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Mukkala AN, David BA, Ailenberg M, Liang J, Vaswani CM, Karakas D, Goldfarb R, Barbour W, Gasner A, Wu RS, Petrut R, Jerkic M, Andreazza AC, Dos Santos C, Ni H, Zhang H, Kapus A, Kubes P, Rotstein OD. Mitochondrial Transplantation: A Novel Therapy for Liver Ischemia/Reperfusion Injury. Ann Surg 2025; 281:1032-1047. [PMID: 39912224 DOI: 10.1097/sla.0000000000006655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2025]
Abstract
OBJECTIVE To investigate the hepatoprotective effects of mitochondrial transplantation (MTx) in a murine liver ischemia/reperfusion (I/R) model. BACKGROUND Sequential liver ischemia, followed by reperfusion (I/R), is a pathophysiological process underlying hepatocellular injury in a number of clinical contexts, such as hemorrhagic shock/resuscitation, major elective liver surgery, and organ transplantation. A unifying pathogenic consequence of I/R is mitochondrial dysfunction. Restoration of mitochondria through transplantation (MTx) has emerged as a potential therapeutic in I/R. However, its role in liver I/R and its mechanisms of action remain poorly defined. METHODS We investigated the hepatoprotective effects of MTx in an in vivo mouse model of liver I/R and used in vivo imaging and various knockout and transgenic mouse models to determine the mechanism of protection. RESULTS We found that I/R-induced hepatocellular injury was prevented by MTx, as measured by plasma ALT, AST, and liver histology. In addition, I/R-induced pro-inflammatory cytokine release (IL-6, TNFα) was dampened by MTx, and anti-inflammatory IL-10 was enhanced. Moreover, MTx lowered neutrophil infiltration into both the liver sinusoids and lung bronchoalveolar lavage fluid, suggesting a local and distant reduction in inflammation. Using in vivo intravital imaging, we found that I/R-subjected Kupffer cells (KCs), rapidly sequestered transplanted mitochondria, and acidified mitochondria within lysosomal compartments. To specifically interrogate the role of KCs, we depleted KCs using the diphtheria toxin-inducible Clec4f/iDTR transgenic mouse, then induced I/R, and discovered that KCs are necessary for the beneficial effects of MTx. Finally, we induced I/R in the complement receptor of the immunoglobulin (CRIg) superfamily knockout mice and found that CRIg was required for mitochondria capture by KCs and mitochondria-mediated hepatoprotection. CONCLUSIONS In this study, we demonstrated that CRIg-dependent capture of mitochondria by I/R-subjected KCs is a hepatoprotective mechanism in vivo . These data progress knowledge on the mechanisms of MTx and open new avenues for clinical translation.
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Affiliation(s)
- Avinash Naraiah Mukkala
- Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada
- Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada
| | - Bruna Araujo David
- Department of Physiology and Pharmacology, University of Calgary; Calgary, AB, Canada
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary; Calgary, AB, Canada
| | - Menachem Ailenberg
- Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada
| | - Jady Liang
- Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada
| | - Chirag Manoj Vaswani
- Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada
| | - Danielle Karakas
- Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada
| | - Rachel Goldfarb
- Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada
| | - William Barbour
- Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada
| | - Avishai Gasner
- Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada
| | - Ruoxian Scarlet Wu
- Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada
| | - Raluca Petrut
- Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada
| | - Mirjana Jerkic
- Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada
| | - Ana Cristina Andreazza
- Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada
| | - Claudia Dos Santos
- Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada
- Interdepartmental Division of Critical Care, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada
| | - Heyu Ni
- Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada
- Canadian Blood Services Centre for Innovation, Canadian Blood Service; Toronto, ON, Canada
| | - Haibo Zhang
- Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada
- Interdepartmental Division of Critical Care, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada
- Department of Anesthesiology and Pain Medicine, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada
| | - Andras Kapus
- Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada
- Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada
| | - Paul Kubes
- Department of Physiology and Pharmacology, University of Calgary; Calgary, AB, Canada
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary; Calgary, AB, Canada
| | - Ori David Rotstein
- Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada
- Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada
- Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada
- Department of Surgery, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada
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Tian C, Wang A, Kuang Y. Remote ischemic conditioning in experimental hepatic ischemia‑reperfusion: A systematic review and meta‑analysis. Biomed Rep 2025; 22:49. [PMID: 39882337 PMCID: PMC11775642 DOI: 10.3892/br.2025.1927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 12/20/2024] [Indexed: 01/31/2025] Open
Abstract
Remote ischemic conditioning (RIC), including pre-conditioning (RIPC, before the ischemic event), per-conditioning (RIPerC, during the ischemic event), and post-conditioning (RIPostC, after the ischemic event), protects the liver in animal hepatic ischemia-reperfusion injuries models. However, several questions regarding the optimal timing of intervention and administration protocols remain unanswered. Therefore, the preclinical evidence on RIC in the HIRI models was systematically reviewed and meta-analyzed in the present review to provide constructive and helpful information for future works. In the present review, 39 articles were identified by searching the PubMed, OVID, Web of Science and Embase databases spanned from database inception to July 2024. According to the preferred reporting items for systematic reviews and meta-analyses guidelines, data were extracted independently by two researchers. The primary outcomes evaluated in this study were those directly related to liver injury, such as alanine transaminase (ALT), aspartate transaminase (AST) and liver histopathology. The risk of bias was assessed using the risk of bias tool of the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE). The findings were expressed as standardized mean difference (SMD) and analyzed using random-effects models. Egger's test was used to evaluate the publication bias. RIC significantly reduced the changes in ALT, AST and liver histopathology (all P<0.00001). These effects had two peaks, with the first peak of RIPerC/RIPostC occurring earlier, regardless of models and species. RIPerC/RIPostC exerted significant effects on changes in ALT and AST [ALT SMD (95% confidence interval (CI]): RIPC -1.97 (-2.40, -1.55) vs. -2.78 (-3.77, -1.78); P=0.142; AST SMD (95%CI): RIPC -1.45 (-1.90, -0.99) vs. -2.13 (-2.91, -1.34); P=0.142], and RIPC had a greater effect on liver histopathology change [SMD (95%CI): RIPC -2.68 (-3.67, -1.69) vs. -1.58 (-2.24, -0.92); P=0.070]; however, no interactions were observed between the two groups in the meta-regression analysis. RIC is the most effective in experimental HIRI, using a 10-25-min dose. These outcomes suggest that RIC may be a promising strategy for treating HIRI; however, future studies using repeated doses in animal models with comorbidities will present novel ideas for its therapeutic application. The protocol of present study was registered with PROSPERO (CRD42023482725).
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Affiliation(s)
- Chun Tian
- Department of Anesthesiology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, P.R. China
| | - Aihua Wang
- Department of Science and Education, Yongchuan District People's Hospital of Chongqing, Chongqing 400010, P.R. China
| | - Yonghong Kuang
- Department of Science and Education, Yongchuan District People's Hospital of Chongqing, Chongqing 400010, P.R. China
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Ailenberg M, Kapus A, Leung CH, Szaszi K, Williams P, diCiano-Oliveira C, Marshall JC, Rotstein OD. ACTIVATION OF THE MITOCHONDRIAL ANTIVIRAL SIGNALING PROTEIN (MAVS) FOLLOWING LIVER ISCHEMIA/REPERFUSION AND ITS EFFECT ON INFLAMMATION AND INJURY. Shock 2022; 58:78-89. [PMID: 35670454 PMCID: PMC9415233 DOI: 10.1097/shk.0000000000001949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 04/14/2022] [Accepted: 05/09/2022] [Indexed: 11/25/2022]
Abstract
ABSTRACT Resuscitation of trauma patients after hemorrhagic shock causes global I/R, which may contribute to organ dysfunction. Oxidative stress resulting from I/R is known to induce signaling pathways leading to the production of inflammatory molecules culminating in organ dysfunction/injury. Our recent work demonstrated that oxidative stress was able to induce activation of the mitochondrial antiviral signaling protein (MAVS), a protein known to be involved in antiviral immunity, in an in vitro model. We therefore hypothesized that the MAVS pathway might be involved in I/R-induced inflammation and injury. The present studies show that MAVS is activated in vivo by liver I/R and in vitro in RAW 264.7 cells by hypoxia/reoxygenation (H/R). We utilized both in vivo (liver I/R in MAVS knockout mice) and in vitro (MAVS siRNA in RAW 264.7 cells followed by H/R) models to study the role of MAVS activation on downstream events. In vivo , we demonstrated augmented injury and inflammation in MAVS knockout mice compared with wild-type animals; as shown by increased hepatocellular injury, induction of hepatocyte apoptosis augmented plasma TNF-α levels. Further, in vitro silencing of MAVS by specific siRNA in RAW 264.7 and exposure of the cells to H/R caused activation of mitophagy. This may represent a compensatory response to increased liver inflammation. We conclude that activation of MAVS by hypoxia/reoxygenation dampens inflammation, potentially suggesting a novel target for intervention.
