Hexafluoroisopropanol decreases liver ischemia–reperfusion injury by downregulation of high mobility group box‐1 protein (original) (raw)
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International journal of molecular sciences, 2017
Ischemia/reperfusion injury (IRI) occurs inevitably in liver transplantations and frequently during major resections, and can lead to liver dysfunction as well as systemic disorders. High-mobility group box 1 (HMGB1) plays a pathogenic role in hepatic IRI. In the normal liver, HMGB1 is located in the nucleus of hepatocytes; after ischemia reperfusion, it translocates to the cytoplasm and it is further released to the extracellular space. Unlike the well-explored functions of nuclear and extracellular HMGB1, the role of cytoplasmic HMGB1 in hepatic IRI remains elusive. We hypothesized that cytoplasmic HMGB1 interacts with binding proteins involved in the hepatocellular response to IRI. In this study, binding proteins of cytoplasmic HMGB1 during hepatic IRI were identified. Liver tissues from rats with warm ischemia reperfusion (WI/R) injury and from normal rats were subjected to cytoplasmic protein extraction. Co-immunoprecipitation using these protein extracts was performed to enric...
Compounds in Liver Ischemia/Reperfusion Injury
2016
Hepatic ischemia/reperfusion (I/R) injury consists of a sequel of cellular and humoral events that finally leads to parenchymal and nonparenchymal cell death. It is of utmost importance as regards the outcome of liver transplantation and liver resections. There is ample evidence that the key role in the inflicted injury is ascribed to reactive oxygen species (ROS) generated mainly by Kupffer cells and neutrophils during reperfusion, with the participation of endothelial cells and hepatocytes. ROS can procure serious damage to cellular membranes and genomic material. The disaster culminates with the initiation of several inflammatory mediators. On the other hand, cells posses a very potent, enzymatic and non enzymatic antioxidant system capable to mitigate oxidant stress or scavenge ROS, thus preserving to some extent cellular redox state. When the imbalance between oxidant stress and antioxidant systems predominates, cell death ensues. The spectre of liver I/R injury therapeutic options includes a plethora of antioxidant agents, natural or synthetic, and extends to genetic modifications. The aim of this article is to review the current knowledge on the generation and mode of action of ROS and to give a further insight on the antioxidant compounds that comprise the therapeutic quiver of this complicated syndrome.
Therapeutic approaches for ischemia/reperfusion injury in the liver
Journal of Molecular Medicine, 1999
Organ injury caused by transient ischemia followed by reperfusion is associated with a number of clinically and environmentally induced conditions. Ischemia/reperfusion (I/R) conditions arise during surgical interventions such as organ transplantation and coronary bypass surgery, and in diseases such as stroke and cardiac infarct. The destructive effects of I/R arise from the acute generation of reactive oxygen species subsequent to reoxygenation, which inflict direct tissue damage and initiate a cascade of deleterious cellular responses leading to inflammation, cell death, and organ failure. This review summarizes existing and potential approaches for treatment that have been developed from research using model systems of I/R injury. Although I/R injury in the liver is emphasized, other organ systems share similar pathophysiological mechanisms and therapeutic approaches. We also review current knowledge of the molecular events controlling cellular responses to I/R injury, such as activation of AP-1 and NF-κB pathways. Therapeutic strategies aimed at ameliorating I/R damage are focused both on controlling ROS generated at the time of oxygen reperfusion and on intervening in the activated signal transduction cascades. Potential therapies include pharmacological treatment with small molecules, antibodies to cytokines, or free-radical scavenging enzymes, such as superoxide dismutase or catalase. Additionally, the use of gene therapy approaches may significantly contribute to the development of strategies aimed at inhibiting of I/R injury.
The Protective Effect of CAPE on Hepatic Ischemia/Reperfusion Injury in Rats
Journal of Surgical Research, 2008
Materials and methods. Wistar rats were submitted to a sham operation, 60 min ischemia, or 60 min ischemia plus saline or CAPE treatment followed by 6 h reperfusion. Liver tissue injury was evaluated by alanine aminotransferase, aspartate aminotransferase, and tissue glutathione measurement, and histological damage score. Apoptotic hepatocytes were determined by the transferase-mediated dUTP-biotin nickend labeling assay. Hepatic neutrophil accumulation was assessed by the naphthol method. Lipid peroxidation and NF-B activation were evaluated by 4-hydroxynonenal and NF-B p65 immunohistochemistry, respectively.
International Journal of Molecular Sciences
Hepatic ischemia-reperfusion injury (IRI) is a multifactorial phenomenon which has been associated with adverse clinical outcomes. IRI related tissue damage is characterized by various chronological events depending on the experimental model or clinical setting. Despite the fact that IRI research has been in the spotlight of scientific interest for over three decades with a significant and continuous increase in publication activity over the years and the large number of pharmacological and surgical therapeutic attempts introduced, not many of these strategies have made their way into everyday clinical practice. Furthermore, the pathomechanism of hepatic IRI has not been fully elucidated yet. In the complex process of the IRI, flow properties of blood are not neglectable. Hemorheological factors play an important role in determining tissue perfusion and orchestrating mechanical shear stress-dependent endothelial functions. Antioxidant and anti-inflammatory agents, ischemic condition...
