Protective Role of Hepatocyte Cyclooxygenase‐2 Expression Against Liver Ischemia–Reperfusion Injury in Mice

Motiño, Omar; Francés, Daniel E.; Casanova, Natalia Muñiz; Fuertes-Agudo, Marina; Cucarella, Carme; Flores, Juana M.; Vallejo‐Cremades, María Teresa; Olmedilla, Luis; Peña, José Pérez; Bañares, Rafael; Boscá, Lisardo; Casado, Marta; Martı́n-Sanz, Paloma

doi:10.1002/hep.30241

Cited by 51 publications

(51 citation statements)

References 48 publications

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“…Excessive production of reactive oxygen species in the early phase of reperfusion is another critical factor in hepatic I/R injury [26, 27]. Some prior researches have indicated that the activation of antioxidative enzymes and antioxidants significantly ameliorated hepatic I/R injury [28, 29].…”

Section: Discussionmentioning

confidence: 99%

Vagus Nerve Stimulation Attenuates Hepatic Ischemia/Reperfusion Injury via the Nrf2/HO-1 Pathway

Zhang

Lai

Deng

et al. 2019

Oxidative Medicine and Cellular Longevity

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It has been demonstrated that vagus nerve stimulation (VNS) plays a protective role in ischemia/reperfusion (I/R) injury of various organs. The present study investigates the protective effect of VNS on hepatic I/R injury and the potential mechanisms. Male Sprague-Dawley rats were randomly allocated into three groups: the sham operation group (Sham; n=6, sham surgery with sham VNS); the I/R group (n=6, hepatic I/R surgery with sham VNS); and the VNS group (n=6, hepatic I/R surgery plus VNS). The I/R model was established by 1 hour of 70% hepatic ischemia. Tissue samples and blood samples were collected after 6 hours of reperfusion. The left cervical vagus nerve was separated and stimulated throughout the whole I/R process. The stimulus intensity was standardized to the voltage level that slowed the sinus rate by 10%. VNS significantly reduced the necrotic area and cell death in I/R tissues. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) were also decreased by VNS. In addition, VNS suppressed inflammation, oxidative stress, and apoptosis in I/R tissues. VNS significantly increased the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) in the liver. These data indicated that VNS may attenuate hepatic I/R injury by inhibiting inflammation, oxidative stress, and apoptosis possibly via the Nrf2/HO-1 pathway.

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Section: Discussionmentioning

confidence: 99%

Vagus Nerve Stimulation Attenuates Hepatic Ischemia/Reperfusion Injury via the Nrf2/HO-1 Pathway

Zhang

Lai

Deng

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…Approximately 10% of early graft failure cases are caused by I/R injury, and the incidences of acute and chronic rejection are higher . Moreover, with the rising demand for organs and steady improvement in immunosuppression strategies, an increasing number of marginal donors, who are more susceptible to I/R injury, will be used . Although great efforts have been made to explore a treatment strategy to alleviate acute liver I/R injury, no strategy has been proven to be absolutely effective in clinical practice .…”

mentioning

confidence: 99%

“…(3) Moreover, with the rising demand for organs and steady improvement in immunosuppression strategies, an increasing number of marginal donors, who are more susceptible to I/R injury, will be used. (4) Although great efforts have been made to explore a treatment strategy to alleviate acute liver I/R injury, no strategy has been proven to be absolutely effective in clinical practice. (5,6) Therefore, more insights into the mechanism of injury and therapeutic measures will need to be developed.…”

mentioning

confidence: 99%

Six‐Transmembrane Epithelial Antigen of the Prostate 3 Deficiency in Hepatocytes Protects the Liver Against Ischemia‐Reperfusion Injury by Suppressing Transforming Growth Factor‐β‐Activated Kinase 1