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Affiliation(s)
- Menachem Ailenberg
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital and the Departments of Surgery, St. Michael's Hospital and the University of Toronto
| | - Andras Kapus
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital and the Departments of Surgery, St. Michael's Hospital and the University of Toronto
| | - Chung Ho Leung
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital and the Departments of Surgery, St. Michael's Hospital and the University of Toronto
| | - Katalin Szaszi
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital and the Departments of Surgery, St. Michael's Hospital and the University of Toronto
| | - Philip Williams
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital and the Departments of Surgery, St. Michael's Hospital and the University of Toronto
| | - Caterina diCiano-Oliveira
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital and the Departments of Surgery, St. Michael's Hospital and the University of Toronto
| | - John C. Marshall
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital and the Departments of Surgery, St. Michael's Hospital and the University of Toronto
| | - Ori D. Rotstein
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital and the Departments of Surgery, St. Michael's Hospital and the University of Toronto
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Myocardial remote ischemic preconditioning: from cell biology to clinical application. Mol Cell Biochem 2021; 476:3857-3867. [PMID: 34125317 DOI: 10.1007/s11010-021-04192-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 05/26/2021] [Indexed: 12/25/2022]
Abstract
Remote ischemic preconditioning (rIPC) is a cardioprotective phenomenon where brief periods of ischemia followed by reperfusion of one organ/tissue can confer subsequent protection against ischemia/reperfusion injury in other organs, such as the heart. It involves activation of humoral, neural or systemic communication pathways inducing different intracellular signals in the heart. The main purpose of this review is to summarize the possible mechanisms involved in the rIPC cardioprotection, and to describe recent clinical trials to establish the efficacy of these strategies in cardioprotection from lethal ischemia/reperfusion injury. In this sense, certain factors weaken the subcellular mechanisms of rIPC in patients, such as age, comorbidities, medication, and anesthetic protocol, which could explain the heterogeneity of results in some clinical trials. For these reasons, further studies, carefully designed, are necessary to develop a clearer understanding of the pathways and mechanism of early and late rIPC. An understanding of the pathways is important for translation to patients.
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Kim YH, Choi SU, Youn JM, Cha SH, Shin HJ, Ko EJ, Lim CH. Effects of remote ischemic preconditioning on the deformability and aggregation of red blood cells in a rat endotoxemia model. Clin Hemorheol Microcirc 2021; 79:407-415. [PMID: 34092622 DOI: 10.3233/ch-201084] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND The prevention of rheologic alterations in erythrocytes may be important for reducing sepsis-associated morbidity and mortality. Remote ischemic preconditioning (RIPC) has been shown to prevent tissue damage caused by severe ischemia and mortality resulting from sepsis. However, the effect of RIPC on erythrocytes in sepsis is yet to be determined. OBJECTIVE To investigate the effect of RIPC on rheologic alterations in erythrocytes in sepsis. METHODS Thirty male Sprague-Dawley rats were used in this study. An endotoxin-induced sepsis model was established by intraperitoneally injecting 20 mg/kg LPS (LPS group). RIPC was induced in the right hind limb using a tourniquet, with three 10-minute of ischemia and 10 min of reperfusion cycles immediately before the injection of LPS (RIPC/LPS group) or phosphate-buffered saline (RIPC group). The aggregation index (AI), time to half-maximal aggregation (T1/2), and maximal elongation index (EImax) of the erythrocytes were measured 8 h after injection. RESULTS The AI, T1/2, and EImax values in the LPS and RIPC/LPS groups differed significantly from those in the RIPC group, but there were no differences between the values in the LPS and RIPC/LPS groups. CONCLUSIONS RIPC did not prevent rheologic alterations in erythrocytes in the rat model of LPS-induced endotoxemia.
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Affiliation(s)
- Yun-Hee Kim
- Department of Anesthesiology and Pain Medicine, Korea University Medical Center, Seoul, Korea
| | - Sung-Uk Choi
- Department of Anesthesiology and Pain Medicine, Korea University Medical Center, Seoul, Korea
| | - Jung-Min Youn
- Department of Surgery, Asan Medical Center, Seoul, Korea
| | - Seung-Ha Cha
- Department of Medicine, School of Medicine, Korea University, Seoul, Korea
| | - Hyeon-Ju Shin
- Department of Anesthesiology and Pain Medicine, Korea University Medical Center, Seoul, Korea
| | - Eun-Ji Ko
- Department of Anesthesiology and Pain Medicine, Korea University Medical Center, Seoul, Korea
| | - Choon-Hak Lim
- Department of Anesthesiology and Pain Medicine, Korea University Medical Center, Seoul, Korea
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Akinci SB, Saricaoglu F, Akinci M, Turgut HC, Zeybek ND, Muftuoglu S. Remote Ischemic Conditioning Increases Organ Injury in Murine Sepsis: Experimental Research. Indian J Surg 2021. [DOI: 10.1007/s12262-021-02866-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Costa CCC, Pereira NG, Machado ALM, Dórea MA, Cruz RMMD, Silva RC, Domingues RJDS, Yasojima EY. Splenic ischemic preconditioning attenuates oxidative stress induced by hepatic ischemia-reperfusion in rats. Acta Cir Bras 2019; 34:e201900707. [PMID: 31531528 PMCID: PMC6756009 DOI: 10.1590/s0102-865020190070000007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 06/11/2019] [Indexed: 01/24/2023] Open
Abstract
Purpose: To evaluate the effects of splenic ischemic preconditioning (sIPC) on oxidative stress induced by hepatic ischemia-reperfusion in rats. Methods: Fifteen male Wistar rats were equally divided into 3 groups: SHAM, IRI and sIPC. Animals from IRI group were subjected to 45 minutes of partial liver ischemia (70%). In the sIPC group, splenic artery was clamped in 2 cycles of 5 min of ischemia and 5 min of reperfusion (20 min total) prior to hepatic ischemia. SHAM group underwent the same surgical procedures as in the remaining groups, but no liver ischemia or sIPC were induced. After 1h, hepatic and splenic tissue samples were harvested for TBARS, CAT, GPx and GSH-Rd measurement. Results: sIPC treatment significantly decreased both hepatic and splenic levels of TBARS when compared to IRI group (p<0.01). Furthermore, the hepatic and splenic activities of CAT, GPx and GSH- Rd were significantly higher in sIPC group than in IRI group. Conclusion: sIPC was able to attenuate hepatic and splenic IRI-induced oxidative stress.
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Affiliation(s)
- Caio César Chaves Costa
- Graduate student, Faculty of Medicine, UEPA, Belem-PA, Brazil. Technical procedures, analysis and interpretation of data, manuscript preparation
| | - Nathalia Gabay Pereira
- Graduate student, Faculty of Medicine, UEPA, Belem-PA, Brazil. Technical procedures, analysis and interpretation of data, manuscript preparation
| | - Anna Luiza Melo Machado
- Graduate student, Faculty of Medicine, UEPA, Belem-PA, Brazil. Technical procedures, analysis and interpretation of data, manuscript preparation
| | - Mariana Albuquerque Dórea
- Graduate student, Faculty of Medicine, UEPA, Belem-PA, Brazil. Technical procedures, analysis and interpretation of data, manuscript preparation
| | - Rafaella Macêdo Monteiro da Cruz
- Graduate student, Faculty of Medicine, UEPA, Belem-PA, Brazil. Technical procedures, analysis and interpretation of data, manuscript preparation
| | - Renata Cunha Silva
- Fellow, Postgraduate Program in Surgery and Experimental Research, UEPA, Belem-PA, Brazil. Technical procedures, analysis and interpretation of data, manuscript preparation
| | - Robson José de Souza Domingues
- PhD, Full Professor, Department of Morphology and Physiological Sciences, UEPA, Belem-PA, Brazil. Scientific and intellectual content of the study, critical revision, final approval
| | - Edson Yuzur Yasojima
- PhD, Full Professor, Postgraduate Program in Surgery and Experimental Research, Universidade do Estado do Pará (UEPA), Belem-PA, Brazil. Conception, design, scientific and intellectual content of the study; critical revision; final approval
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Kim YH, Kim YS, Kim BH, Lee KS, Park HS, Lim CH. Remote ischemic preconditioning ameliorates indirect acute lung injury by modulating phosphorylation of IκBα in mice. J Int Med Res 2019; 47:936-950. [PMID: 30614352 PMCID: PMC6381478 DOI: 10.1177/0300060518818300] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 11/19/2018] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE Acute lung injury is responsible for mortality in seriously ill patients. Previous studies have shown that systemic inflammation is attenuated by remote ischemic preconditioning (RIPC) via reducing nuclear factor-kappa B (NF-κB). Therefore, we investigated whether lipopolysaccharide (LPS)-induced indirect acute lung injury (ALI) can be protected by RIPC. METHODS RIPC was accomplished by 10 minutes of occlusion using a tourniquet on the right hind limb of mice, followed by 10 minutes of reperfusion. This process was repeated three times. Intraperitoneal LPS (20 mg/kg) was administered to induce indirect ALI. Inflammatory cytokines in bronchoalveolar lavage fluid were analyzed using an enzyme-linked immunosorbent assay. Pulmonary tissue was excised for histological examination, and for examining NF-κB activity and phosphorylation of inhibitor of κBα (IκBα). RESULTS NF-κB activation and LPS-induced histopathological changes in the lungs were significantly alleviated in the RIPC group. RIPC reduced phosphorylation of IκBα in lung tissue of ALI mice. CONCLUSIONS RIPC attenuates endotoxin-induced indirect ALI. This attenuation might occur through modification of NF-κB mediation of cytokines by modulating phosphorylation of IκBα.