Anesthesia & Analgesia
BACKGROUND Randomized controlled trials (RCTs) data demonstrate that sevoflurane postconditioning improves clinical outcomes of liver resection with inflow occlusion, presumably due to hepatocyte protection from ischemic injury. However, mechanisms remain unclear. This study examines liver biopsy samples obtained in an RCT of sevoflurane postconditioning to test the hypothesis that sevoflurane attenuates hepatocyte apoptosis. METHODS Messenger ribonucleic acid (mRNA) of pro-and antiapoptotic regulators Bax and B-cell lymphoma 2 (Bcl2) was examined in hepatic biopsies obtained during the RCT. Hepatic stellate cells (HSCs) and hepatocytes were exposed to hypoxia/reoxygenation (H/R) in vitro to evaluate the effect of sevoflurane postconditioning on apoptosis. The role of HSC as a potential apoptosis trigger in hepatocytes through the production of reactive oxygen species induced by H/R was explored by transferring supernatants from H/R-exposed HSC to hepatocytes as target cells. RESULTS In patients of the RCT, the Bax/Bcl2 mRNA ratio in liver tissue was markedly decreased in the sevoflurane arm (25% ± 21% reduction; P = .001). In vitro, H/R increased reactive oxygen species production in HSC by 33% ± 16% (P = .025), while it was abolished in the presence of sevoflurane (P < .001). In hepatocytes, caspase was minimally activated by H/R. However, incubation of hepatocytes with supernatants of HSC, previously exposed to H/R, increased caspase activity by 28% ± 13% (P < .001). When exposed to supernatants from HSC undergoing sevoflurane postconditioning, caspase activation in hepatocytes was reduced by 20% ± 9% (P < .001), similarly to the sevoflurane effect on the BAX/Bcl2 mRNA ratio in the liver samples. CONCLUSIONS The study shows that sevoflurane postconditioning affects apoptosis of hepatocytes after ischemia-reperfusion injury in patients. It also demonstrates that HSC may be the effector cells of sevoflurane protection.
HPB, 2018
time was higher for STSCC (39 minutes vs. 30, p < 0.01). There was no difference in total graft ischemia time (345 min vs. 345, p = 0.933) and operative time was significantly reduced (246 min vs. 303, p < 0.01). STSCC was associated with significantly reduced intraoperative blood loss (3 vs. 6 liters), red blood cell transfusions (2 units vs. 4), fresh frozen plasma (6 units vs. 9), cell saver (0.8 L vs. 2), and rates of temporary abdominal closure (4% vs. 22%) compared to TP (all p < 0.05). Postoperative intensive care unit transfusions were also significantly lower for STSCC, with 82% requiring no red blood cell transfusions. Conclusion: STSCC is superior to TP implantation with regard to technical ease, operative time, blood loss, and transfusion requirements during LT. Future studies evaluating long-term outcomes including graft and patient survival following STSCC are warranted.
Gastroenterology and hepatology, 2014
Ischemia-reperfusion injury (IRI) is a common phenomenon occurring during liver surgery, transplantation, and trauma. IRI causes oxidative stress which plays a critical role in causing organ damage. The Nrf2 is the master regulator of numerous genes, encoding antioxidant, detoxifying, and cytoprotective molecules. Nrf2 dysfunction has been implicated in the pathogenesis of several inflammatory disorders, cancer, and aging. This study was undertaken to investigate the effect of Nrf2 pathway activator (dh404) on warm liver IRI in a rodent model. Ten Sprague-Dawley rats were treated with dh404 or vehicle. Dh404 was dissolved in sesame oil and was given orally (1.5mg/kg) the night before and 5 hours before procedures. Rat livers were subjected to 60 minutes of 70% ischemia followed by 3 hours of reperfusion. Serum ALT and Malondialdehyde (MDA) were determined and liver tissue was processed for histological examination, and determination of apoptosis, myeloperoxidase (MPO) activity, ADP/...
American journal of surgery, 2015
The purpose of this study is to determine the effects of anti-high mobility group box 1 (HMGB1) monoclonal antibody (mAb) on ischemia/reperfusion injury (IRI) and the mode of liver regeneration. Rats underwent 70% hepatectomy with IRI caused by clamping the hepatoduodenal ligament for 20 minutes, followed by the administration of anti-HMGB1 mAb immediately before declamping the hepatoduodenal ligament. Five animals were used for each time point. We then evaluated IRI, regeneration parameters and the status of HMGB1 in remnant livers. The anti-HMGB1 mAb significantly ameliorated the degree of IRI in the remnant livers in association with the downregulation of HMGB1 protein. The ratio of Ki67-positive hepatocytes at 48 hours after 70% hepatectomy was significantly improved. Mean hepatocyte size was significantly reduced and cyclin-dependent kinase inhibitor 1 expression was significantly attenuated. Anti-HMGB1 mAb ameliorated IRI and improved the mode of liver regeneration after IRI f...
Novel Pharmacologic Strategies to Protect the Liver from Ischemia- Reperfusion Injury
Recent Patents on Cardiovascular Drug Discovery, 2008
Ischemia and reperfusion (I/R) injury develops when blood flow is interrupted for a long period of time and then restarted. In the liver, this type of damage occurs in clinical settings such as liver transplantation and hepatic resection. Given the shortage of donor organs it is essential to maximize the use of sub-optimal organs, those previously rejected due to elevated risk of malfunction, and to increase split-liver transplantation interventions. Therefore, the development of strategies that preserve organ viability and promote liver regeneration is urgently needed. As observed for other organs, a brief period of ischemia followed by short reperfusion before the surgical procedure significantly increases liver resistance towards prolonged periods of ischemia. This phenomenon is known as ischemic preconditioning, and is the only protective strategy that has reached clinical practice. Recently, intensive research has improved our understanding of the mechanisms involved in I/R liver injury, and the biologic bases of ischemic preconditioning. This knowledge has generated relevant patented advances in the field, including the targeted inhibition of pro-apoptotic pathways, the interference with neutrophil activation, and the identification of cytoprotective cytokines. Here, we briefly review the mechanisms of hepatic ischemic damage, and present the most promising pharmacologic approaches against I/R injury. This article also includes recent patents on this topic.