et al. 2019

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Background and Aims Hepatic ischemia‐reperfusion (I/R) injury remains a major challenge affecting the morbidity and mortality of liver transplantation. Effective strategies to improve liver function after hepatic I/R injury are limited. Six‐transmembrane epithelial antigen of the prostate 3 (Steap3), a key regulator of iron uptake, was reported to be involved in immunity and apoptotic processes in various cell types. However, the role of Steap3 in hepatic I/R‐induced liver damage remains largely unclear. Approach and Results In the present study, we found that Steap3 expression was significantly up‐regulated in liver tissue from mice subjected to hepatic I/R surgery and primary hepatocytes challenged with hypoxia/reoxygenation insult. Subsequently, global Steap3 knockout (Steap3‐KO) mice, hepatocyte‐specific Steap3 transgenic (Steap3‐HTG) mice, and their corresponding controls were subjected to partial hepatic warm I/R injury. Hepatic histology, the inflammatory response, and apoptosis were monitored to assess liver damage. The molecular mechanisms of Steap3 function were explored in vivo and in vitro. The results demonstrated that, compared with control mice, Steap3‐KO mice exhibited alleviated liver damage after hepatic I/R injury, as shown by smaller necrotic areas, lower serum transaminase levels, decreased apoptosis rates, and reduced inflammatory cell infiltration, whereas Steap3‐HTG mice had the opposite phenotype. Further molecular experiments showed that Steap3 deficiency could inhibit transforming growth factor‐β–activated kinase 1 (TAK1) activation and downstream c‐Jun N‐terminal kinase (JNK) and p38 signaling during hepatic I/R injury. Conclusions Steap3 is a mediator of hepatic I/R injury that functions by regulating inflammatory responses as well as apoptosis through TAK1‐dependent activation of the JNK/p38 pathways. Targeting hepatocytes, Steap3 may be a promising approach to protect the liver against I/R injury.

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“…In concanavalin A (ConA) induced liver injury model, depleted COX2 in mice accelerated liver injury 24 . Hepatocyte COX2 expression protected against liver ischemia-reperfusion injury (IRI), meanwhile, in patients underwent liver transplantation, there was a signi cant positive correlation of plasma PGE 2 levels and graft function 25 . These results indicated that PGE 2 might have great therapeutic potentials in treating in ammatory liver diseases.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cells Secreted-Prostaglandin E2 Ameliorates Acute Liver Failure via Attenuation Cell Death and Regulation of Macrophage Polarization

Liu

Wang

Ding

et al. 2020

Preprint

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Background: Acute liver failure (ALF) is an acute inflammatory liver disease with high mortality. Previous preclinical and clinical trials have confirmed that mesenchymal stem cell (MSC) is a promising therapeutic approach, however the effect is not satisfied as the underlying molecular mechanisms of MSC in treating ALF remain unclear.Methods: MSC isolated from 4- to 6-week-old C57BL/6 mice were used to treat ALF. Histological and serological parameters were analyzed to evaluate the efficacy of MSC. We explored the molecular mechanism of MSC in the treatment of ALF by detecting liver inflammatory response and hepatocyte death.Results: In this study, we found that therapeutic potential of MSC on ALF dependent on secretion of prostaglandin E2 (PGE2), a bioactive lipid. MSC-derived PGE2 inhibited TGF-β-activated kinase 1 (TAK1) signaling and NLRP3 inflammasome activation in liver macrophages to decrease the production of inflammatory cytokines. Meanwhile, macrophages in liver could be induced to anti-inflammatory (M2) macrophages by MSC-derived PGE2 via STAT6 and mechanistic target of rapamycin (mTOR) signaling, which then to promote inflammatory resolution and limit liver injury. Finally, administrating of EP4 antagonist significantly ameliorated the therapeutic ability of MSC, which promoted liver inflammation and decreased M2 macrophages.Conclusions: Our results indicate that PGE2 might be a novel important mediator of MSC on treating ALF, which through inhibiting liver inflammatory response and hepatocyte death.

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Protective Role of Hepatocyte Cyclooxygenase‐2 Expression Against Liver Ischemia–Reperfusion Injury in Mice

Abstract: These data support the view of a novel protective effect of hepatic COX-2 induction and the consequent rise of derived prostaglandins against IRI. This article is protected by copyright. All rights reserved.

Cited by 51 publications

References 48 publications

Vagus Nerve Stimulation Attenuates Hepatic Ischemia/Reperfusion Injury via the Nrf2/HO-1 Pathway

Vagus Nerve Stimulation Attenuates Hepatic Ischemia/Reperfusion Injury via the Nrf2/HO-1 Pathway

Six‐Transmembrane Epithelial Antigen of the Prostate 3 Deficiency in Hepatocytes Protects the Liver Against Ischemia‐Reperfusion Injury by Suppressing Transforming Growth Factor‐β‐Activated Kinase 1

Mesenchymal Stem Cells Secreted-Prostaglandin E2 Ameliorates Acute Liver Failure via Attenuation Cell Death and Regulation of Macrophage Polarization

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