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Affiliation(s)
- Yun-Hee Kim
- Department of Anesthesiology and Pain Medicine, Korea University Ansan Hospital, Ansan, Korea
| | - Young-Sung Kim
- Department of Anesthesiology and Pain Medicine, Korea University Guro Hospital, Seoul, Korea
| | - Byung-Hwa Kim
- Department of Anesthesiology and Pain Medicine, Korea University Ansan Hospital, Ansan, Korea
| | - Kuen-Su Lee
- Department of Anesthesiology and Pain Medicine, Korea University Ansan Hospital, Ansan, Korea
| | - Hyung-Sun Park
- Department of Anesthesiology and Pain Medicine, Korea University Anam Hospital, Seoul, Korea
| | - Choon-Hak Lim
- Department of Anesthesiology and Pain Medicine, Korea University Anam Hospital, Seoul, Korea
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Delaune V, Lacotte S, Gex Q, Slits F, Kahler-Quesada A, Lavallard V, Peloso A, Orci LA, Berney T, Toso C. Effects of remote ischaemic preconditioning on intraportal islet transplantation in a rat model. Transpl Int 2018; 32:323-333. [PMID: 30318858 DOI: 10.1111/tri.13360] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 07/23/2018] [Accepted: 10/08/2018] [Indexed: 12/29/2022]
Abstract
Remote ischaemic preconditioning (RIPC), which is the intermittent interruption of blood flow to a site distant from the target organ, is known to improve solid organ resistance to ischaemia-reperfusion injury. This procedure could be of interest in islet transplantation to mitigate hypoxia-related loss of islet mass after isolation and transplantation. Islets isolated from control or RIPC donors were analyzed for yield, metabolic activity, gene expression and high mobility group box-1 (HMGB1) content. Syngeneic marginal mass transplantation was performed in four streptozotocin-induced diabetic groups: control, RIPC in donor only, RIPC in recipient only, and RIPC in donor and recipient. Islets isolated from RIPC donors had an increased yield of 20% after 24 h of culture compared to control donors (P = 0.007), linked to less cell death (P = 0.08), decreased expression of hypoxia-related genes (Hif1a P = 0.04; IRP94 P = 0.008), and increased intra-cellular (P = 0.04) and nuclear HMGB1. The use of RIPC in recipients only did not allow for reversal of diabetes, with increased serum HMGB1 at day 1; the three other groups demonstrated significantly better outcomes. Performing RIPC in the donors increases islet yield and resistance to hypoxia. Validation is needed, but this strategy could help to decrease the number of donors per islet recipient.
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Affiliation(s)
- Vaihere Delaune
- Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Divisions of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
| | - Stéphanie Lacotte
- Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Quentin Gex
- Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Florence Slits
- Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Arianna Kahler-Quesada
- Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Vanessa Lavallard
- Cell Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Andrea Peloso
- Divisions of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
| | - Lorenzo A Orci
- Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Divisions of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
| | - Thierry Berney
- Cell Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Transplantation Division, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
| | - Christian Toso
- Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Divisions of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
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Endogenous Protection from Ischemic Brain Injury by Preconditioned Monocytes. J Neurosci 2018; 38:6722-6736. [PMID: 29946039 DOI: 10.1523/jneurosci.0324-18.2018] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 06/09/2018] [Accepted: 06/18/2018] [Indexed: 12/24/2022] Open
Abstract
Exposure to low-dose lipopolysaccharide (LPS) before cerebral ischemia is neuroprotective in stroke models, a phenomenon termed preconditioning (PC). Although it is well established that LPS-PC induces central and peripheral immune responses, the cellular mechanisms modulating ischemic injury remain unclear. Here, we investigated the role of immune cells in the brain protection afforded by PC and tested whether monocytes may be reprogrammed by ex vivo LPS exposure, thus modulating inflammatory injury after cerebral ischemia in male mice. We found that systemic injection of low-dose LPS induces a Ly6Chi monocyte response that protects the brain after transient middle cerebral artery occlusion (MCAO) in mice. Remarkably, adoptive transfer of monocytes isolated from preconditioned mice into naive mice 7 h after transient MCAO reduced brain injury. Gene expression and functional studies showed that IL-10, inducible nitric oxide synthase, and CCR2 in monocytes are essential for neuroprotection. This protective activity was elicited even if mouse or human monocytes were exposed ex vivo to LPS and then injected into male mice after stroke. Cell-tracking studies showed that protective monocytes are mobilized from the spleen and reach the brain and meninges, where they suppress postischemic inflammation and neutrophil influx into the brain parenchyma. Our findings unveil a previously unrecognized subpopulation of splenic monocytes capable of protecting the brain with an extended therapeutic window and provide the rationale for cell therapies based on the delivery of autologous or allogeneic protective monocytes in patients after ischemic stroke.SIGNIFICANCE STATEMENT Inflammation is a key component of the pathophysiology of the brain in stroke, a leading cause of death and disability with limited therapeutic options. Here, we investigate endogenous mechanisms of protection against cerebral ischemia. Using lipopolysaccharide (LPS) preconditioning (PC) as an approach to induce ischemic tolerance in mice, we found generation of neuroprotective monocytes within the spleen, from which they traffic to the brain and meninges, suppressing postischemic inflammation. Importantly, systemic LPS-PC can be mimicked by adoptive transfer of in vitro-preconditioned mouse or human monocytes at translational relevant time points after stroke. This model of neuroprotection may facilitate clinical efforts to increase the efficacy of BM mononuclear cell treatments in acute neurological diseases such as cerebral ischemia.
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Bromage DI, Pickard JMJ, Rossello X, Ziff OJ, Burke N, Yellon DM, Davidson SM. Remote ischaemic conditioning reduces infarct size in animal in vivo models of ischaemia-reperfusion injury: a systematic review and meta-analysis. Cardiovasc Res 2017; 113:288-297. [PMID: 28028069 PMCID: PMC5408955 DOI: 10.1093/cvr/cvw219] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 09/22/2016] [Indexed: 12/15/2022] Open
Abstract
Aims The potential of remote ischaemic conditioning (RIC) to ameliorate myocardial ischaemia-reperfusion injury (IRI) remains controversial. We aimed to analyse the pre-clinical evidence base to ascertain the overall effect and variability of RIC in animal in vivo models of myocardial IRI. Furthermore, we aimed to investigate the impact of different study protocols on the protective utility of RIC in animal models and identify gaps in our understanding of this promising therapeutic strategy. Methods and results Our primary outcome measure was the difference in mean infarct size between RIC and control groups in in vivo models of myocardial IRI. A systematic review returned 31 reports, from which we made 22 controlled comparisons of remote ischaemic preconditioning (RIPreC) and 21 of remote ischaemic perconditioning and postconditioning (RIPerC/RIPostC) in a pooled random-effects meta-analysis. In total, our analysis includes data from 280 control animals and 373 animals subject to RIC. Overall, RIPreC reduced infarct size as a percentage of area at risk by 22.8% (95% CI 18.8–26.9%), when compared with untreated controls (P < 0.001). Similarly, RIPerC/RIPostC reduced infarct size by 22.2% (95% CI 17.1–25.3%; P < 0.001). Interestingly, we observed significant heterogeneity in effect size (T2 = 92.9% and I2 = 99.4%; P < 0.001) that could not be explained by any of the experimental variables analysed by meta-regression. However, few reports have systematically characterized RIC protocols, and few of the included in vivo studies satisfactorily met study quality requirements, particularly with respect to blinding and randomization. Conclusions RIC significantly reduces infarct size in in vivo models of myocardial IRI. Heterogeneity between studies could not be explained by the experimental variables tested, but studies are limited in number and lack consistency in quality and study design. There is therefore a clear need for more well-performed in vivo studies with particular emphasis on detailed characterization of RIC protocols and investigating the potential impact of gender. Finally, more studies investigating the potential benefit of RIC in larger species are required before translation to humans.
