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Elsayed Abouzed DE, Ezelarab HAA, Selim HMRM, Elsayed MMA, El Hamd MA, Aboelez MO. Multimodal modulation of hepatic ischemia/reperfusion-induced injury by phytochemical agents: A mechanistic evaluation of hepatoprotective potential and safety profiles. Int Immunopharmacol 2024; 138:112445. [PMID: 38944946 DOI: 10.1016/j.intimp.2024.112445] [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] [Received: 03/30/2024] [Revised: 06/04/2024] [Accepted: 06/06/2024] [Indexed: 07/02/2024]
Abstract
BACKGROUND Hepatic ischemia-reperfusion (I/R) injury is a clinically fundamental phenomenon that occurs through liver resection surgery, trauma, shock, and transplantation. AIMS OF THE REVIEW This review article affords an expanded and comprehensive overview of various natural herbal ingredients that have demonstrated hepatoprotective effects against I/R injury through preclinical studies in animal models. MATERIALS AND METHODS For the objective of this investigation, an extensive examination was carried out utilizing diverse scientific databases involving PubMed, Google Scholar, Science Direct, Egyptian Knowledge Bank (EKB), and Research Gate. The investigation was conducted based on specific identifiable terms, such as hepatic ischemia/reperfusion injury, liver resection and transplantation, cytokines, inflammation, NF-kB, interleukins, herbs, plants, natural ingredients, phenolic extract, and aqueous extract. RESULTS Bioactive ingredients derived from ginseng, curcumin, resveratrol, epigallocatechin gallate, quercetin, lycopene, punicalagin, crocin, celastrol, andrographolide, silymarin, and others and their effects on hepatic IRI were discussed. The specific mechanisms of action, signaling pathways, and clinical relevance for attenuation of liver enzymes, cytokine production, immune cell infiltration, oxidative damage, and cell death signaling in rodent studies are analyzed in depth. Their complex molecular actions involve modulation of pathways like TLR4, NF-κB, Nrf2, Bcl-2 family proteins, and others. CONCLUSION The natural ingredients have promising values in the protection and treatment of various chronic aggressive clinical conditions, and that need to be evaluated on humans by clinical studies.
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Affiliation(s)
- Deiaa E Elsayed Abouzed
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt.
| | - Hend A A Ezelarab
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt.
| | - Heba Mohammed Refat M Selim
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, AlMaarefa University, Diriyah 13713, Riyadh, Saudi Arabia; Department of Microbiology and Immunology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 35527, Egypt.
| | - Mahmoud M A Elsayed
- Department of Pharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt.
| | - Mohamed A El Hamd
- Department of Pharmaceutical Chemistry, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia; Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, South Valley University, Qena 83523, Egypt.
| | - Moustafa O Aboelez
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt
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Xiong Y, Chen J, Liang W, Li K, Huang Y, Song J, Zhang B, Qiu X, Qiu D, Zhang Q, Qin Y. Blockade of the mitochondrial DNA release ameliorates hepatic ischemia-reperfusion injury through avoiding the activation of cGAS-Sting pathway. J Transl Med 2024; 22:796. [PMID: 39198913 PMCID: PMC11351313 DOI: 10.1186/s12967-024-05588-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 08/07/2024] [Indexed: 09/01/2024] Open
Abstract
BACKGROUND Liver surgery during the perioperative period often leads to a significant complication known as hepatic ischemia-reperfusion (I/R) injury. Hepatic I/R injury is linked to the innate immune response. The cGAS-STING pathway triggers the activation of innate immune through the detection of DNA within cells. Nevertheless, the precise mechanism and significance of the cGAS-STING pathway in hepatic I/R injury are yet to be investigated. METHODS Mouse model of hepatic I/R injury was used in the C57BL/6 WT mice and the STING knockout (STING-KO) mice. In addition, purified primary hepatocytes were used to construct oxygen-glucose deprivation reperfusion (OGD-Rep) treatment models. RESULTS Our research revealed a notable increase in mRNA and protein levels of cGAS and STING in liver during I/R injury. Interestingly, the lack of STING exhibited a safeguarding impact on hepatic I/R injury by suppressing the elevation of liver enzymes, liver cell death, and inflammation. Furthermore, pharmacological cGAS and STING inhibition recapitulated these phenomena. Macrophages play a crucial role in the activation of the cGAS-STING pathway during hepatic I/R injury. The cGAS-STING pathway experiences a significant decrease in activity and hepatic I/R injury is greatly diminished following the elimination of macrophages. Significantly, we demonstrate that the activation of the cGAS-STING pathway is primarily caused by the liberation of mitochondrial DNA (mtDNA) rather than nuclear DNA (nDNA). Moreover, the safeguarding of the liver against I/R injury is also attributed to the hindrance of mtDNA release through the utilization of inhibitors targeting mPTP and VDAC oligomerization. CONCLUSIONS The results of our study suggest that the release of mtDNA plays a significant role in causing damage to liver by activating the cGAS-STING pathway during I/R injury. Furthermore, inhibiting the release of mtDNA can provide effective protection against hepatic I/R injury.
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Affiliation(s)
- Yi Xiong
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China
| | - Jiawen Chen
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China
| | - Wei Liang
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China
| | - Kun Li
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China
| | - Yingqi Huang
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China
| | - Jingwen Song
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China
| | - Baoyu Zhang
- Neurosurgery Department, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China
| | - Xiusheng Qiu
- Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat- sen University, Guangzhou, 510630, Guangdong, PR China
| | - Dongbo Qiu
- Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat- sen University, Guangzhou, 510630, Guangdong, PR China.
| | - Qi Zhang
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China.
- Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat- sen University, Guangzhou, 510630, Guangdong, PR China.
| | - Yunfei Qin
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China.
- Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat- sen University, Guangzhou, 510630, Guangdong, PR China.
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3
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Deng RM, Zhou J. Targeting NF-κB in Hepatic Ischemia-Reperfusion Alleviation: from Signaling Networks to Therapeutic Targeting. Mol Neurobiol 2024; 61:3409-3426. [PMID: 37991700 DOI: 10.1007/s12035-023-03787-w] [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] [Received: 09/15/2023] [Accepted: 11/09/2023] [Indexed: 11/23/2023]
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is a major complication of liver trauma, resection, and transplantation that can lead to liver dysfunction and failure. Scholars have proposed a variety of liver protection methods aimed at reducing ischemia-reperfusion damage, but there is still a lack of effective treatment methods, which urgently needs to find new effective treatment methods for patients. Many studies have reported that signaling pathway plays a key role in HIRI pathological process and liver function recovery mechanism, among which nuclear transfer factor-κB (NF-κB) signaling pathway is one of the signal transduction closely related to disease. NF-κB pathway is closely related to HIRI pathologic process, and inhibition of this pathway can delay oxidative stress, inflammatory response, cell death, and mitochondrial dysfunction. In addition, NF-κB can also interact with PI3K/Akt, MAPK, and Nrf2 signaling pathways to participate in HIRI regulation. Based on the role of NF-κB pathway in HIRI, it may be a potential target pathway for HIRI. This review emphasizes the role of inhibiting the NF-κB signaling pathway in oxidative stress, inflammatory response, cell death, and mitochondrial dysfunction in HIRI, as well as the effects of related drugs or inhibitors targeting NF-κB on HIRI. The objective of this review is to elucidate the role and mechanism of NF-κB pathway in HIRI, emphasize the important role of NF-κB pathway in the prevention and treatment of HIRI, and provide a theoretical basis for the target NF-κB pathway as a therapy for HIRI.
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Affiliation(s)
- Rui-Ming Deng
- Department of Anesthesiology, Ganzhou People's Hospital, 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China
- The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China
| | - Juan Zhou
- The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China.
- Department of Thyroid and Breast Surgery, Ganzhou People's Hospital, 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China.
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Pan J, Ye F, Li H, Yu C, Mao J, Xiao Y, Chen H, Wu J, Li J, Fei L, Wu Y, Meng X, Guo G, Wang Y. Dissecting the immune discrepancies in mouse liver allograft tolerance and heart/kidney allograft rejection. Cell Prolif 2024; 57:e13555. [PMID: 37748771 PMCID: PMC10905343 DOI: 10.1111/cpr.13555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 08/23/2023] [Accepted: 09/15/2023] [Indexed: 09/27/2023] Open
Abstract
The liver is the most tolerogenic of transplanted organs. However, the mechanisms underlying liver transplant tolerance are not well understood. The comparison between liver transplantation tolerance and heart/kidney transplantation rejection will deepen our understanding of tolerance and rejection in solid organs. Here, we built a mouse model of liver, heart and kidney allograft and performed single-cell RNA sequencing of 66,393 cells to describe the cell composition and immune cell interactions at the early stage of tolerance or rejection. We also performed bulk RNA-seq of mouse liver allografts from Day 7 to Day 60 post-transplantation to map the dynamic transcriptional variation in spontaneous tolerance. The transcriptome of lymphocytes and myeloid cells were characterized and compared in three types of organ allografts. Cell-cell interaction networks reveal the coordinated function of Kupffer cells, macrophages and their associated metabolic processes, including insulin receptor signalling and oxidative phosphorylation in tolerance induction. Cd11b+ dendritic cells (DCs) in liver allografts were found to inhibit cytotoxic T cells by secreting anti-inflammatory cytokines such as Il10. In summary, we profiled single-cell transcriptome analysis of mouse solid organ allografts. We characterized the immune microenvironment of mouse organ allografts in the acute rejection state (heart, kidney) and tolerance state (liver).
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Affiliation(s)
- Jun Pan
- Department of Thyroid Surgery, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Fang Ye
- Liangzhu LaboratoryZhejiang UniversityHangzhouChina
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Hui Li
- Key Laboratory of Combined Multiorgan Transplantation, Ministry of Public Health, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Chengxuan Yu
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jiajia Mao
- Kidney Disease Center, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Yanyu Xiao
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Haide Chen
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Junqing Wu
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jiaqi Li
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Lijiang Fei
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yijun Wu
- Department of Thyroid Surgery, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Xiaoming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of PharmacyAnhui Medical University, The Key Laboratory of Anti‐inflammatory of Immune Medicines, Ministry of EducationHefeiChina
| | - Guoji Guo
- Liangzhu LaboratoryZhejiang UniversityHangzhouChina
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative MedicineDr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative MedicineHangzhouZhejiangChina
| | - Yingying Wang
- Kidney Disease Center, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
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5
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Wang Y, Piao C, Liu T, Lu X, Ma Y, Zhang J, Liu G, Wang H. Effects of the exosomes of adipose-derived mesenchymal stem cells on apoptosis and pyroptosis of injured liver in miniature pigs. Biomed Pharmacother 2023; 169:115873. [PMID: 37979374 DOI: 10.1016/j.biopha.2023.115873] [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] [Received: 07/25/2023] [Revised: 11/07/2023] [Accepted: 11/07/2023] [Indexed: 11/20/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is a complication of hepatectomy that affects the functional recovery of the remnant liver, which has been demonstrated to be associated with pyroptosis and apoptosis. Mesenchymal stem cells (MSCs) can protect against HIRI in rodents. Paracrine mechanisms of MSCs indicated that MSCs-derived exosomes (MSCs-exo) are one of the important components within the paracrine substances of MSCs. Moreover, miniature pigs are ideal experimental animals in comparative medicine compared to rodents. Accordingly, this study aimed to investigate whether hepatectomy combined with HIRI in miniature pigs would induce pyroptosis and whether adipose-derived MSCs (ADSCs) and their exosomes (ADSCs-exo) could positively mitigate apoptosis and pyroptosis. The study also compared the differences in the effects and the role of ADSCs and ADSCs-exo in pyroptosis and apoptosis. Results showed that severe ultrastructure damage occurred in liver tissues and systemic inflammatory response was induced after surgery, with TLR4/MyD88/NFκB/HMGB1 activation, NLRP3-ASC-Caspase1 complex generation, GSDMD revitalization, and IL-1β, IL-18, and LDH elevation in the serum. Furthermore, expression of Fas-Fasl-Caspase8 and CytC-APAF1-Caspase9 was increased in the liver. The ADSCs or ADSCs-exo intervention could inhibit the expression of these indicators and improve the ultrastructural pathological changes and systemic inflammatory response. There was no significant difference between the two intervention groups. In summary, ADSCs-exo could effectively inhibit pyroptosis and apoptosis similar to ADSCs and may be considered a safe and effective cell-free therapy to protect against liver injury.
