hepatic IRI experiments in mice. Four experiments were conducted, using three different strategies for core temperature maintenance. Animals underwent hepatic IRI and euthanized 24 h postoperatively for measurement of plasma alanine aminotransferase (ALT). Duration of ischaemia was used to adjust the severity of injury. Experiment 1 utilized a constant output heating system and resulted in rising postoperative ALTs following increasing durations of hepatic ischaemia. Experiment 2, using the same constant output heating system confirmed a difference between ischaemic and sham-operated animals. Experiment 3 used a thermostatically controlled heating system and resulted in highly variable results with a small, but statistically significant correlation between ALT levels and rectal temperature readings. Experiment 4 used a homeothermic warming system and demonstrated highly reproducible data from increasing durations of ischaemia. High-quality data from hepatic ischaemia/reperfusion models are dependent upon careful control of intraoperative temperature. The use of homeothermic warming systems is recommended and conversely, the use of thermostatically controlled warming mats is to be avoided in these models.