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Affiliation(s)
| | | | | | | | | | - Derek M. Yellon
- Corresponding author. Tel: +44 203 447 9591; fax: +44 203 447 9818, E-mail:
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Zheng W, Zhang Z, Liu S, Bi J, Zhang J, Du L, Ding X, Liu C. Remote ischemic conditioning protects against acetaminophen-induced acute liver injury in mice. Hepatol Res 2017; 47:234-245. [PMID: 26990366 DOI: 10.1111/hepr.12702] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Revised: 02/22/2016] [Accepted: 03/14/2016] [Indexed: 12/20/2022]
Abstract
AIM Acetaminophen (APAP) overdose is a major cause of drug-induced acute liver failure. Studies have shown that remote ischemic pre- and post-conditioning (R-IPC and R-IPOST) can protect the liver against ischemia-reperfusion (I/R) and lipopolysaccharide-induced injuries. The aim of this study was to investigate the effect of R-IPC and R-IPOST on APAP-induced hepatotoxicity in mice. METHODS Mice were randomized (n = 6 per group) to seven major groups: (i) normal control; (ii) sham operated; (iii) APAP; (iv) R-IPC + APAP; (v) R-IPC + APAP + zinc protoporphyrin (ZnPP); (vi) R-IPOST + APAP; and (vii) R-IPOST + APAP + ZnPP. Sixteen hours after APAP treatment, mouse liver and serum were collected to determine the severity of liver injury. RESULTS The results showed that R-IPC and R-IPOST significantly decreased APAP-induced serum levels of alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor-α, interleukin-6, and hepatic malondialdehyde, as well as nitrotyrosine formation. Both R-IPC and R-IPOST could improve the hepatic superoxide dismutase, glutathione, and glutathione peroxidase activities and depress the expressions of pro-inflammatory associated proteins, such as inducible nitric oxide synthetase and nuclear factor-κB. They could also increase heme oxygenase-1 expression; however, ZnPP could counteract this protective effect. CONCLUSION Remote ischemic conditioning has significant therapeutic potential in APAP-induced hepatotoxicity by inhibiting oxidative stress and inflammation and promoting heme oxygenase-1 expression.
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Affiliation(s)
- Wei Zheng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University.,Department of Hepatobiliary Surgery, Shaanxi Provincial People's Hospital
| | - Zhiyong Zhang
- Department of Hepatobiliary Surgery, Shaanxi Provincial People's Hospital
| | - Sushun Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University
| | - Jianbin Bi
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University
| | - Jingyao Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University
| | - Lixue Du
- Department of Hepatobiliary Surgery, Shaanxi Provincial People's Hospital
| | - Xiaoming Ding
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University
| | - Chang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University
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Hormesis, cellular stress response and neuroinflammation in schizophrenia: Early onset versus late onset state. J Neurosci Res 2016; 95:1182-1193. [DOI: 10.1002/jnr.23967] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 09/25/2016] [Accepted: 09/26/2016] [Indexed: 12/27/2022]
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Remote Ischemic Conditioning Prevents Lung and Liver Injury After Hemorrhagic Shock/Resuscitation: Potential Role of a Humoral Plasma Factor. Ann Surg 2016; 261:1215-25. [PMID: 25185480 DOI: 10.1097/sla.0000000000000877] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
OBJECTIVE To evaluate the efficacy of remote ischemic conditioning (RIC) on organ protection after hemorrhagic shock/resuscitation (S/R) in a murine model. BACKGROUND Ischemia/reperfusion resulting from S/R contributes to multiple organ dysfunction in trauma patients. We hypothesized that RIC before shock (remote ischemic preconditioning), during shock (remote ischemic "PER"conditioning), or during resuscitation (remote ischemic "POST"conditioning) could confer organ protection. We also tested the effect of ischemic conditioned plasma on neutrophil migration in vivo using transgenic zebrafish models. METHODS C57Bl/6 mice were subjected to S/R with or without hindlimb RIC. Serum levels of alanine aminotransferase and tumor necrosis factor-alpha, and liver tumor necrosis factor-alpha and interleukin 1β mRNA were evaluated. In some experiments, lung protein leakage, cytokines, and myeloperoxidase activity were investigated. Plasma from mice subjected to RIC was microinjected into zebrafish, and neutrophil migration was assessed after tailfin transection or copper sulfate treatment. RESULTS In mice subjected to S/R, remote ischemic preconditioning, remote ischemic "PER"conditioning, and remote ischemic "POST"conditioning each significantly reduced serum alanine aminotransferase and liver mRNA expression of tumor necrosis factor-alpha and interleukin 1β and improved liver histology compared with control S/R mice. Lung injury and inflammation were also significantly reduced in mice treated with remote ischemic preconditioning. Zebrafish injected with plasma or dialyzed plasma (fraction >14 kDa) from ischemic conditioned mice had reduced neutrophil migration toward sites of injury compared with zebrafish injected with control plasma. CONCLUSIONS RIC protects against S/R-induced organ injury, in part, through a humoral factor(s), which alters neutrophil function. The beneficial effects of RIC, performed during the S/R phase of care, suggest a role for its application early in the posttrauma period.
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Clinical applications of remote ischaemic preconditioning in native and transplant acute kidney injury. Pediatr Nephrol 2015; 30:1749-59. [PMID: 25280959 PMCID: PMC4549377 DOI: 10.1007/s00467-014-2965-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2014] [Revised: 09/08/2014] [Accepted: 09/10/2014] [Indexed: 12/12/2022]
Abstract
Ischaemia-reperfusion (IR) injury is a composite of the injury sustained during a period of reduced or absent blood flow to a tissue or organ and the additional insult sustained upon reperfusion that limits the amount of tissue that can be salvaged. IR injury plays a central role in both native and transplant acute kidney injury (AKI). Native AKI is associated with increased morbidity and mortality in hospital inpatients, and transplant AKI contributes to graft dysfunction, ultimately limiting graft longevity. In this review, we discuss the potential therapeutic benefits of a cost-effective and low-risk intervention, remote ischaemic preconditioning (RIPC), and its applicability in the prevention and reduction of AKI.
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Vicencio JM, Yellon DM, Sivaraman V, Das D, Boi-Doku C, Arjun S, Zheng Y, Riquelme JA, Kearney J, Sharma V, Multhoff G, Hall AR, Davidson SM. Plasma exosomes protect the myocardium from ischemia-reperfusion injury. J Am Coll Cardiol 2015; 65:1525-36. [PMID: 25881934 DOI: 10.1016/j.jacc.2015.02.026] [Citation(s) in RCA: 425] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 02/02/2015] [Accepted: 02/03/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND Exosomes are nanometer-sized vesicles released from cells into the blood, where they can transmit signals throughout the body. Shown to act on the heart, exosomes' composition and the signaling pathways they activate have not been explored. We hypothesized that endogenous plasma exosomes can communicate signals to the heart and provide protection against ischemia and reperfusion injury. OBJECTIVES This study sought to isolate and characterize exosomes from rats and healthy volunteers, evaluate their cardioprotective actions, and identify the molecular mechanisms involved. METHODS The exosome-rich fraction was isolated from the blood of adult rats and human volunteers and was analyzed by protein marker expression, transmission electron microscopy, and nanoparticle tracking analysis. This was then used in ex vivo, in vivo, and in vitro settings of ischemia-reperfusion, with the protective signaling pathways activated on cardiomyocytes identified using Western blot analyses and chemical inhibitors. RESULTS Exosomes exhibited the expected size and expressed marker proteins CD63, CD81, and heat shock protein (HSP) 70. The exosome-rich fraction was powerfully cardioprotective in all tested models of cardiac ischemia-reperfusion injury. We identified a pro-survival signaling pathway activated in cardiomyocytes involving toll-like receptor (TLR) 4 and various kinases, leading to activation of the cardioprotective HSP27. Cardioprotection was prevented by a neutralizing antibody against a conserved HSP70 epitope expressed on the exosome surface and by blocking TLR4 in cardiomyocytes, identifying the HSP70/TLR4 communication axis as a critical component in exosome-mediated cardioprotection. CONCLUSIONS Exosomes deliver endogenous protective signals to the myocardium by a pathway involving TLR4 and classic cardioprotective HSPs.