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Affiliation(s)
- Yue Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Chenxi Piao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Tao Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Xiangyu Lu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Yajun Ma
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Jiantao Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Guodong Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Hongbin Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
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Chen G, Hu X, Huang Y, Xiang X, Pan S, Chen R, Xu X. Role of the immune system in liver transplantation and its implications for therapeutic interventions. MedComm (Beijing) 2023; 4:e444. [PMID: 38098611 PMCID: PMC10719430 DOI: 10.1002/mco2.444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 11/23/2023] [Accepted: 11/24/2023] [Indexed: 12/17/2023] Open
Abstract
Liver transplantation (LT) stands as the gold standard for treating end-stage liver disease and hepatocellular carcinoma, yet postoperative complications continue to impact survival rates. The liver's unique immune system, governed by a microenvironment of diverse immune cells, is disrupted during processes like ischemia-reperfusion injury posttransplantation, leading to immune imbalance, inflammation, and subsequent complications. In the posttransplantation period, immune cells within the liver collaboratively foster a tolerant environment, crucial for immune tolerance and liver regeneration. While clinical trials exploring cell therapy for LT complications exist, a comprehensive summary is lacking. This review provides an insight into the intricacies of the liver's immune microenvironment, with a specific focus on macrophages and T cells as primary immune players. Delving into the immunological dynamics at different stages of LT, we explore the disruptions after LT and subsequent immune responses. Focusing on immune cell targeting for treating liver transplant complications, we provide a comprehensive summary of ongoing clinical trials in this domain, especially cell therapies. Furthermore, we offer innovative treatment strategies that leverage the opportunities and prospects identified in the therapeutic landscape. This review seeks to advance our understanding of LT immunology and steer the development of precise therapies for postoperative complications.
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Affiliation(s)
- Guanrong Chen
- The Fourth School of Clinical MedicineZhejiang Chinese Medical UniversityHangzhouChina
| | - Xin Hu
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Yingchen Huang
- The Fourth School of Clinical MedicineZhejiang Chinese Medical UniversityHangzhouChina
| | - Xiaonan Xiang
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Sheng Pan
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Ronggao Chen
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiao Xu
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
- Zhejiang Chinese Medical UniversityHangzhouChina
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7
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Mouratidou C, Pavlidis ET, Katsanos G, Kotoulas SC, Mouloudi E, Tsoulfas G, Galanis IN, Pavlidis TE. Hepatic ischemia-reperfusion syndrome and its effect on the cardiovascular system: The role of treprostinil, a synthetic prostacyclin analog. World J Gastrointest Surg 2023; 15:1858-1870. [PMID: 37901735 PMCID: PMC10600776 DOI: 10.4240/wjgs.v15.i9.1858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/20/2023] [Accepted: 07/25/2023] [Indexed: 09/21/2023] Open
Abstract
Hepatic ischemia-reperfusion syndrome has been the subject of intensive study and experimentation in recent decades since it is responsible for the outcome of several clinical entities, such as major hepatic resections and liver transplantation. In addition to the organ's post reperfusion injury, this syndrome appears to play a central role in the dysfunction of distant tissues and systems. Thus, continuous research should be directed toward finding effective therapeutic options to improve the outcome and reduce the postoperative morbidity and mortality rates. Treprostinil is a synthetic analog of prostaglandin I2, and its experimental administration has shown encouraging results. It has already been approved by the Food and Drug Administration in the United States for pulmonary arterial hypertension and has been used in liver transplantation, where preliminary encouraging results showed its safety and feasibility by using continuous intravenous administration at a dose of 5 ng/kg/min. Treprostinil improves renal and hepatic function, diminishes hepatic oxidative stress and lipid peroxidation, reduces hepatictoll-like receptor 9 and inflammation, inhibits hepatic apoptosis and restores hepatic adenosine triphosphate (ATP) levels and ATP synthases, which is necessary for functional maintenance of mitochondria. Treprostinil exhibits vasodilatory properties and antiplatelet activity and regulates proinflammatory cytokines; therefore, it can potentially minimize ischemia-reperfusion injury. Additionally, it may have beneficial effects on cardiovascular parameters, and much current research interest is concentrated on this compound.
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Affiliation(s)
| | - Efstathios T Pavlidis
- 2nd Propedeutic Department of Surgery, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Georgios Katsanos
- Department of Transplantation, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | | | - Eleni Mouloudi
- Intensive Care Unit, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Georgios Tsoulfas
- Department of Transplantation, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Ioannis N Galanis
- 2nd Propedeutic Department of Surgery, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Theodoros E Pavlidis
- 2nd Propedeutic Department of Surgery, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
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8
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Inhibition of γδ-TcR or IL17a Reduces T-Cell and Neutrophil Infiltration after Ischemia/Reperfusion Injury in Mouse Liver. J Clin Med 2023; 12:jcm12051751. [PMID: 36902538 PMCID: PMC10002490 DOI: 10.3390/jcm12051751] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 02/08/2023] [Accepted: 02/12/2023] [Indexed: 02/24/2023] Open
Abstract
Neutrophil and T-cell recruitment contribute to hepatic ischemia/reperfusion injury. The initial inflammatory response is orchestrated by Kupffer cells and liver sinusoid endothelial cells. However, other cell types, including γδ-Τ cells, seem to be key mediators in further inflammatory cell recruitment and proinflammatory cytokine release, including IL17a. In this study, we used an in vivo model of partial hepatic ischemia/reperfusion injury (IRI) to investigate the role of the γδ-Τ-cell receptor (γδTcR) and the role of IL17a in the pathogenesis of liver injury. Forty C57BL6 mice were subjected to 60 min of ischemia followed by 6 h of reperfusion (RN 6339/2/2016). Pretreatment with either anti-γδΤcR antibodies or anti-IL17a antibodies resulted in a reduction in histological and biochemical markers of liver injury as well as neutrophil and T-cell infiltration, inflammatory cytokine production and the downregulation of c-Jun and NF-κΒ. Overall, neutralizing either γδTcR or IL17a seems to have a protective role in liver IRI.
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Pretzsch E, Nieß H, Khaled NB, Bösch F, Guba M, Werner J, Angele M, Chaudry IH. Molecular Mechanisms of Ischaemia-Reperfusion Injury and Regeneration in the Liver-Shock and Surgery-Associated Changes. Int J Mol Sci 2022; 23:12942. [PMID: 36361725 PMCID: PMC9657004 DOI: 10.3390/ijms232112942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/16/2022] [Accepted: 10/20/2022] [Indexed: 09/01/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (IRI) represents a major challenge during liver surgery, liver preservation for transplantation, and can cause hemorrhagic shock with severe hypoxemia and trauma. The reduction of blood supply with a concomitant deficit in oxygen delivery initiates various molecular mechanisms involving the innate and adaptive immune response, alterations in gene transcription, induction of cell death programs, and changes in metabolic state and vascular function. Hepatic IRI is a major cause of morbidity and mortality, and is associated with an increased risk for tumor growth and recurrence after oncologic surgery for primary and secondary hepatobiliary malignancies. Therapeutic strategies to prevent or treat hepatic IRI have been investigated in animal models but, for the most part, have failed to provide a protective effect in a clinical setting. This review focuses on the molecular mechanisms underlying hepatic IRI and regeneration, as well as its clinical implications. A better understanding of this complex and highly dynamic process may allow for the development of innovative therapeutic approaches and optimize patient outcomes.
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Affiliation(s)
- Elise Pretzsch
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Hanno Nieß
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Florian Bösch
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany
| | - Markus Guba
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Martin Angele
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Irshad H. Chaudry
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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10
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Funken D, Brüggemann A, Mende K, Lerchenberger M, Rentsch M, Khandoga A. Blocking of CX3CL1 attenuates platelet and leukocyte recruitment in murine hepatic I/R. Eur Surg Res 2022; 63:000524024. [PMID: 35279656 PMCID: PMC9808741 DOI: 10.1159/000524024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 01/26/2022] [Indexed: 01/07/2023]
Abstract
BACKGROUND The chemokine fractalkine (CX3CL1) is critically involved in the pathophysiology of different inflammatory diseases and myocardial ischemia-reperfusion (I/R). This study aims to analyze the role of fractalkine in the activation of platelets and leukocytes during hepatic I/R. METHODS Under inhalation anesthesia, C57BL6 mice were subjected to warm hepatic I/R (90min/240min). The animals were pretreated either with a function-blocking anti-mouse CX3CL1 antibody or IgG control administered systemically before ischemia. Sham-operated animals served as controls (n=7 each group). The inflammatory response and sinusoidal perfusion failure were evaluated by intravital microscopy. Hepatic transaminases plasma levels and histopathological tissue damage were determined as markers of hepatocellular injury. RESULTS Sinusoidal perfusion failure, leukocyte recruitment to the liver, and transaminase activities were sharply increased upon I/R compared to sham-operated mice. Firm adhesion of platelets and concordantly leukocytes to endothelial cells is reduced significantly by a function-blocking anti-fractalkine antibody. We demonstrate that inhibition of fractalkine signaling attenuates leukocyte adhesion in the postischemic liver but does not significantly ameliorate overall perfusion failure and hepatocellular injury. DISCUSSION/CONCLUSION Our in vivo data demonstrate a mild attenuating effect of CX3CL1 blockade on platelet and leukocyte, but not CD4+ T cell accumulation and activation in hepatic I/R injury. We report a significant effect of blocking chemokine fractalkine on sinusoidal perfusion failure without considerably improving overall hepatocellular injury during early reperfusion.
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Affiliation(s)
- Dominik Funken
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital of Munich, Ludwig-Maximilians-University of Munich, Munich, Germany,Walter-Brendel Centre for Experimental Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany,Department of Pediatric Pulmonology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany,*Dominik Funken,
| | - Alexandra Brüggemann
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital of Munich, Ludwig-Maximilians-University of Munich, Munich, Germany,Walter-Brendel Centre for Experimental Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Konstantin Mende
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital of Munich, Ludwig-Maximilians-University of Munich, Munich, Germany,Walter-Brendel Centre for Experimental Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Maximilian Lerchenberger
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital of Munich, Ludwig-Maximilians-University of Munich, Munich, Germany,Walter-Brendel Centre for Experimental Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Markus Rentsch
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital of Munich, Ludwig-Maximilians-University of Munich, Munich, Germany,Walter-Brendel Centre for Experimental Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Andrej Khandoga
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital of Munich, Ludwig-Maximilians-University of Munich, Munich, Germany,Walter-Brendel Centre for Experimental Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany,Department of General, Visceral and Vascular Surgery, Main-Kinzig-Clinics, Gelnhausen, Germany,**Andrej Khandoga,
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11
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Ntamo Y, Ziqubu K, Chellan N, Nkambule BB, Nyambuya TM, Mazibuko-Mbeje SE, Gabuza KB, Orlando P, Tiano L, Dludla PV. Clinical use of N-acetyl cysteine during liver transplantation: Implications of oxidative stress and inflammation as therapeutic targets. Biomed Pharmacother 2022; 147:112638. [DOI: 10.1016/j.biopha.2022.112638] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 01/05/2022] [Accepted: 01/12/2022] [Indexed: 02/09/2023] Open
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12
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Valade G, Libert N, Martinaud C, Vicaut E, Banzet S, Peltzer J. Therapeutic Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in the Prevention of Organ Injuries Induced by Traumatic Hemorrhagic Shock. Front Immunol 2021; 12:749659. [PMID: 34659252 PMCID: PMC8511792 DOI: 10.3389/fimmu.2021.749659] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/06/2021] [Indexed: 12/28/2022] Open
Abstract
Severe trauma is the principal cause of death among young people worldwide. Hemorrhagic shock is the leading cause of death after severe trauma. Traumatic hemorrhagic shock (THS) is a complex phenomenon associating an absolute hypovolemia secondary to a sudden and significant extravascular blood loss, tissue injury, and, eventually, hypoxemia. These phenomena are responsible of secondary injuries such as coagulopathy, endotheliopathy, microcirculation failure, inflammation, and immune activation. Collectively, these dysfunctions lead to secondary organ failures and multi-organ failure (MOF). The development of MOF after severe trauma is one of the leading causes of morbidity and mortality, where immunological dysfunction plays a central role. Damage-associated molecular patterns induce an early and exaggerated activation of innate immunity and a suppression of adaptive immunity. Severe complications are associated with a prolonged and dysregulated immune–inflammatory state. The current challenge in the management of THS patients is preventing organ injury, which currently has no etiological treatment available. Modulating the immune response is a potential therapeutic strategy for preventing the complications of THS. Mesenchymal stromal cells (MSCs) are multipotent cells found in a large number of adult tissues and used in clinical practice as therapeutic agents for immunomodulation and tissue repair. There is growing evidence that their efficiency is mainly attributed to the secretion of a wide range of bioactive molecules and extracellular vesicles (EVs). Indeed, different experimental studies revealed that MSC-derived EVs (MSC-EVs) could modulate local and systemic deleterious immune response. Therefore, these new cell-free therapeutic products, easily stored and available immediately, represent a tremendous opportunity in the emergency context of shock. In this review, the pathophysiological environment of THS and, in particular, the crosstalk between the immune system and organ function are described. The potential therapeutic benefits of MSCs or their EVs in treating THS are discussed based on the current knowledge. Understanding the key mechanisms of immune deregulation leading to organ damage is a crucial element in order to optimize the preparation of EVs and potentiate their therapeutic effect.
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Affiliation(s)
- Guillaume Valade
- Institut de Recherche Biomédicale des Armées (IRBA), Inserm UMRS-MD-1197, Clamart, France
| | - Nicolas Libert
- Service d'Anesthésie-Réanimation, Hôpital d'instruction des armées Percy, Clamart, France
| | - Christophe Martinaud
- Unité de Médicaments de Thérapie Innovante, Centre de Transfusion Sanguine des Armées, Clamart, France
| | - Eric Vicaut
- Laboratoire d'Etude de la Microcirculation, Université de Paris, UMRS 942 INSERM, Paris, France
| | - Sébastien Banzet
- Institut de Recherche Biomédicale des Armées (IRBA), Inserm UMRS-MD-1197, Clamart, France
| | - Juliette Peltzer
- Institut de Recherche Biomédicale des Armées (IRBA), Inserm UMRS-MD-1197, Clamart, France
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13
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How Machine Perfusion Ameliorates Hepatic Ischaemia Reperfusion Injury. Int J Mol Sci 2021; 22:ijms22147523. [PMID: 34299142 PMCID: PMC8307386 DOI: 10.3390/ijms22147523] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 07/07/2021] [Accepted: 07/11/2021] [Indexed: 02/07/2023] Open
Abstract
The increasing disparity between the number of patients listed for transplantation and the number of suitable organs has led to the increasing use of extended criteria donors (ECDs). ECDs are at increased risk of developing ischaemia reperfusion injury and greater risk of post-transplant complications. Ischaemia reperfusion injury is a major complication of organ transplantation defined as the inflammatory changes seen following the disruption and restoration of blood flow to an organ—it is a multifactorial process with the potential to cause both local and systemic organ failure. The utilisation of machine perfusion under normothermic (37 degrees Celsius) and hypothermic (4–10 degrees Celsius) has proven to be a significant advancement in organ preservation and restoration. One of the key benefits is its ability to optimise suboptimal organs for successful transplantation. This review is focused on examining ischaemia reperfusion injury and how machine perfusion ameliorates the graft’s response to this.
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14
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Dossi CG, Vargas RG, Valenzuela R, Videla LA. Beneficial effects of natural compounds on experimental liver ischemia-reperfusion injury. Food Funct 2021; 12:3787-3798. [PMID: 33977997 DOI: 10.1039/d1fo00289a] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Liver ischemia-reperfusion injury (IRI) is a phenomenon inherent to hepatic surgery that severely compromises the organ functionality, whose underlying mechanisms involve cellular and molecular interrelated processes leading to the development of an excessive inflammatory response. Liver resident cells and those recruited in response to injury generate pro-inflammatory signals such as reactive oxygen species, cytokines, chemokines, proteases and lipid mediators that contribute to hepatocellular necrosis and apoptosis. Besides, dying hepatocytes release damage-associated molecular patterns that actívate inflammasomes to further stimulate inflammatory responses leading to massive cell death. Since liver IRI is a complication of hepatic surgery in man, extensive preclinical studies have assessed potential protective strategies, including the supplementation with natural compounds, with the objective to downregulate nuclear factor-κB functioning, the main effector of inflammatory responses. This can be accomplished by either the activation of peroxisome proliferator-activated receptor-α, G protein-coupled receptor 120 or antioxidant signaling pathways, the synthesis of specific pro-resolving mediators, downregulation of Toll-like receptor 4 activity or additional contributory mechanisms that are beginning to be understood. The latter aspect is a crucial issue to be accomplished in preclinical studies, in order to establish adequate conditions for the supplementation with natural products before major liver surgeries in man involving warm IR, such as hepatic trauma or resection of large intrahepatic tumors.
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Affiliation(s)
- Camila G Dossi
- Escuela de Medicina Veterinaria, Facultad Ciencias de La Vida, Universidad Andres Bello, Viña del Mar, Chile.
| | - Romina G Vargas
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Rodrigo Valenzuela
- Department of Nutrition, Faculty of Medicine, Uiversity of Chile, Santiago, Chile and Nutritional Sciences Department, Faculty of Medicine, University of Toronto, Toronto, ON M2J4A6, Canada
| | - Luis A Videla
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
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15
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Ahmed O, Robinson MW, O'Farrelly C. Inflammatory processes in the liver: divergent roles in homeostasis and pathology. Cell Mol Immunol 2021; 18:1375-1386. [PMID: 33864004 PMCID: PMC8166849 DOI: 10.1038/s41423-021-00639-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 01/10/2021] [Indexed: 02/07/2023] Open
Abstract
The hepatic immune system is designed to tolerate diverse harmless foreign moieties to maintain homeostasis in the healthy liver. Constant priming and regulation ensure that appropriate immune activation occurs when challenged by pathogens and tissue damage. Failure to accurately discriminate, regulate, or effectively resolve inflammation offsets this balance, jeopardizing overall tissue health resulting from an either overly tolerant or an overactive inflammatory response. Compelling scientific and clinical evidence links dysregulated hepatic immune and inflammatory responses upon sterile injury to several pathological conditions in the liver, particularly nonalcoholic steatohepatitis and ischemia-reperfusion injury. Murine and human studies have described interactions between diverse immune repertoires and nonhematopoietic cell populations in both physiological and pathological activities in the liver, although the molecular mechanisms driving these associations are not clearly understood. Here, we review the dynamic roles of inflammatory mediators in responses to sterile injury in the context of homeostasis and disease, the clinical implications of dysregulated hepatic immune activity and therapeutic developments to regulate liver-specific immunity.
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Affiliation(s)
- Ola Ahmed
- School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Mark W Robinson
- Department of Biology, Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland
| | - Cliona O'Farrelly
- School of Medicine, Trinity College Dublin, Dublin, Ireland.
- School of Biochemistry & Immunology, Trinity College Dublin, Dublin 2, Ireland.
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16
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Ferreira-Silva M, Faria-Silva C, Baptista PV, Fernandes E, Fernandes AR, Corvo ML. Drug delivery nanosystems targeted to hepatic ischemia and reperfusion injury. Drug Deliv Transl Res 2021; 11:397-410. [PMID: 33660214 DOI: 10.1007/s13346-021-00915-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2021] [Indexed: 02/07/2023]
Abstract
Hepatic ischemia and reperfusion injury (IRI) is an acute inflammatory process that results from surgical interventions, such as liver resection surgery or transplantation, or hemorrhagic shock. This pathology has become a severe clinical issue, due to the increasing incidence of hepatic cancer and the high number of liver transplants. So far, an effective treatment has not been implemented in the clinic. Despite its importance, hepatic IRI has not attracted much interest as an inflammatory disease, and only a few reviews addressed it from a therapeutic perspective with drug delivery nanosystems. In the last decades, drug delivery nanosystems have proved to be a major asset in therapy because of their ability to optimize drug delivery, either by passive or active targeting. Passive targeting is achieved through the enhanced permeability and retention (EPR) effect, a main feature in inflammation that allows the accumulation of the nanocarriers in inflammation sites, enabling a higher efficacy of treatment than conventional therapies. These systems also can be actively targeted to specific compounds, such as inflammatory markers and overexpressed receptors in immune system intermediaries, allowing an even more specialized therapy that have already showed encouraging results. In this manuscript, we review drug delivery nanosystems designed for hepatic IRI treatment, addressing their current state in clinical trials, discussing the main hurdles that hinder their successful translation to the market and providing some suggestions that could potentially advance their clinical translation.