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Affiliation(s)
- Jose M Vicencio
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Derek M Yellon
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
| | - Vivek Sivaraman
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Debashish Das
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Claire Boi-Doku
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Sapna Arjun
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Ying Zheng
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Jaime A Riquelme
- Advanced Center for Chronic Diseases and Centro Estudios Moleculares de la Célula, Facultad de Ciencias Químicas y Farmacéuticas and Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Jessica Kearney
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Vikram Sharma
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Gabriele Multhoff
- Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | - Andrew R Hall
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Sean M Davidson
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
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Jia J, Li J, Jiang L, Zhang J, Chen S, Wang L, Zhou Y, Xie H, Zhou L, Zheng S. Protective effect of remote limb ischemic perconditioning on the liver grafts of rats with a novel model. PLoS One 2015; 10:e0121972. [PMID: 25785455 PMCID: PMC4364967 DOI: 10.1371/journal.pone.0121972] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 02/05/2015] [Indexed: 12/16/2022] Open
Abstract
Background Remote ischemic conditioning (RIC) is a known manual conditioning to decrease ischemic reperfusion injury (IRI) but not increase ischemic time. Here we tried to establish a rat RIC model of liver transplantation (LT), optimize the applicable protocols and investigate the protective mechanism. Methods The RIC model was developed by a standard tourniquet. Sprague-Dawley rats were assigned randomly to the sham operated control (N), standard rat liver transplantation (OLT) and RIC groups. According to the different protocols, RIC group was divided into 3 subgroups （10min×3, n = 6; 5min×3, n = 6; 1min×3, n = 6）respectively. Serum transaminases (ALT, AST), creatine kinase (CK), histopathologic changes, malondialdehyde (MDA), myeloperoxidase (MPO) and expressions of p-Akt were evaluated. Results Compared with the OLT group, the grafts subjected to RIC 5min*3 algorithm showed significant reduction of morphological damage and improved the graft function. Also, production of reactive oxygen species (MDA) and neutrophil accumulation (MPO) were markedly depressed and p-Akt was upregulated. Conclusion In conclusion, we successfully established a novel model of RIC in rat LT, the optimal RIC 5min*3 algorithm seemed to be more efficient to alleviate IRI of the liver graft in both functional and morphological categories, which due to its antioxidative, anti-inflammation activities and activating PI3K Akt pathway.
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Affiliation(s)
- Junjun Jia
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianhui Li
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Li Jiang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jing Zhang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shasha Chen
- Department of Anesthesia, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Li Wang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yanfei Zhou
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haiyang Xie
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lin Zhou
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shusen Zheng
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- * E-mail:
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Jia JJ, Li JH, Jiang L, Lin BY, Wang L, Su R, Zhou L, Zheng SS. Liver protection strategies in liver transplantation. Hepatobiliary Pancreat Dis Int 2015; 14:34-42. [PMID: 25655288 DOI: 10.1016/s1499-3872(15)60332-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Liver transplantation is the therapy of choice for patients with end-stage liver diseases. However, the gap between the low availability of organs and high demand is continuously increasing. Innovative strategies for organ protection are necessary to expand donor pool and to achieve better outcomes for liver transplantation. The present review analyzed and compared various strategies of liver protection. DATA SOURCES Databases such as PubMed, Embase and Ovid were searched for the literature related to donor liver protection strategies using following key words: "ischemia reperfusion injury", "graft preservation", "liver transplantation", "machine perfusion" and "conditioning". Of the 146 studies identified, only those with cutting edge strategies were analyzed. RESULTS A variety of therapeutic approaches were proposed to alleviate graft ischemia/reperfusion injury, which included static cold storage, machine perfusion (hypothermic, normothermic and subnormothermic), manual conditioning (pre, post and remote), and pharmacological conditioning. Evidences from animal experiments and clinical trials suggested that all these strategies could potentially protect liver graft; however, their clinical applications are limited partially due to their own disadvantages. CONCLUSIONS There are a plenty of methods suggested to decrease the degree of donor liver transplantation-related injury. However, none of these approaches is perfect in clinical practice. More translational researches (molecular and clinical studies) are needed to improve the techniques in liver graft protection.
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Affiliation(s)
- Jun-Jun Jia
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Health; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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Lin E, Snell GI, Levvey BJ, Mifsud N, Paul M, Buckland MR, Gooi J, Marasco S, Sharland AF, Myles PS. Safety, feasibility, and effect of remote ischemic conditioning in patients undergoing lung transplantation. J Heart Lung Transplant 2014; 33:1139-48. [DOI: 10.1016/j.healun.2014.04.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 03/02/2014] [Accepted: 04/30/2014] [Indexed: 10/25/2022] Open
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Starlinger P, Gruenberger T. Role of platelets in systemic tissue protection after remote ischemic preconditioning. Hepatology 2014; 60:1136-8. [PMID: 24668800 DOI: 10.1002/hep.27146] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Accepted: 03/23/2014] [Indexed: 12/20/2022]
Affiliation(s)
- Patrick Starlinger
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
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Li S, Ma C, Shao G, Esmail F, Hua Y, Jia L, Qin J, Ren C, Luo Y, Ding Y, Borlongan CV, Ji X. Safety and Feasibility of Remote Limb Ischemic Preconditioning in Patients With Unilateral Middle Cerebral Artery Stenosis and Healthy Volunteers. Cell Transplant 2014; 24:1901-11. [PMID: 25198862 DOI: 10.3727/096368914x683520] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Previous studies have indicated a neuroprotective effect of remote limb ischemic preconditioning. The aim of the present study was to assess whether upper arm ischemic preconditioning is feasible and safe in patients with unilateral middle cerebral artery (MCA) stenosis compared to healthy volunteers. Ten patients with unilateral MCA stenosis and 24 healthy volunteers underwent limb ischemic preconditioning, consisting of five cycles of 5-min inflations of a blood pressure cuff to 200 mmHg around an upper limb followed by 5 min of reperfusion. Limb ischemic preconditioning has no significant effect on the heart rate, oxygenation index, or mean flow velocity in patients with unilateral MCA stenosis or healthy volunteers. However, healthy volunteers showed a reduction in blood pressure 30 min following reperfusion of the last cycle. Limb ischemic preconditioning was found to be safe and well tolerated in both patients and healthy volunteers. We highlight the potential of limb ischemic preconditioning as an adjunct to neuroprotective treatment.
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Affiliation(s)
- Sijie Li
- Emergency Department, Xuan Wu Hospital, Capital Medical University, Beijing, China
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Björnsson B, Winbladh A, Bojmar L, Sundqvist T, Gullstrand P, Sandström P. Conventional, but not remote ischemic preconditioning, reduces iNOS transcription in liver ischemia/reperfusion. World J Gastroenterol 2014; 20:9506-9512. [PMID: 25071345 PMCID: PMC4110582 DOI: 10.3748/wjg.v20.i28.9506] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 04/12/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effects of preconditioning on inducible nitric oxide synthase (iNOS) and interleukin 1 (IL-1) receptor transcription in rat liver ischemia/reperfusion injury (IRI).
METHODS: Seventy-two male rats were randomized into 3 groups: the one-hour segmental ischemia (IRI, n = 24) group, the ischemic preconditioning (IPC, n = 24) group or the remote ischemic preconditioning (R-IPC, n = 24) group. The IPC and R-IPC were performed as 10 min of ischemia and 10 min of reperfusion. The iNOS and the IL-1 receptor mRNA in the liver tissue was analyzed with real time PCR. The total Nitrite and Nitrate (NOx) in continuously sampled microdialysate (MD) from the liver was analyzed. In addition, the NOx levels in the serum were analyzed.
RESULTS: After 4 h of reperfusion, the iNOS mRNA was significantly higher in the R-IPC (ΔCt: 3.44 ± 0.57) group than in the IPC (ΔCt: 5.86 ± 0.82) group (P = 0.025). The IL-1 receptor transcription activity was reduced in the IPC group (ΔCt: 1.88 ± 0.53 to 4.81 ± 0.21), but not in the R-IPC group, during reperfusion (P = 0.027). In the MD, a significant drop in the NOx levels was noted in the R-IPC group (12.3 ± 2.2 to 4.7 ± 1.2 μmol/L) at the end of ischemia compared with the levels in early ischemia (P = 0.008). A similar trend was observed in the IPC group (11.8 ± 2.1 to 6.4 ± 1.5 μmol/L), although this difference was not statistically significant. The levels of NOx rose quickly during reperfusion in both groups.
CONCLUSION: IPC, but not R-IPC, reduces iNOS and IL-1 receptor transcription during early reperfusion, indicating a lower inflammatory reaction. NOx is consumed in the ischemic liver lobe.