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Affiliation(s)
- Margarida Ferreira-Silva
- Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal
| | - Catarina Faria-Silva
- Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal
| | - Pedro Viana Baptista
- UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, 2829-516, Caparica, Portugal
| | - Eduarda Fernandes
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal
| | - Alexandra Ramos Fernandes
- UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, 2829-516, Caparica, Portugal
| | - Maria Luísa Corvo
- Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal.
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Abstract
Ample evidence suggests that hepatic macrophages play key roles in the injury and repair mechanisms during liver disease progression. There are two major populations of hepatic macrophages: the liver resident Kupffer cells and the monocyte-derived macrophages, which rapidly infiltrate the liver during injury. Under different disease conditions, the tissue microenvironmental cues of the liver critically influence the phenotypes and functions of hepatic macrophages. Furthermore, hepatic macrophages interact with multiple cells types in the liver, such as hepatocytes, neutrophils, endothelial cells, and platelets. These crosstalk interactions are of paramount importance in regulating the extents of liver injury, repair, and ultimately liver disease progression. In this review, we summarize the novel findings highlighting the impact of injury-induced microenvironmental signals that determine the phenotype and function of hepatic macrophages. Moreover, we discuss the role of hepatic macrophages in homeostasis and pathological conditions through crosstalk interactions with other cells of the liver.
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Affiliation(s)
- Zhao Shan
- Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, China
| | - Cynthia Ju
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
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18
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El-Sayed LA, Osama E, Mehesen MN, Rashed LA, Aboulkhair AG, Omar AI, Shams Eldeen AM. Contribution of angiotensin II in hepatic ischemia /reperfusion induced lung injury: Acute versus chronic usage of captopril. Pulm Pharmacol Ther 2020; 60:101888. [PMID: 31923459 DOI: 10.1016/j.pupt.2020.101888] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 01/04/2020] [Accepted: 01/04/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Acute lung injury is one of the most popular consequences of hepatic ischemia/reperfusion (I/R) injury. Recently it was documented that renin-angiotensin system plays a key role in tissue inflammation, generation of reactive oxygen species (ROS) and tumor necrosis factor-alpha (TNF-α) (the principal liver injury mediators) during I/R. MATERIAL AND METHODS We investigated the effect of acute versus chronic usage of angiotensin converting enzyme inhibitor (captopril) on liver inflammation and lung injury caused by hepatic ischemia for 1h followed by 24h reperfusion. Forty adult Wistar male rats were divided into sham, I/R, I/R-acute captopril (100 mg/kg, 24 and 1.5 h before surgery) and I/R-chronic captopril (10 mg/kg/day for 28 days before surgery) groups. RESULTS We found captopril pretreatment significantly decreased liver damage indices, adhesion molecules, and TNF-α level in hepatic and tracheal tissues. Histologically, acute captopril pretreatment significantly decreased hepatic Kupffer cells number and lung α-smooth muscle actin expression more than chronic pretreatment. Increased tracheal tone, in response to acetylcholine, was suppressed by acute and chronic captopril pretreatment. CONCLUSION Angiotensin II plays a key role in tissue inflammation and airway hyperresponsiveness (AHR) via enhancing production of TNF-α. With more protection observed in lung, acute captopril could attenuate liver-induced lung injury via lowering TNF-α; a suggested possible mediator of airway hyperreactivity.
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Affiliation(s)
| | - Eman Osama
- Department of Physiology, Faculty of Medicine, Cairo University, Egypt
| | - Marwa Nagi Mehesen
- Department of Pharmacology, Faculty of Medicine, Cairo University, Egypt
| | | | | | - Abeer Ibraheem Omar
- Department of Medical Histology, Faculty of Medicine, Cairo University, Egypt
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Sun H, McKeen T, Wang H, Ni HM. Necroptosis in ischemia-reperfusion injury of lean and steatotic livers. LIVER RESEARCH 2019. [DOI: 10.1016/j.livres.2019.09.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Protective Role of mTOR in Liver Ischemia/Reperfusion Injury: Involvement of Inflammation and Autophagy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:7861290. [PMID: 31827701 PMCID: PMC6885218 DOI: 10.1155/2019/7861290] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 08/24/2019] [Accepted: 10/14/2019] [Indexed: 02/06/2023]
Abstract
Liver ischemia/reperfusion (IR) injury is a common phenomenon after liver resection and transplantation, which often results in liver graft dysfunction such as delayed graft function and primary nonfunction. The mammalian target of rapamycin (mTOR) is an evolutionarily highly conserved serine/threonine protein kinase, which coordinates cell growth and metabolism through sensing environmental inputs under physiological or pathological conditions, involved in the pathophysiological process of IR injury. In this review, we mainly present current evidence of the beneficial role of mTOR in modulating inflammation and autophagy under liver IR to provide some evidence for the potential therapies for liver IR injury.
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21
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Zhao QH, Zhang XS, Wu K, Zhang J, Xia TF, Chen J, Qin ZS, Pang LQ. Preparation of Zoledronate liposome and its impact on apoptosis of Kupffer cells in rat liver. Acta Cir Bras 2019; 33:1052-1060. [PMID: 30624510 DOI: 10.1590/s0102-865020180120000002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 11/16/2018] [Indexed: 01/07/2023] Open
Abstract
PURPOSE To establish a method for the preparation of zoledronate liposome and to observe its effect on inducing the apoptosis of rat liver Kupffer cells. METHODS Zoledronate was encapsulated in liposomes, and then the entrapment rate was detected on a spectrophotometer. The prepared Zoledronate liposome (0.01 mg/mL) was injected into the tail vein of SD rats. Three days later, the number of Kupffer cells (CD68 positive) in rat liver tissue was detected by immunohistochemistry. Flow cytometry was used to detect the apoptosis rate of the isolated liver Kupffer cell cultured in vitro. RESULTS The entrapment rate of Zoledronate was 43.4±7.8%. Immunohistochemistry revealed that the number of Kupffer cells was 19.3±2.1 in PBS group and 5.5±1.7 in Zoledronate liposome group, with a significant difference (P<0.05). The apoptosis rate of Kupffer cells was 4.1±0.8% in PBS group, while it was 9±2.2% and 23.3±5.9% in Zoledronate liposomes groups with different concentrations of Zoledronate liposome (P<0.05). CONCLUSIONS Zoledronate liposomes can effectively induce the apoptosis of Kupffer cells in vivo and in vitro, and the apoptosis rate is related to the concentration of Zoledronate liposome. To establish a rat liver Kupffer cell apoptosis model can provide a new means for further study on Kupffer cell function.
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Affiliation(s)
- Qiao-Hong Zhao
- Bachelor of Medical Science, Department of Nursing, Jiangsu College of Nursing, Huai'an, China. Conception of the study, acquisition and interpretation of data
| | - Xi-Shan Zhang
- Bachelor of Medical Science, Department of General Surgery, Lian'shui County People's Hospital, Lian'shui, China. Analysis and interpretation of data
| | - Kun Wu
- Fellow Master degree, Postgraduate Program in Surgical Science, Department of General Surgery, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China. Immunohistochemical and flow cytometry analysis
| | - Jie Zhang
- Fellow Master degree, Postgraduate Program in Surgical Science, Department of General Surgery, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China. Immunohistochemical and flow cytometry analysis
| | - Tian-Fang Xia
- Fellow Master degree, Postgraduate Program in Surgical Science, Department of General Surgery, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China. Immunohistochemical and flow cytometry analysis
| | - Jian Chen
- Fellow Master degree, Postgraduate Program in Surgical Science, Department of General Surgery, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China. Immunohistochemical and flow cytometry analysis
| | - Zhen-Shen Qin
- PhD, Associate Professor, Department of General Surgery, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China. Conception and design of the study, critical revision
| | - Li-Qun Pang
- PhD, Associate Professor, Department of General Surgery, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China. Conception and design of the study, critical revision
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22
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Zhang ZB, Gao W, Liu L, Shi Y, Ma N, Huai MS, Shen ZY. Normothermic Machine Perfusion Protects Against Liver Ischemia-Reperfusion Injury During Reduced-Size Liver Transplantation in Pigs. Ann Transplant 2019; 24:9-17. [PMID: 30607000 PMCID: PMC6338011 DOI: 10.12659/aot.910774] [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] [Indexed: 12/12/2022] Open
Abstract
Background Normothermic machine perfusion (NMP) preservation is superior to cold preservation during reduced-size liver transplantation (RSLT) in pigs. However, the mechanism of this protective effect has not been explained. We aimed to compare the effects of NMP preservation with that of cold preservation (CS) in protecting against ischemia-reperfusion injury (IRI) during RSLT in pigs. Material/Methods Twenty-four healthy Bama miniature pigs were randomized into 2 groups: 1) the NMP group in which donor livers harvested without warm ischemia time and cardiac activity were connected to the NMP system to reduce liver size under normothermic conditions, and 2) the CS group in which donor livers harvested without warm ischemia time and cardiac activity were perfused using the University of Wisconsin (UW) solution and then preserved in the 0–4°C UW solution to reduce liver size under cold conditions. Livers were then transplanted without veno-venous bypass. Amounts of bile secretion for the NMP groups were recorded hourly. The serological indices were measured. Expressions of cytochrome C, caspase 3, and NF-κB p65 in liver tissue were observed. Results The levels of bile secretions were gradually diminished from 16.50±2.66 mL/h before splitting to 6.35±1.24 mL/h after splitting. With the exception of TNF-α on postoperative day 2, overall, levels of TNF-α, IL-1, IL-6, and MDA were significantly lower in the NMP group versus CS group for all 5 days postoperatively. Finally, cytochrome C, caspase 3, and NF-κB p65 expressions were all significantly suppressed in the NMP group as compared with the CS group. Conclusions MP preservation is superior to cold preservation in protecting against liver IRI during RSLT in pigs.
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Affiliation(s)
- Zhi-Bin Zhang
- Department of General Surgery, Tianjin First Central Hospital, Tianjin, China (mainland)
| | - Wei Gao
- Department of Transplantation Surgery, Tianjin First Central Hospital, Tianjin Clinical Research Center for Organ Transplantation, Tianjin, China (mainland)
| | - Lei Liu
- Department of Transplantation Surgery, Tianjin First Central Hospital, Key Laboratory of Organ Transplant of Tianjin, Tianjin, China (mainland)
| | - Yuan Shi
- Department of Transplantation Surgery, Tianjin First Central Hospital, Tianjin Clinical Research Center for Organ Transplantation, Tianjin, China (mainland)
| | - Ning Ma
- Department of Transplantation Surgery, Tianjin First Central Hospital, Tianjin Clinical Research Center for Organ Transplantation, Tianjin, China (mainland)
| | - Ming-Sheng Huai
- Department of Transplantation Surgery, Tianjin First Central Hospital, Tianjin Clinical Research Center for Organ Transplantation, Tianjin, China (mainland)
| | - Zhong-Yang Shen
- Department of Transplantation Surgery, Tianjin First Central Hospital, Tianjin Clinical Research Center for Organ Transplantation, Tianjin, China (mainland)
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Rampes S, Ma D. Hepatic ischemia-reperfusion injury in liver transplant setting: mechanisms and protective strategies. J Biomed Res 2019; 33:221-234. [PMID: 32383437 DOI: 10.7555/jbr.32.20180087] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatic ischemia-reperfusion injury is a major cause of liver transplant failure, and is of increasing significance due to increased use of expanded criteria livers for transplantation. This review summarizes the mechanisms and protective strategies for hepatic ischemia-reperfusion injury in the context of liver transplantation. Pharmacological therapies, the use of pre-and post-conditioning and machine perfusion are discussed as protective strategies. The use of machine perfusion offers significant potential in the reconditioning of liver grafts and the prevention of hepatic ischemia-reperfusion injury, and is an exciting and active area of research, which needs more study clinically.
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Affiliation(s)
- Sanketh Rampes
- Faculty of Life Sciences & Medicine, King's College London, London SE1 1U, UK
| | - Daqing Ma
- Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London SW10 9NH, UK
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The posttraumatic activation of CD4+ T regulatory cells is modulated by TNFR2- and TLR4-dependent pathways, but not by IL-10. Cell Immunol 2018; 331:137-145. [PMID: 29954581 DOI: 10.1016/j.cellimm.2018.06.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 06/10/2018] [Accepted: 06/18/2018] [Indexed: 12/21/2022]
Abstract
Platelets modulate the immune system following injury by interacting with CD4+ T regulatory cells (CD4+ Tregs). The underlying mechanisms remain unsolved. We hypothesize paracrine interactions via Tumor necrosis factor-alpha (TNFα)-, Toll like receptor-4 (TLR4)-, and Interleukin-10 (IL-10). In the murine burn injury model, CD4+ Treg activation pathways were selectively addressed using TNFR2-, TLR4- and IL-10-deficient mice. The CD4+ Treg signalling molecule PKC-θ was analyzed using phospho-flow cytometry to detect rapid cell activation. Thromboelastometry (ROTEM®) was used to assess platelet activation. Injury induced significant early activation of CD4+ Tregs, disruption of TNFR2 and TLR4 activation pathways resulted in lower activity. The disruption of IL-10 crosstalk had no significant impact. Selective disruption of paracrine interactions is associated with changes in posttraumatic hemostasis parameters. TNFR2- and TLR4-dependent pathways modulate the activation of CD4+ Tregs following trauma. In contrast, we did not observe a role of IL-10 in the posttraumatic activation of CD4+ Tregs. ONE SENTENCE SUMMARY TLR4- and TNFR2-dependent mechanisms, but not IL-10-dependent pathways, modulate the anti-inflammatory response of CD4+ Tregs following trauma.
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Abstract
Hepatic ischemia/reperfusion (I/R) injury is a major complication of liver surgery, including liver resection, liver transplantation, and trauma surgery. Much has been learned about the inflammatory injury response induced by I/R, including the cascade of proinflammatory mediators and recruitment of activated leukocytes. In this review, we discuss the complex network of events that culminate in liver injury after I/R, including cellular, protein, and molecular mechanisms. In addition, we address the known endogenous regulatory mediators that function to maintain homeostasis and resolve injury. Finally, we cover more recent insights into how the liver repairs and regenerates after I/R injury, a setting in which physical mass remains unchanged, but functional liver mass is greatly reduced. In this regard, we focus on recent work highlighting a novel role of CXC chemokines as important regulators of hepatocyte proliferation and liver regeneration after I/R injury.
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Affiliation(s)
- Takanori Konishi
- Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Alex B. Lentsch
- Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
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MicroRNA-155 Deficiency in Kupffer Cells Ameliorates Liver Ischemia-Reperfusion Injury in Mice. Transplantation 2017. [PMID: 28640790 DOI: 10.1097/tp.0000000000001765] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND MicroRNA-155 (miR-155) is known to be involved in autoimmune diseases, inflammation, and transplantation. However, its role in a warm hepatic ischemia-reperfusion (IR) model has not been fully elucidated. METHODS Partial hepatic IR was performed in wild-type and miR-155-deficient mice treated with or without GdCl3, and then the serum transaminase concentration and histology were analyzed. Kupffer cells (KCs) were isolated from the liver after IR, and immunohistochemistry was used to evaluate activation and polarization. In addition, the mRNA concentrations of various inflammatory cytokines were measured. Macrophages were obtained from the abdominal cavity and challenged with or without lipopolysaccharide to determine the influence of miR-155 deficiency on macrophage polarization in vitro. Furthermore, we used in vitro coculture assays to determine the effect of miR-155 deficiency on hepatocyte apoptosis induced directly by KCs. RESULTS miR-155 deficiency ameliorated liver IR injury, and inhibition of KCs by GdCl3 abolished this protective effect. miR-155 deficiency decreased CD80, CD86, and major histocompatibility complex class II expression in KCs after IR and tipped the M1/M2 balance toward an anti-inflammatory profile, where proinflammatory cytokine secretion was suppressed and IL-10 was enhanced. In addition, hepatocyte apoptosis was reduced in coculture with miR-155-deficient KCs in vitro. CONCLUSIONS miR-155 deficiency plays an effective role in attenuating liver IR injury likely by regulating the activation and inflammatory response, as well as modifying the polarization of KCs.
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Funken D, Ishikawa-Ankerhold H, Uhl B, Lerchenberger M, Rentsch M, Mayr D, Massberg S, Werner J, Khandoga A. In situ targeting of dendritic cells sets tolerogenic environment and ameliorates CD4 + T-cell response in the postischemic liver. FASEB J 2017; 31:4796-4808. [PMID: 28720647 DOI: 10.1096/fj.201601358r] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 07/05/2017] [Indexed: 12/27/2022]
Abstract
CD4+ T cells recruited to the liver play a key role in the pathogenesis of ischemia/reperfusion (I/R) injury. The mechanism of their activation during alloantigen-independent I/R is not completely understood. We hypothesized that liver-resident dendritic cells (DCs) interact with CD4+ T cells in the postischemic liver and that modulation of DCs or T-cell-DC interactions attenuates liver inflammation. In mice, warm hepatic I/R (90/120-240 min) was induced. Tolerogenic DCs were generated in situ by pretreatment of animals with the vitamin D analog paricalcitol. A mAb-CD44 was used for blockade of CD4+ T-cell-DC interactions. As shown by 2-photon in vivo microscopy as well as confocal microscopy, CD4+ T cells were closely colocalized with DCs in the postischemic liver. Pretreatment with paricalcitol attenuated I/R-induced maturation of DCs (flow cytometry), CD4+ T-cell recruitment into the liver (intravital microscopy), and hepatocellular/microvascular damage (intravital microscopy, alanine aminotransferase/aspartate aminotransferase, histology). However, interruption of T-cell-DC interaction increased proinflammatory DC maturation and even enhanced tissue damage. Simultaneous treatment with an anti-CD44mAb completely abolished the beneficial effect of paricalcitol on T-cell migration and tissue injury. Our study demonstrates for the first time that hepatic DCs interact with CD4+ T cells in the postischemic liver in vivo; modulation of DCs and/or generation of tolerogenic DCs attenuates intrahepatic CD4+ T-cell recruitment and reduces I/R injury; and interruption of CD44-dependent CD4+ T-cell-DC interactions enhances tissue injury by preventing the modulatory effect of hepatic DCs on T cells, especially type 1 T helper effector cells. Thus, hepatic DCs are strongly involved in the promotion of CD4+ T-cell-dependent postischemic liver inflammation.-Funken, D., Ishikawa-Ankerhold, H., Uhl, B., Lerchenberger, M., Rentsch, M., Mayr, D., Massberg, S., Werner, J., Khandoga, A. In situ targeting of dendritic cells sets tolerogenic environment and ameliorates CD4+ T-cell response in the postischemic liver.
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Affiliation(s)
- Dominik Funken
- Department of General, Visceral, and Transplant Surgery, University of Munich, Munich, Germany
| | - Hellen Ishikawa-Ankerhold
- Walter-Brendel Centre of Experimental Medicine, University of Munich, Munich, Germany.,Department of Cardiology, University of Munich, Munich, Germany
| | - Bernd Uhl
- Walter-Brendel Centre of Experimental Medicine, University of Munich, Munich, Germany
| | | | - Markus Rentsch
- Department of General, Visceral, and Transplant Surgery, University of Munich, Munich, Germany
| | - Doris Mayr
- Department of Pathology, University of Munich, Munich, Germany
| | | | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, University of Munich, Munich, Germany
| | - Andrej Khandoga
- Department of General, Visceral, and Transplant Surgery, University of Munich, Munich, Germany;
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Golden-Mason L, Rosen HR. Galectin-9: Diverse roles in hepatic immune homeostasis and inflammation. Hepatology 2017; 66:271-279. [PMID: 28195343 PMCID: PMC5521806 DOI: 10.1002/hep.29106] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 01/27/2017] [Accepted: 02/06/2017] [Indexed: 12/11/2022]
Abstract
Glycan-binding proteins, which include galectins, are involved at all stages of immunity and inflammation, from initiation through resolution. Galectin-9 (Gal-9) is highly expressed in the liver and has a wide variety of biological functions in innate and adaptive immunity that are instrumental in the maintenance of hepatic homeostasis. In the setting of viral hepatitis, increased expression of Gal-9 drives the expansion of regulatory T cells and contraction of effector T cells, thereby favoring viral persistence. The dichotomous nature of Gal-9 is evident in hepatocellular carcinoma, where loss of expression in hepatocytes promotes tumor growth and metastasis, whereas overexpression by Kupffer cells and endothelial cells inhibits the antitumor immune response. In nonalcoholic fatty liver disease, Gal-9 is involved indirectly in the expansion of protective natural killer T-cell populations. In ischemic liver injury, hepatocyte-derived Gal-9 is both diagnostic and cytoprotective. In drug-induced acute liver failure, plasma levels correlate with outcome. Here, we offer a synthesis of recent and emerging findings on Gal-9 in the regulation of hepatic inflammation. Ongoing studies are warranted to better elucidate the pathophysiology of hepatic immune-mediated diseases and to develop new therapeutic interventions using glycan-binding proteins. (Hepatology 2017;66:271-279).