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Remote ischemic preconditioning prevents lipopolysaccharide-induced liver injury through inhibition of NF-κB activation in mice. J Anesth 2014; 28:898-905. [DOI: 10.1007/s00540-014-1850-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2012] [Accepted: 05/07/2014] [Indexed: 01/13/2023]
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Camara-Lemarroy CR. Remote ischemic preconditioning as treatment for non-ischemic gastrointestinal disorders: Beyond ischemia-reperfusion injury. World J Gastroenterol 2014; 20:3572-3581. [PMID: 24707140 PMCID: PMC3974524 DOI: 10.3748/wjg.v20.i13.3572] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 10/23/2013] [Accepted: 01/02/2014] [Indexed: 02/06/2023] Open
Abstract
Common gastrointestinal diseases such as radiation enteritis (RE), acute pancreatitis, inflammatory bowel diseases (IBD) and drug-induced hepatotoxicity share pathophysiological mechanisms at the molecular level, mostly involving the activation of many pathways of the immune response, ultimately leading to tissue injury. Increased oxidative stress, inflammatory cytokine release, inflammatory cell infiltration and activation and the up-regulation of inflammatory transcription factors participate in the pathophysiology of these complex entities. Treatment varies in each specific disease, but at least in the cases of RE and IBD immunosuppressors are effective. However, full therapeutic responses are not always achieved. The pathophysiology of ischemia-reperfusion (IR) injury shares many of these mechanisms. Brief and repetitive periods of ischemia in an organ or limb have been shown to protect against subsequent major IR injury in distant organs, a phenomenon called remote ischemic preconditioning (RIP). This procedure has been shown to protect the gut, pancreas and liver by modulating many of the same inflammatory mechanisms. Since RIP is safe and tolerable, and has shown to be effective in some recent clinical trials, I suggest that RIP could be used as a physiologically relevant adjunct treatment for non-ischemic gastrointestinal inflammatory conditions.
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Garcia-Bonilla L, Benakis C, Moore J, Iadecola C, Anrather J. Immune mechanisms in cerebral ischemic tolerance. Front Neurosci 2014; 8:44. [PMID: 24624056 PMCID: PMC3940969 DOI: 10.3389/fnins.2014.00044] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Accepted: 02/17/2014] [Indexed: 12/21/2022] Open
Abstract
Stressor-induced tolerance is a central mechanism in the response of bacteria, plants, and animals to potentially harmful environmental challenges. This response is characterized by immediate changes in cellular metabolism and by the delayed transcriptional activation or inhibition of genetic programs that are not generally stressor specific (cross-tolerance). These programs are aimed at countering the deleterious effects of the stressor. While induction of this response (preconditioning) can be established at the cellular level, activation of systemic networks is essential for the protection to occur throughout the organs of the body. This is best signified by the phenomenon of remote ischemic preconditioning, whereby application of ischemic stress to one tissue or organ induces ischemic tolerance (IT) in remote organs through humoral, cellular and neural signaling. The immune system is an essential component in cerebral IT acting simultaneously both as mediator and target. This dichotomy is based on the fact that activation of inflammatory pathways is necessary to establish IT and that IT can be, in part, attributed to a subdued immune activation after index ischemia. Here we describe the components of the immune system required for induction of IT and review the mechanisms by which a reprogrammed immune response contributes to the neuroprotection observed after preconditioning. Learning how local and systemic immune factors participate in endogenous neuroprotection could lead to the development of new stroke therapies.
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Affiliation(s)
- Lidia Garcia-Bonilla
- Brain and Mind Research Institute, Weill Cornell Medical College New York, NY, USA
| | - Corinne Benakis
- Brain and Mind Research Institute, Weill Cornell Medical College New York, NY, USA
| | - Jamie Moore
- Brain and Mind Research Institute, Weill Cornell Medical College New York, NY, USA
| | - Costantino Iadecola
- Brain and Mind Research Institute, Weill Cornell Medical College New York, NY, USA
| | - Josef Anrather
- Brain and Mind Research Institute, Weill Cornell Medical College New York, NY, USA
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The effects of remote ischemic preconditioning and N-acetylcysteine with remote ischemic preconditioning in rat hepatic ischemia reperfusion injury model. BIOMED RESEARCH INTERNATIONAL 2014; 2014:892704. [PMID: 24511549 PMCID: PMC3910499 DOI: 10.1155/2014/892704] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Accepted: 11/22/2013] [Indexed: 02/06/2023]
Abstract
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.
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Peralta C, Jiménez-Castro MB, Gracia-Sancho J. Hepatic ischemia and reperfusion injury: effects on the liver sinusoidal milieu. J Hepatol 2013; 59:1094-1106. [PMID: 23811302 DOI: 10.1016/j.jhep.2013.06.017] [Citation(s) in RCA: 456] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 06/17/2013] [Accepted: 06/18/2013] [Indexed: 12/16/2022]
Abstract
Ischemia-reperfusion injury is an important cause of liver damage occurring during surgical procedures including hepatic resection and liver transplantation, and represents the main underlying cause of graft dysfunction post-transplantation. Cellular and biochemical processes occurring during hepatic ischemia-reperfusion are diverse and complex, and include the deregulation of the healthy phenotype of all liver cellular components. Nevertheless, a significant part of these processes are still unknown or unclear. The present review aims at summarizing the current knowledge in liver ischemia-reperfusion, but specifically focusing on liver cell phenotype and paracrine interaction deregulations. Moreover, the most updated therapeutic strategies including pharmacological, genetic and surgical interventions, as well as some of the scientific controversies in the field will be described. Finally, the importance of considering the subclinical situation of liver grafts when translating basic knowledge to the bedside is discussed.
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Affiliation(s)
- Carmen Peralta
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
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Liu Q, Izamis ML, Xu H, Berendsen T, Yarmush M, Uygun K. Strategies to rescue steatotic livers before transplantation in clinical and experimental studies. World J Gastroenterol 2013; 19:4638-4650. [PMID: 23922462 PMCID: PMC3732837 DOI: 10.3748/wjg.v19.i29.4638] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Revised: 12/07/2012] [Accepted: 12/17/2012] [Indexed: 02/06/2023] Open
Abstract
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.
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Candilio L, Malik A, Hausenloy DJ. Protection of organs other than the heart by remote ischemic conditioning. J Cardiovasc Med (Hagerstown) 2013; 14:193-205. [PMID: 23079610 DOI: 10.2459/jcm.0b013e328359dd7b] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Organ or tissue dysfunction due to acute ischemia-reperfusion injury (IRI) is the leading cause of death and disability worldwide. Acute IRI induces cell injury and death in a wide variety of organs and tissues in a large number of different clinical settings. One novel therapeutic noninvasive intervention, capable of conferring multiorgan protection against acute IRI, is 'remote ischemic conditioning' (RIC). This describes an endogenous protective response to acute IRI, which is triggered by the application of one or more brief cycles of nonlethal ischemia and reperfusion to one particular organ or tissue. Originally discovered as a therapeutic strategy for protecting the myocardium against acute IRI, it has been subsequently demonstrated that RIC may confer protection against acute IRI in a number of different noncardiac organs and tissues including the kidneys, lungs, liver, skin flaps, ovaries, intestine, stomach and pancreas. The discovery that RIC can be induced noninvasively by applying the RIC stimulus to the skeletal tissue of the upper or lower limb has facilitated its application to a number of clinical settings in which organs and tissues are at high risk of acute IRI. In this article, we review the experimental studies that have investigated RIC in organs and tissues other than the heart, and we explore the therapeutic potential of RIC in preventing organ and tissue dysfunction induced by acute IRI.
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Affiliation(s)
- Luciano Candilio
- Hatter Cardiovascular Institute, University College London, London, UK
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Pillon NJ, Bilan PJ, Fink LN, Klip A. Cross-talk between skeletal muscle and immune cells: muscle-derived mediators and metabolic implications. Am J Physiol Endocrinol Metab 2013; 304:E453-65. [PMID: 23277185 DOI: 10.1152/ajpendo.00553.2012] [Citation(s) in RCA: 205] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Skeletal muscles contain resident immune cell populations and their abundance and type is altered in inflammatory myopathies, endotoxemia or different types of muscle injury/insult. Within tissues, monocytes differentiate into macrophages and polarize to acquire pro- or anti-inflammatory phenotypes. Skeletal muscle macrophages play a fundamental role in repair and pathogen clearance. These events require a precisely regulated cross-talk between myofibers and immune cells, involving paracrine/autocrine and contact interactions. Skeletal muscle also undergoes continuous repair as a result of contractile activity that involves participation of myokines and anti-inflammatory input. Finally, skeletal muscle is the major site of dietary glucose disposal; therefore, muscle insulin resistance is essential to the development of whole body insulin resistance. Notably, muscle inflammation is emerging as a potential contributor to insulin resistance. Recent reports show that inflammatory macrophage numbers within muscle are elevated during obesity and that muscle cells in vitro can mount autonomous inflammatory responses under metabolic challenge. Here, we review the nature of skeletal muscle inflammation associated with muscle exercise, damage, and regeneration, endotoxin presence, and myopathies, as well as the new evidence of local inflammation arising with obesity that potentially contributes to insulin resistance.