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Affiliation(s)
- Lucy Golden-Mason
- Division of Gastroenterology & Hepatology, University of Colorado Denver Medical Center, Aurora, CO
| | - Hugo R Rosen
- Division of Gastroenterology & Hepatology, University of Colorado Denver Medical Center, Aurora, CO
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Sawada T, Inoue K, Tanabe D, Kawamoto S, Tsuji T, Tashiro S. Experimental Studies on Protective Effects of FK506 Against Hepatic Ischemia-Reperfusion Injury. THE JOURNAL OF MEDICAL INVESTIGATION 2017; 63:262-9. [PMID: 27644569 DOI: 10.2152/jmi.63.262] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Purposes; FK506 (strong immunosuppressive agent) was investigated experimentally whether to protect the hepatic IRI. Methods; Warm ischemic experiment using pigs and rats were performed and examined whether FK506 is effective. Results; The results obtained are as follows. 1. Warm ischemia allowed time of the pigs without FK506 was 150 minutes, but as for that of FK506 group, the extension of 30 minutes was got in 180 minutes. 2. Biliary excretion rate of BSP after reperfusion were better in the group of 180 minutes ischemia with FK506 than in without FK506 group. 3. Chemiluminescence intensity in the peripheral neutrophils and adhered and infiltrated leukocytes in the liver were suppressed markedly by FK506. 4. The vascular endothelium with the scanning electron microscope was relatively preserved in the FK506 group comparing to the placebo group on 30 minutes after reperfusion. 5. Stress gastric ulcer was controlled and myeloperoxidase activity in the gastric mucosa was suppressed by FK506. Conclusion; Based on the results of theses experiments, it was suggested that FK506 has a protective effect on IRI by suppressing: the impairment of sinusoidal endothelial cells; the activation of KCs; the disturbance of micro-circulation; oxidative stress; inflammation; and the accumulation of leukocytes. J. Med. Invest. 63: 262-269, August, 2016.
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Bystrom P, Foley N, Toledo-Pereyra L, Quesnelle K. Ischemic preconditioning modulates ROS to confer protection in liver ischemia and reperfusion. EXCLI JOURNAL 2017; 16:483-496. [PMID: 28694752 PMCID: PMC5491905 DOI: 10.17179/excli2017-166] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 03/20/2017] [Indexed: 12/24/2022]
Abstract
Ischemia reperfusion (IR) injury is a significant cause of morbidity and mortality in liver transplantation. When oxygen is reintroduced to the liver graft it initiates a cascade of molecular reactions leading to the release of reactive oxygen species (ROS) and pro-inflammatory cytokines. These soluble mediators propagate a sterile immune response to cause significant tissue damage. Ischemic preconditioning (IPC) is one method that reduces hepatocellular injury by altering the immune response and inhibiting the production of ROS. Studies quantifying the effects of IPC in humans have demonstrated an improved liver enzyme panel in patients receiving grafts pretreated with IPC as compared to patients receiving the standard of care. In our review, we explore current literature in the field in order to describe the mechanism through which IPC regulates the production of ROS and improves IR injury.
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Affiliation(s)
- Phillip Bystrom
- Western Michigan University, Homer Stryker M.D. School of Medicine Department of Biomedical Sciences
| | - Nicole Foley
- Western Michigan University, Homer Stryker M.D. School of Medicine Department of Biomedical Sciences
| | - Luis Toledo-Pereyra
- Western Michigan University, Homer Stryker M.D. School of Medicine Department of Surgery
| | - Kelly Quesnelle
- Western Michigan University, Homer Stryker M.D. School of Medicine Department of Biomedical Sciences
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31
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Brown DL. Immunopathology of the Hepatobiliary System. MOLECULAR AND INTEGRATIVE TOXICOLOGY 2017:329-417. [DOI: 10.1007/978-3-319-47385-7_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Liraglutide attenuates partial warm ischemia-reperfusion injury in rat livers. Naunyn Schmiedebergs Arch Pharmacol 2016; 390:311-319. [DOI: 10.1007/s00210-016-1330-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Accepted: 12/07/2016] [Indexed: 12/27/2022]
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Abstract
Ischemic disorders, such as myocardial infarction, stroke, and peripheral vascular disease, are the most common causes of debilitating disease and death in westernized cultures. The extent of tissue injury relates directly to the extent of blood flow reduction and to the length of the ischemic period, which influence the levels to which cellular ATP and intracellular pH are reduced. By impairing ATPase-dependent ion transport, ischemia causes intracellular and mitochondrial calcium levels to increase (calcium overload). Cell volume regulatory mechanisms are also disrupted by the lack of ATP, which can induce lysis of organelle and plasma membranes. Reperfusion, although required to salvage oxygen-starved tissues, produces paradoxical tissue responses that fuel the production of reactive oxygen species (oxygen paradox), sequestration of proinflammatory immunocytes in ischemic tissues, endoplasmic reticulum stress, and development of postischemic capillary no-reflow, which amplify tissue injury. These pathologic events culminate in opening of mitochondrial permeability transition pores as a common end-effector of ischemia/reperfusion (I/R)-induced cell lysis and death. Emerging concepts include the influence of the intestinal microbiome, fetal programming, epigenetic changes, and microparticles in the pathogenesis of I/R. The overall goal of this review is to describe these and other mechanisms that contribute to I/R injury. Because so many different deleterious events participate in I/R, it is clear that therapeutic approaches will be effective only when multiple pathologic processes are targeted. In addition, the translational significance of I/R research will be enhanced by much wider use of animal models that incorporate the complicating effects of risk factors for cardiovascular disease. © 2017 American Physiological Society. Compr Physiol 7:113-170, 2017.
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Affiliation(s)
- Theodore Kalogeris
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Christopher P. Baines
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
- Department of Biomedical Sciences, University of Missouri College of Veterinary Medicine, Columbia, Missouri, USA
| | - Maike Krenz
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
| | - Ronald J. Korthuis
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
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Esteban-Zubero E, García-Gil FA, López-Pingarrón L, Alatorre-Jiménez MA, Ramírez JM, Tan DX, García JJ, Reiter RJ. Melatonin role preventing steatohepatitis and improving liver transplantation results. Cell Mol Life Sci 2016; 73:2911-2927. [PMID: 27022943 PMCID: PMC11108472 DOI: 10.1007/s00018-016-2185-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 03/18/2016] [Indexed: 12/18/2022]
Abstract
Liver steatosis is a prevalent process that is induced due to alcoholic or non-alcoholic intake. During the course of these diseases, the generation of reactive oxygen species, followed by molecular damage to lipids, protein and DMA occurs generating organ cell death. Transplantation is the last-resort treatment for the end stage of both acute and chronic hepatic diseases, but its success depends on ability to control ischemia-reperfusion injury, preservation fluids used, and graft quality. Melatonin is a powerful endogenous antioxidant produced by the pineal gland and a variety of other because of its efficacy in organs; melatonin has been investigated to improve the outcome of organ transplantation by reducing ischemia-reperfusion injury and due to its synergic effect with organ preservation fluids. Moreover, this indolamine also prevent liver steatosis. That is important because this disease may evolve leading to an organ transplantation. This review summarizes the observations related to melatonin beneficial actions in organ transplantation and ischemic-reperfusion models.
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Affiliation(s)
- Eduardo Esteban-Zubero
- Department of Pharmacology and Physiology, University of Zaragoza, Calle Domingo Miral s/n, 50009, Saragossa, Spain.
| | - Francisco Agustín García-Gil
- Department of Surgery, Gynaecology and Obstetrics, University of Zaragoza, Calle Domingo Miral s/n, 50009, Saragossa, Spain
| | - Laura López-Pingarrón
- Department of Medicine, Psychiatry and Dermatology, University of Zaragoza, Calle Domingo Miral s/n, 50009, Saragossa, Spain
| | - Moisés Alejandro Alatorre-Jiménez
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA
| | - José Manuel Ramírez
- Department of Surgery, Gynaecology and Obstetrics, University of Zaragoza, Calle Domingo Miral s/n, 50009, Saragossa, Spain
| | - Dun-Xian Tan
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA
| | - José Joaquín García
- Department of Pharmacology and Physiology, University of Zaragoza, Calle Domingo Miral s/n, 50009, Saragossa, Spain
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA.
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Fahrner R, Dondorf F, Ardelt M, Settmacher U, Rauchfuss F. Role of NK, NKT cells and macrophages in liver transplantation. World J Gastroenterol 2016; 22:6135-6144. [PMID: 27468206 PMCID: PMC4945975 DOI: 10.3748/wjg.v22.i27.6135] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/25/2016] [Accepted: 06/15/2016] [Indexed: 02/07/2023] Open
Abstract
Liver transplantation has become the treatment of choice for acute or chronic liver disease. Because the liver acts as an innate immunity-dominant organ, there are immunological differences between the liver and other organs. The specific features of hepatic natural killer (NK), NKT and Kupffer cells and their role in the mechanism of liver transplant rejection, tolerance and hepatic ischemia-reperfusion injury are discussed in this review.
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Pratschke S, Arnold H, Zollner A, Heise M, Pascher A, Schemmer P, Scherer MN, Bauer A, Jauch KW, Werner J, Guba M, Angele MK. Results of the TOP Study: Prospectively Randomized Multicenter Trial of an Ex Vivo Tacrolimus Rinse Before Transplantation in EDC Livers. Transplant Direct 2016; 2:e76. [PMID: 27500266 PMCID: PMC4946517 DOI: 10.1097/txd.0000000000000588] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 03/30/2016] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Organ shortage results in the transplantation of extended donor criteria (EDC) livers which is associated with increased ischemia-reperfusion injury (IRI). Experimental studies indicate that an organ rinse with the calcineurin inhibitor tacrolimus before implantation protects against IRI. The tacrolimus organ perfusion study was initiated to examine the effects of ex vivo tacrolimus perfusion on IRI in transplantation of EDC livers. METHODS A prospective randomized multicenter trial comparing ex vivo perfusion of marginal liver grafts (≥2 EDC according to Eurotransplant manual) with tacrolimus (20 ng/mL) or histidine-tryptophane-ketoglutarate solution (control) was carried out at 5 German liver transplant centers (Munich Ludwig-Maximilians University, Berlin, Heidelberg, Mainz, Regensburg) between October 2011 and July 2013. Primary endpoint was the maximum alanine transaminase (ALT) level within 48 hours after transplantation. Secondary endpoints were aspartate transaminase (AST), prothrombine ratio, and graft-patient survival within an observation period of 1 week. After an interim analysis, the study was terminated by the scientific committee after the treatment of 24 patients (tacrolimus n = 11, Control n = 13). RESULTS Tacrolimus rinse did not reduce postoperative ALT peaks compared with control (P = 0.207; tacrolimus: median, 812; range, 362-3403 vs control: median, 652; range, 147-2034). Moreover, ALT (P = 0.100), prothrombine ratio (P = 0.553), and bilirubin (P = 0.815) did not differ between the groups. AST was higher in patients treated with tacrolimus (P = 0.011). Survival was comparable in both groups (P > 0.05). CONCLUSIONS Contrary to experimental findings, tacrolimus rinse failed to improve the primary endpoint of the study (ALT). Because 1 secondary endpoint (AST) was even higher in the intervention group, the study was terminated prematurely. Thus, tacrolimus rinse cannot be recommended in transplantation of EDC livers.
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Affiliation(s)
- Sebastian Pratschke
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the Ludwig-Maximilians-University, Munich, Germany
| | - Hannah Arnold
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the Ludwig-Maximilians-University, Munich, Germany
| | - Alfred Zollner
- Münchner Studienzentrum, University Hospital Rechts der Isar, Technical University of Munich, Munich, Germany
| | - Michael Heise
- Department of General, Visceral and Transplantation Surgery, University Medical Center, Johannes Gutenberg University, Mainz, Germany
| | - Andreas Pascher
- Department of General, Visceral and Transplantation Surgery, Charité Campus Virchow-Klinikum, Berlin, Germany
| | - Peter Schemmer
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Ruprecht-Karls-University, Heidelberg, Germany
| | - Marcus N Scherer
- Department of Surgery, University Hospital Regensburg, University of Regensburg, Regensburg, Germany
| | - Andreas Bauer
- Department of Anaesthesiology, Hospital of the Ludwig-Maximilians-University, Munich, Germany
| | - Karl-Walter Jauch
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the Ludwig-Maximilians-University, Munich, Germany
| | - Jens Werner
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the Ludwig-Maximilians-University, Munich, Germany
| | - Markus Guba
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the Ludwig-Maximilians-University, Munich, Germany
| | - Martin K Angele
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the Ludwig-Maximilians-University, Munich, Germany
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Model for end-stage liver disease score in the first 3 weeks after liver transplantation as a predictor for long-term outcome. Eur J Gastroenterol Hepatol 2016; 28:153-8. [PMID: 26545081 DOI: 10.1097/meg.0000000000000505] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Early allograft dysfunction after liver transplantation (LTX) is not well defined. The aim of this study was to evaluate the value of early post-transplant model for end-stage liver disease (MELD) scores for predicting long-term outcome after transplantation. METHODS In this single-center retrospective study, 362 consecutive patients after LTX were included. MELD scores at 7, 14, and 21 postoperative days (PODs) were calculated from primary lab values. Receiver operating characteristic (ROC) analyses were carried out to determine the critical cutoff MELD scores for patient and graft survival. RESULTS One year after transplantation, the patient and graft survival rates were 85 and 69%, respectively. Although pretransplant MELD scores were similar, they were significantly different at POD7, POD14, and POD21 between patients who died and those who survived the first year after transplantation. As shown by ROC curves, for patient survival, the optimal time point is POD14 with a cutoff MELD of 17. At this time point, patients with a MELD below 17 showed a 1-year survival rate of 94.3% and patients with a MELD of 17 and higher showed a 1-year survival rate of only 75.4%. For graft survival, the optimal time point was day 7 and a cutoff MELD of 29 (92% at MELD<29; 56.4% at MELD≥29). A multivariate analysis of potential risk factors indicated a significant role of serum bilirubin and MELD score determined on POD14 for patient survival. CONCLUSION In conclusion, early postoperative MELD scores predict outcome after LTX. The postoperative MELD score at POD14 is a good predictor for patient survival and at POD7 for the graft survival after LTX.
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Mesenchymal Stromal Cell-Derived Factors Promote Tissue Repair in a Small-for-Size Ischemic Liver Model but Do Not Protect against Early Effects of Ischemia and Reperfusion Injury. J Immunol Res 2015; 2015:202975. [PMID: 26380314 PMCID: PMC4561317 DOI: 10.1155/2015/202975] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 05/27/2015] [Indexed: 12/21/2022] Open
Abstract
Loss of liver mass and ischemia/reperfusion injury (IRI) are major contributors to postresectional liver failure and small-for-size syndrome. Mesenchymal stromal cell- (MSC-) secreted factors are described to stimulate regeneration after partial hepatectomy. This study investigates if liver-derived MSC-secreted factors also promote liver regeneration after resection in the presence of IRI.
C57BL/6 mice underwent IRI of 70% of their liver mass, alone or combined with 50% partial hepatectomy (PH). Mice were treated with MSC-conditioned medium (MSC-CM) or unconditioned medium (UM) and sacrificed after 6 or 24 hours (IRI group) or after 48 hours (IRI + PH group). Blood and liver tissue were analyzed for tissue injury, hepatocyte proliferation, and gene expression. In the IRI alone model, serum ALT and AST levels, hepatic tissue damage, and inflammatory cytokine gene expression showed no significant differences between both treatment groups. In the IRI + PH model, significant reduction in hepatic tissue damage as well as a significant increase in hepatocyte proliferation was observed after MSC-CM treatment. Conclusion. Mesenchymal stromal cell-derived factors promote tissue regeneration of small-for-size livers exposed to ischemic conditions but do not protect against early ischemia and reperfusion injury itself. MSC-derived factors therefore represent a promising treatment strategy for small-for-size syndrome and postresectional liver failure.
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Zhang J, Zhang M, Zhang J, Xia Q. A Novel Mouse Model of Liver Ischemic/Reperfusion Injury and its Differences to the Existing Model. J INVEST SURG 2015. [PMID: 26204139 DOI: 10.3109/08941939.2014.983621] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Ischemia of the cephalad lobes (70% of liver mass) is a frequently employed mouse hepatic ischemia/reperfusion (I/R) model that does not involve outflow occlusion. This model produces results with relatively large variances. MATERIALS AND METHODS A novel model of ischemia of the left lateral lobe (35% of liver mass) that involves temporarily occluding the blood supply to the cephalad lobes to expel blood followed by occlusion of both the inflow and outflow of the left lateral lobe, was developed. Mice in the 35% (novel) and 70% (existing) model groups were subjected to I/R injury, and biochemical and histological analyses of blood and liver samples were performed. Tissue oxygen partial pressure (tPO2) measurements in the ischemic lobes were also performed to determine whether the hepatic tissue was in a stable hypoxic state. Statistical analyses of the biochemical results, histological scores, and tPO2 levels were performed from which coefficients of variation (CV) were calculated. RESULTS The CVs of the aminotransferase activities, histological scores, and tPO2 levels were much lower in the 35% group than those in the 70% group. The tPO2 measurements demonstrated that inflow occlusion in the 70% model did not result in a stable hypoxic state, even after the portal triads were ligated and severed, indicating that there was blood reflux from the vena cava, which would be responsible for the variations in results with the 70% I/R model. CONCLUSIONS The new 35% I/R model leads to reproducible results because both inflow and outflow of the ischemic lobe are occluded.
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Affiliation(s)
- Jianjian Zhang
- a Department of Transplantation and Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University , Shanghai , China
| | - Ming Zhang
- a Department of Transplantation and Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University , Shanghai , China
| | - Jianjun Zhang
- a Department of Transplantation and Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University , Shanghai , China
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Hirao H, Uchida Y, Kadono K, Tanaka H, Niki T, Yamauchi A, Hata K, Watanabe T, Terajima H, Uemoto S. The protective function of galectin-9 in liver ischemia and reperfusion injury in mice. Liver Transpl 2015; 21:969-81. [PMID: 25931247 PMCID: PMC4744675 DOI: 10.1002/lt.24159] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Revised: 03/31/2015] [Accepted: 04/07/2015] [Indexed: 12/31/2022]
Abstract
Galectin-9 (Gal-9) has gained attention as a multifaceted player in adaptive and innate immunity. To elucidate the role of Gal-9, we used a mouse model of partial liver ischemia/reperfusion injury (IRI) with wild type (WT) and Gal-9 knockout (KO) mice as well as a recombinant galectin-9 (reGal-9) protein. We found that the expression of Gal-9 was enhanced endogenously in the liver especially by hepatocytes and Kupffer cells during warm IRI for a mouse liver, which causes massive destruction of liver tissue. Gal-9 was released into the extracellular space in the liver and the highest levels in the plasma at 1 hour after reperfusion. The present study elucidates a novel role of Gal-9 signaling in mouse liver IRI, by using Gal-9-deficient mice and a stable form of reGal-9 protein. In the circumstance of Gal-9 absence, liver damage due to ischemia/reperfusion (IR) exacerbated the severity as compared with WT. On the other hand, exogenously administered reGal-9 significantly ameliorated hepatocellular damage. It decreased the local infiltration of the inflammatory cells such as T cells, neutrophils, and macrophages, and it reduced the expression of proinflammatory cytokines/chemokines; then, it strongly suppressed the apoptosis of the liver cells. Interestingly, severe liver damage due to IR in Gal-9 KO mice was improved by the administration of reGal-9. In conclusion, Gal-9 engagement ameliorated local inflammation and liver damage induced by IR, and the present study suggests a significant role of Gal-9 in the maintenance of hepatic homeostasis. In conclusion, targeting Gal-9 represents a novel approach to protect from inflammation such as liver IRI. Exogenous Gal-9 treatment will be a new therapeutic strategy against innate immunity-dominated liver tissue damage.
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Affiliation(s)
- Hirofumi Hirao
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Departments of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan
| | - Yoichiro Uchida
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Departments of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan
| | - Kentaro Kadono
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Departments of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan
| | - Hirokazu Tanaka
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshiro Niki
- Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, Kagawa, Japan.,GalPharma Co., Ltd., Kagawa, Japan
| | | | - Koichiro Hata
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takeshi Watanabe
- Department of Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan
| | - Hiroaki Terajima
- Departments of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan
| | - Shinji Uemoto
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Modulating CD4+ T cell migration in the postischemic liver: hepatic stellate cells as new therapeutic target? Transplantation 2015; 99:41-7. [PMID: 25360872 DOI: 10.1097/tp.0000000000000461] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND CD4+ T cells play a critical role during hepatic ischemia-reperfusion (I/R) injury although the mechanisms of their migration in the postischemic liver remain unclear. We answered the questions of whether hepatic stellate cells (HSCs) interact with CD4+ T cells during I/R of the liver and whether modulation of HSC activity affects T cell-dependent I/R injury. METHODS In mice, migration of CD4+ T cells was analyzed in vivo using conventional intravital microscopy and two-photon microscopy. CD4+ T cell-HSC interactions were visualized after infusion of fluorescence-labeled CD4+ T cells into Cx3CR1 mice (mice exhibiting GFP-labeled HSCs) after I/R. Because the activation of HSC is controlled by endocannabinoid receptors, CB-1 and CB-2, the mice received treatment before I/R with the CB-2 agonist JWH-133 to reach HSC depletion or the CB-1 agonist arachidonylcyclopropylamide to activate HSCs. Sinusoidal perfusion and liver transaminases were used as markers of I/R injury. RESULTS Hepatic I/R induced CD4+ T cell recruitment in sinusoids. More than 25% of adherent CD4+ T cells were colocalized with HSCs during reperfusion, suggesting a direct cell-cell interaction. The HSC deactivation with JWH-133 significantly attenuated the CD4+ T cell recruitment in the postischemic liver and reduced I/R injury as compared to the vehicle-treated group. The HSC hyperactivation by CB-1, however, did not affect T-cell migration and even increased perfusion failure. CONCLUSION Our in vivo data suggest that CD4+ T cells interact with HSCs on their migration into the hepatic parenchyma, and a depletion or deactivation of HSCs protects the liver from T cell-dependent I/R injury.