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Affiliation(s)
- Nicolas J Pillon
- Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
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In vivo hypoxic preconditioning protects from warm liver ischemia-reperfusion injury through the adenosine A2B receptor. Transplantation 2013; 94:894-902. [PMID: 23073466 DOI: 10.1097/tp.0b013e31826a9a46] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Liver ischemia-reperfusion injury (IRI) is a known risk factor for the postoperative outcome of patients undergoing liver surgery/transplantation. Attempts to protect from organ damage require multidisciplinary strategies and are of emerging interest in view of patients with higher age and American Society of Anesthesiology status. Ischemic preconditioning has been successfully applied to prevent from IRI during liver resection/transplantation. Because even short periods of ischemia during preconditioning inevitably lead to hypoxia and formation of anti-inflammatory/cytoprotective acting adenosine, we reasoned that short nonischemic hypoxia also protects against hepatic IRI. METHODS Mice underwent hypoxic preconditioning (HPC) by breathing 10% oxygen for 10 min followed by 10 min of 21% oxygen before left liver lobe ischemia (45 min) and reperfusion (4 hr). The interactions of hypoxia→adenosine→adenosine receptors were tested by pharmacologic antagonism at adenosine receptor (AR) sites in wild-type mice and in mice with genetic deletions at the A1, A2A, A2B, and A3 ARs. Hepatocellular damage, inflammation, and metabolic effects were quantified by enzyme activities, cytokines, liver myeloperoxidase, blood adenosine, and tissue AMP, respectively. RESULTS Hepatoprotection by HPC was significant in wild-type and A1, A2A, and A3 AR knockout mice as quantified by lower alanine aminotransferase serum activities, cytokine levels, histologic damage scores, tissue myeloperoxidase concentrations, and preserved AMP concentrations. Protection by HPC was blunted in mice pretreated with the A2B AR antagonist MRS1754 or in A2B AR knockout mice. CONCLUSIONS Because liver protective effects of HPC are negated when the A2B receptor is nonfunctional, the hypoxia→adenosine→A2B receptor pathway plays a critical role in the prevention of warm IRI in vivo. Hypoxic activation of this pathway warrants use of selective A2B AR agonists or even intermittent hypoxia (e.g., in deceased organ donors) to protect from liver IRI.
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Wang M, Shen J, Feng B, Gui L, Chen Q, Zhang B, Tang J, Li X. Remote ischemic preconditioning promotes early liver cell proliferation in a rat model of small-for-size liver transplantation. J Surg Res 2013; 179:e245-e253. [PMID: 22487396 DOI: 10.1016/j.jss.2012.02.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2011] [Revised: 01/31/2012] [Accepted: 02/03/2012] [Indexed: 11/30/2022]
Abstract
BACKGROUND The size of the liver donor graft is a major concern in living donor liver transplantation. Rapid regeneration is essential for the survival of these grafts. The purpose of this study was to investigate the effect of remote ischemic preconditioning (RIPC) on liver regeneration in a rat small-for-size liver transplantation model. METHODS We established rat models of small-for-size liver transplantation (30%) in the presence or absence (control) of remote ischemic preconditioning. We observed liver mass regeneration, serum alanine aminotransferase, hepatic pathologic alterations, flow cytometry, and Ki-67 antigen immunohistochemistry. In addition, using Western blotting and reverse-transcriptase-polymerase chain reaction, we assessed the activation of cell cycle progression as well as tumor necrosis factor-α and interleukin-6 expression. RESULTS Compared with the control group, serum alanine aminotransferase activity was significantly lower and histopathology changes were significantly attenuated in the RIPC group. Remote ischemic preconditioning induced a high level of interleukin-6 mRNA in small grafts, but suppressed the expression of tumor necrosis factor-α. The proliferation index, indicated by the S-phase and G2/M-phase ratio [(S+G2/M)/(G0/G1+S+G2/M)], was significantly increased in the RIPC group at 24 h (58.25% ± 0.506% versus 53.405% ± 1.25%; P = .007). Meanwhile, cell cycle progression and regeneration (Ki-67) were initiated early in liver grafts treated with RIPC. CONCLUSIONS These results suggest that RIPC can protect liver cells against ischemia reperfusion injury in the small grafts and enhance liver regeneration. Interleukin-6 may be a critical mediator in the stimulatory effect on liver cell regeneration, which may make RIPC valuable as a hepatoprotective modality.
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Affiliation(s)
- Meng Wang
- Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, China
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Selzner N, Boehnert M, Selzner M. Preconditioning, postconditioning, and remote conditioning in solid organ transplantation: basic mechanisms and translational applications. Transplant Rev (Orlando) 2011; 26:115-24. [PMID: 22000660 DOI: 10.1016/j.trre.2011.07.003] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Revised: 05/06/2011] [Accepted: 07/05/2011] [Indexed: 02/07/2023]
Abstract
Ischemia and reperfusion (I/Rp) injury is inherent to solid organ transplantation and can result in primary nonfunction or delayed function of grafts, which is associated with a significant morbidity and mortality posttransplantation. It is also a major obstacle for the use of marginal grafts to increase the donor pool, as these grafts are prone to a higher degree of I/Rp injury. Pre-, post-, and remote conditioning are protective strategies against I/Rp injury, which can be applied in the transplant setting. These strategies hold the potential to reduce graft injury and to safely expand the donor pool. However, despite convincing experimental data, the protective effects of the "conditioning" protocols remain unclear, and only few have translated to clinical practice. This review summarizes pre-, post-, and remote conditioning strategies in clinical use in solid organ transplantation and discusses an overview of the mechanistic pathways involved in each strategy.
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Affiliation(s)
- Nazia Selzner
- Multi Organ Transplant Program, University Health Network, University of Toronto, Toronto, Canada
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Björnsson B, Winbladh A, Bojmar L, Trulsson LM, Olsson H, Sundqvist T, Gullstrand P, Sandström P. Remote or conventional ischemic preconditioning--local liver metabolism in rats studied with microdialysis. J Surg Res 2011; 176:55-62. [PMID: 21962739 DOI: 10.1016/j.jss.2011.07.038] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2011] [Revised: 07/16/2011] [Accepted: 07/22/2011] [Indexed: 01/17/2023]
Abstract
BACKGROUND Ischemic preconditioning (IPC) of the liver decreases liver injury secondary to ischemia and reperfusion. An attractive alternative to IPC is remote ischemic preconditioning (R-IPC), but these two methods have not previously been compared. MATERIAL AND METHODS Eighty-seven rats were randomized into four groups: sham operated (n = 15), 1 h segmental ischemia (IRI, n = 24), preceded by IPC (n = 24), or R-IPC (n = 24) (to the left hindleg). IPC and R-IPC were performed with 10 min ischemia and 10 min of reperfusion. Analyses of liver microdialysate (MD), serum transaminase levels, and liver histology were made. RESULTS Rats treated with IPC and R-IPC had significantly lower AST, 71.5 (19.6) IU/L respective 96.6 (12.4) at 4 h reperfusion than those subjected to IRI alone, 155 (20.9), P = 0.0004 and P = 0.04 respectively. IPC also had lower ALT levels, 41.6 (11.3) IU/L than had IRI 107.4 (15.5), P = 0.003. The MD glycerol was significantly higher during ischemia in the R-IPC [759 (84) μM] and the IRI [732 (67)] groups than in the IPC 514 (70) group, P = 0.022 and P = 0.046 respectively. The MD glucose after ischemia was lower in the IPC group 7.1 (1.2) than in the IRI group 12.7 (1.6), P = 0.005. Preconditioning to the liver caused an direct increase in lactate, glucose and glycerol in the ischemic segment compared with the control segment an effect not seen in the R-IPC and IRI groups. CONCLUSIONS IPC affects glucose metabolism in the rat liver, observed with MD. IPC reduces liver cell injury during ischemic and reperfusion in rats. R-IPC performed over the same length of time as IPC does not have the same effect as the latter on ALT levels and MD glycerol; this may suggest that R-IPC does not offer the same protection as IPC in this setting of rat liver IRI.
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Affiliation(s)
- Bergthor Björnsson
- Department of Surgery, Faculty of Health Sciences, Linköping University, Surgical Clinic, County Council of Östergötland, Linköping, Sweden.
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Remote ischemic preconditioning by hindlimb occlusion prevents liver ischemic/reperfusion injury. Ann Surg 2011; 254:178-80. [PMID: 21606831 DOI: 10.1097/sla.0b013e318221ff34] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Systemic inflammation and liver injury following hemorrhagic shock and peripheral tissue trauma involve functional TLR9 signaling on bone marrow-derived cells and parenchymal cells. Shock 2011; 35:164-70. [PMID: 20577143 DOI: 10.1097/shk.0b013e3181eddcab] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Hemorrhagic shock due to trauma (HS/T) induces an inflammatory response that can contribute to end-organ injury. The pathways involved in the initiation and propagation of HS/T-induced inflammation are incompletely understood. Here, we hypothesized that the DNA sensor TLR9 would have a role in inflammatory signaling after HS/T. Using mice expressing a nonfunctional, mutant form of TLR9, we identified a role of TLR9 in driving the initial cytokine response and liver damage in a model of hemorrhagic shock and bilateral femur fracture. Circulating DNA levels were found to correlate with the degree of tissue damage. Experiments using chimeric mice show that TLR9 on both bone marrow-derived cells and parenchymal cells are important for the TLR9-mediated liver and tissue damage, as well as systemic inflammation after HS/T. These data suggest that release of DNA may be a driver of the inflammatory response to severe injury as well as a marker of the extent of tissue damage. One of the sensors of DNA in the setting of HS/T seems to be TLR9.
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Holzner PA, Kulemann B, Kuesters S, Timme S, Hoeppner J, Hopt UT, Marjanovic G. Impact of remote ischemic preconditioning on wound healing in small bowel anastomoses. World J Gastroenterol 2011; 17:1308-16. [PMID: 21455330 PMCID: PMC3068266 DOI: 10.3748/wjg.v17.i10.1308] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2010] [Revised: 11/17/2010] [Accepted: 11/24/2010] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the influence of remote ischemic preconditioning (RIPC) on anastomotic integrity.
METHODS: Sixty male Wistar rats were randomized to six groups. The control group (n = 10) had an end-to-end ileal anastomosis without RIPC. The preconditioned groups (n = 34) varied in time of ischemia and time of reperfusion. One group received the amino acid L-arginine before constructing the anastomosis (n = 9). On postoperative day 4, the rats were re-laparotomized, and bursting pressure, hydroxyproline concentration, intra-abdominal adhesions, and a histological score concerning the mucosal ischemic injury were collected. The data are given as median (range).
RESULTS: On postoperative day 4, median bursting pressure was 124 mmHg (60-146 mmHg) in the control group. The experimental groups did not show a statistically significant difference (P > 0.05). Regarding the hydroxyproline concentration, we did not find any significant variation in the experimental groups. We detected significantly less mucosal injury in the RIPC groups. Furthermore, we assessed more extensive intra-abdominal adhesions in the preconditioned groups than in the control group.
CONCLUSION: RIPC directly before performing small bowel anastomosis does not affect anastomotic stability in the early period, as seen in ischemic preconditioning.
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Jan WC, Chen CH, Tsai PS, Huang CJ. Limb ischemic preconditioning mitigates lung injury induced by haemorrhagic shock/resuscitation in rats. Resuscitation 2011; 82:760-6. [PMID: 21398019 DOI: 10.1016/j.resuscitation.2011.02.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2010] [Revised: 01/23/2011] [Accepted: 02/15/2011] [Indexed: 11/25/2022]
Abstract
AIM OF THE STUDY Haemorrhagic shock and subsequent resuscitation induce acute lung injury. We elucidated whether bilateral lower limb ischemic pre-conditioning (IP) could mitigate lung injury in haemorrhagic shock/resuscitation rats. The role of heme oxygenase-1 (HO-1) was also elucidated. METHOD Adult male rats were randomized to receive haemorrhagic shock/resuscitation (HS), HS plus IP, or HS plus IP plus the HO-1 inhibitor tin protoporphyrin (SnPP) (n = 12 in each group). Sham groups were employed simultaneously. For pre-conditioning, 3 cycles of limb IP (10 min ischemia followed by 10 min reperfusion) were performed immediately before haemorrhagic shock. Haemorrhagic shock (mean arterial pressure: 40-45 mmHg) was induced by blood drawing and maintained for 120 min. SnPP was injected 5 min before resuscitation. Shed blood/saline mixtures were re-infused to achieve resuscitation. After monitoring for another 8h, rats were sacrificed. Arterial blood gas and alveolar-arterial oxygen difference (lung function index), histology, polymorphonuclear leukocytes/alveoli ratio (leukocyte infiltration index), wet/dry weight ratio (water content index), inflammatory molecules (e.g., chemokine, cytokine, prostaglandin E(2)), and malondialdehyde (lipid peroxidation index) assays were preformed. RESULTS Haemorrhagic shock/resuscitation induced significant lung function alterations and significant increases in leukocyte infiltration, water content, inflammation, and lipid peroxidation in lungs. Histological analysis confirmed that haemorrhagic shock/resuscitation caused marked lung injury. Limb IP significantly mitigated the adverse effects of haemorrhagic shock/resuscitation. Moreover, the protective effects of limb IP were reversed by SnPP. CONCLUSIONS Limb IP mitigates lung injury in haemorrhagic shock/resuscitation rats. The mechanisms may involve HO-1.
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Affiliation(s)
- Woan-Ching Jan
- Department of Nursing, Mackay Medicine, Nursing and Management College, Taipei, Taiwan
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Abu-Amara M, Yang SY, Quaglia A, Rowley P, Tapuria N, Seifalian AM, Fuller BJ, Davidson BR. Effect of remote ischemic preconditioning on liver ischemia/reperfusion injury using a new mouse model. Liver Transpl 2011; 17:70-82. [PMID: 21254347 DOI: 10.1002/lt.22204] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ischemic preconditioning of remote organs (RIPC) reduces liver ischemia/reperfusion (IR) injury in the rabbit and rat. Mice are the only species available with a large number of transgenic strains. This study describes development and validation of a mouse model of hindlimb RIPC that attenuates liver IR injury. Mice were allocated to 4 groups: (1) Sham surgery; (2) RIPC: 6 cycles of 4 × 4 minutes ischemia/reperfusion of hindlimb; (3) IR: 40 minutes lobar (70%) hepatic ischemia and 2 hours reperfusion; (4) RIPC+IR: RIPC followed by IR group procedures. Plasma liver aminotransferases and hepatic histopathological and transmission electron microscopy studies were performed at the end of the experiment. Hepatic microcirculatory blood flow was measured throughout the experiment. Postoperative complications and animal survival were evaluated. Hindlimb RIPC using a tourniquet resulted in limb paralysis. Hindlimb RIPC using direct clamping of the femoral vessels showed no side effects. Compared to liver IR alone, RIPC+IR reduced plasma aminotransferases (P < 0.05) and histopathological and ultrastructural features of injury. Hepatic microcirculatory blood flow was preserved in the RIPC+IR compared to IR group (P < 0.05). There was no mortality in any of the groups. By demonstrating a consistent improvement in these features of liver IR injury with antecedent hindlimb RIPC and by minimizing experimental confounding variables, we validated this mouse model. In conclusion, we describe a validated mouse model of hindlimb RIPC that reduces liver IR injury. With the availability of transgenic mice strains, this model should prove useful in unraveling the mechanisms of protection of hindlimb RIPC.
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Affiliation(s)
- Mahmoud Abu-Amara
- Division of Surgery and Interventional Science, University College London, United Kingdom
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Yannopoulos FS, Mäkelä T, Niemelä E, Tuominen H, Lepola P, Alestalo K, Kaakinen H, Kiviluoma K, Anttila V, Juvonen T. Improved cerebral recovery from hypothermic circulatory arrest after remote ischemic preconditioning. Ann Thorac Surg 2010; 90:182-8. [PMID: 20609771 DOI: 10.1016/j.athoracsur.2010.03.058] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2010] [Revised: 03/11/2010] [Accepted: 03/16/2010] [Indexed: 01/07/2023]
Abstract
BACKGROUND Remote ischemic preconditioning is a novel method of reducing ischemia-reperfusion injury in which a transient ischemic period of the limb provides systemic protection against a prolonged ischemic insult. This method of preconditioning has shown some potential in ameliorating ischemia-related injury in various organs and experimental settings. We hypothesized that remote ischemic preconditioning might also improve the recovery from hypothermic circulatory arrest (HCA). METHODS Twenty-four juvenile pigs underwent 60 minutes of HCA at 18 degrees C with either transient right hind leg ischemic preconditioning or no ischemic preconditioning. Preconditioning was induced by four cycles of 5-minute ischemia periods with three 5-minute reperfusion periods in between. Microdialysis and electroencephalography (EEG) data were recorded to detect any possible changes during the recovery phase. RESULTS The EEG data showed that the remote ischemic preconditioning group had significantly better EEG recovery time and a lower burst suppression ratio throughout the follow-up period. Cerebral extracellular glucose and glycerol content rose significantly immediately after HCA in the control group compared with the remote ischemic preconditioning group, and significantly higher lactate concentrations were measured in the control group at 5 and 6 hours after reperfusion, indicating a difference in cerebral metabolism. CONCLUSIONS Our data imply that remote ischemic preconditioning improves the recovery from HCA. It provides a faster recovery of cortical neuronal activity and protection against potential oxygen radical-mediated ischemia damage during and after HCA. In addition, it seems to protect from a late phase lactate and pyruvate burst, mitigating possible damage from an anaerobic metabolism phase.
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