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Molecular responses to ischemia and reperfusion in the liver. Arch Toxicol 2015; 89:651-7. [PMID: 25566829 DOI: 10.1007/s00204-014-1437-x] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 12/09/2014] [Indexed: 01/03/2023]
Abstract
Ischemia/reperfusion (IR) injury occurs when oxygen is rapidly reintroduced into ischemic tissue, resulting in cell death and necrotic tissue damage. This is a major concern during liver transplantation procedures since there is an inevitable interruption and subsequent restoration of circulation. IR injury in liver tissue is initiated through reactive oxygen species (ROS), which are generated by hepatocytes during IR insult. Although these ROS are thought to play a protective roll since they are known to activate several pathways involved in the hypoxic response, they also trigger a localized sterile immune response that results in the recruitment of Kupffer cells and neutrophils to the site of IR insult. These immune cells generate larger quantities of ROS that trigger apoptosis and oncotic necrosis in liver tissue. In this review, we will summarize what is currently known about the response of liver tissue to IR insult at the molecular level.
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Khandoga A, Mende K, Iskandarov E, Rosentreter D, Schelcher C, Reifart J, Jauch KW, Thasler WE. Augmenter of liver regeneration attenuates inflammatory response in the postischemic mouse liver in vivo. J Surg Res 2014; 192:187-94. [DOI: 10.1016/j.jss.2014.05.026] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2014] [Revised: 05/02/2014] [Accepted: 05/13/2014] [Indexed: 12/12/2022]
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Targeting platelet migration in the postischemic liver by blocking protease-activated receptor 4. Transplantation 2014; 97:154-60. [PMID: 24434483 DOI: 10.1097/01.tp.0000437430.89485.a0] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Platelets play a critical role during hepatic ischemia/reperfusion (I/R). Antiplatelet strategies during liver transplantation are, however, limited because of bleeding complications. Thrombin is activated during reperfusion and regulates platelet and endothelial cell function via protease-activated receptor 4 (PAR-4). Interventions at the level of PAR-4, the main platelet receptor for thrombin, are assumed to attenuate the proinflammatory effects of thrombin without affecting blood coagulation. The aim of our study was to analyze the impact of PAR-4 blockade on platelet recruitment and microvascular injury during hepatic I/R. METHODS C57BL/6 mice undergoing hepatic I/R (90 min/60 min and 240 min) were treated either with a selective PAR-4 antagonist TcY-NH2 or vehicle. Sham-operated animals served as controls. Recruitment of freshly isolated and fluorescence-labeled platelets and CD4 T cells was analyzed using intravital video fluorescence microscopy. Parameters of tissue injury, regeneration, and blood coagulation were assessed in tissue/blood samples. RESULTS Results show that treatment with TcY-NH2 attenuated I/R-induced platelet and CD4 T-cell recruitment, improved sinusoidal perfusion failure, and reduced apoptotic and necrotic injury. The protective effect of PAR-4 blockade did not suppress hemostasis or liver regeneration. CONCLUSION Our in vivo data suggest PAR-4 as a potential target for future therapeutic strategies against platelet-mediated liver injury on transplantation.
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Bacigalupo ML, Manzi M, Rabinovich GA, Troncoso MF. Hierarchical and selective roles of galectins in hepatocarcinogenesis, liver fibrosis and inflammation of hepatocellular carcinoma. World J Gastroenterol 2013; 19:8831-8849. [PMID: 24379606 PMCID: PMC3870534 DOI: 10.3748/wjg.v19.i47.8831] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Revised: 11/02/2013] [Accepted: 11/18/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) represents a global health problem. Infections with hepatitis B or C virus, non-alcoholic steatohepatitis disease, alcohol abuse, or dietary exposure to aflatoxin are the major risk factors to the development of this tumor. Regardless of the carcinogenic insult, HCC usually develops in a context of cirrhosis due to chronic inflammation and advanced fibrosis. Galectins are a family of evolutionarily-conserved proteins defined by at least one carbohydrate recognition domain with affinity for β-galactosides and conserved sequence motifs. Here, we summarize the current literature implicating galectins in the pathogenesis of HCC. Expression of "proto-type" galectin-1, "chimera-type" galectin-3 and "tandem repeat-type" galectin-4 is up-regulated in HCC cells compared to their normal counterparts. On the other hand, the "tandem-repeat-type" lectins galectin-8 and galectin-9 are down-regulated in tumor hepatocytes. The abnormal expression of these galectins correlates with tumor growth, HCC cell migration and invasion, tumor aggressiveness, metastasis, postoperative recurrence and poor prognosis. Moreover, these galectins have important roles in other pathological conditions of the liver, where chronic inflammation and/or fibrosis take place. Galectin-based therapies have been proposed to attenuate liver pathologies. Further functional studies are required to delineate the precise molecular mechanisms through which galectins contribute to HCC.
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Abstract
Because of its unique function and anatomical location, the liver is exposed to a multitude of toxins and xenobiotics, including medications and alcohol, as well as to infection by hepatotropic viruses, and therefore, is highly susceptible to tissue injury. Cell death in the liver occurs mainly by apoptosis or necrosis, with apoptosis also being the physiologic route to eliminate damaged or infected cells and to maintain tissue homeostasis. Liver cells, especially hepatocytes and cholangiocytes, are particularly susceptible to death receptor-mediated apoptosis, given the ubiquitous expression of the death receptors in the organ. In a quite unique way, death receptor-induced apoptosis in these cells is mediated by both mitochondrial and lysosomal permeabilization. Signaling between the endoplasmic reticulum and the mitochondria promotes hepatocyte apoptosis in response to excessive free fatty acid generation during the metabolic syndrome. These cell death pathways are partially regulated by microRNAs. Necrosis in the liver is generally associated with acute injury (i.e., ischemia/reperfusion injury) and has been long considered an unregulated process. Recently, a new form of "programmed" necrosis (named necroptosis) has been described: the role of necroptosis in the liver has yet to be explored. However, the minimal expression of a key player in this process in the liver suggests this form of cell death may be uncommon in liver diseases. Because apoptosis is a key feature of so many diseases of the liver, therapeutic modulation of liver cell death holds promise. An updated overview of these concepts is given in this article.
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Affiliation(s)
- Maria Eugenia Guicciardi
- 1Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
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Pan S, Liu L, Pan H, Ma Y, Wang D, Kang K, Wang J, Sun B, Sun X, Jiang H. Protective effects of hydroxytyrosol on liver ischemia/reperfusion injury in mice. Mol Nutr Food Res 2013; 57:1218-1227. [PMID: 23650136 DOI: 10.1002/mnfr.201300010] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2013] [Revised: 02/11/2013] [Accepted: 02/15/2013] [Indexed: 01/18/2023]
Abstract
SCOPE Hydroxytyrosol (HT), a main phenolic compound in olive oil, has been proved to be a potent antioxidant and has beneficial effects on health. However, the effect of HT on oxidative liver damage, as seen in ischemia/reperfusion (I/R) injury, is unknown. Here, we examined whether HT could protect liver against I/R injury. METHODS AND RESULTS By using a mouse model, we found that HT administration protects against hepatic I/R injury, as indicated by the decreased levels of serum aminotransferase and less parenchymal necrosis and apoptosis. Serum levels of tumor necrosis factor-α, interleukin-6, macrophage inflammatory protein 2, as well as reactive oxygen species (ROS) content in liver tissues, were all decreased by HT, the latter correlated with the reduction of hepatic malondialdehyde (an index of oxidative stress) content and increased activities and expressions of liver antioxidant enzymes superoxide dismutase and catalase. The protective effect was also seen in isolated hepatocytes anoxia/reoxygenation assay. CONCLUSION HT exerts protective effects against hepatic I/R injury in mice, which might be associated with its anti-oxidative, anti-inflammatory, and anti-apoptotic properties. HT may be an effective hepatoprotective agent and a promising candidate for the treatment of liver I/R injury.
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Affiliation(s)
- Shangha Pan
- Key Laboratory of Hepatosplenic Surgery, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, PR China
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Datta G, Fuller BJ, Davidson BR. Molecular mechanisms of liver ischemia reperfusion injury: Insights from transgenic knockout models. World J Gastroenterol 2013; 19:1683-98. [PMID: 23555157 PMCID: PMC3607745 DOI: 10.3748/wjg.v19.i11.1683] [Citation(s) in RCA: 149] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 06/29/2012] [Accepted: 07/09/2012] [Indexed: 02/06/2023] Open
Abstract
Ischemia reperfusion injury is a major obstacle in liver resection and liver transplantation surgery. Understanding the mechanisms of liver ischemia reperfusion injury (IRI) and developing strategies to counteract this injury will therefore reduce acute complications in hepatic resection and transplantation, as well as expanding the potential pool of usable donor grafts. The initial liver injury is initiated by reactive oxygen species which cause direct cellular injury and also activate a cascade of molecular mediators leading to microvascular changes, increased apoptosis and acute inflammatory changes with increased hepatocyte necrosis. Some adaptive pathways are activated during reperfusion that reduce the reperfusion injury. IRI involves a complex interplay between neutrophils, natural killer T-cells cells, CD4+ T cell subtypes, cytokines, nitric oxide synthases, haem oxygenase-1, survival kinases such as the signal transducer and activator of transcription, Phosphatidylinositol 3-kinases/Akt and nuclear factor κβ pathways. Transgenic animals, particularly genetic knockout models, have become a powerful tool at elucidating mechanisms of liver ischaemia reperfusion injury and are complementary to pharmacological studies. Targeted disruption of the protein at the genetic level is more specific and maintained than pharmacological inhibitors or stimulants of the same protein. This article reviews the evidence from knockout models of liver IRI about the cellular and molecular mechanisms underlying liver IRI.
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Ogawa K, Kondo T, Tamura T, Matsumura H, Fukunaga K, Oda T, Ohkohchi N. Influence of Kupffer cells and platelets on ischemia-reperfusion injury in mild steatotic liver. World J Gastroenterol 2013; 19:1396-1404. [PMID: 23539073 PMCID: PMC3602499 DOI: 10.3748/wjg.v19.i9.1396] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Accepted: 01/19/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of mild steatotic liver on ischemia-reperfusion injury by focusing on Kupffer cells (KCs) and platelets.
METHODS: Wistar rats were divided into a normal liver group (N group) and a mild steatotic liver group (S group) induced by feeding a choline-deficient diet for 2 wk. Both groups were subjected to 20 min of warm ischemia followed by 120 min of reperfusion. The number of labeled KCs and platelets in sinusoids and the blood perfusion in sinusoids were observed by intravital microscopy (IVM), which was performed at 30, 60 and 120 min after reperfusion. To evaluate serum alanine aminotransferase as a marker of liver deterioration, blood samples were taken at the same time as IVM.
RESULTS: In the S group, the number of platelets adhering to KCs decreased significantly compared with the N group (120 after reperfusion; 2.9 ± 1.1 cells/acinus vs 4.8 ± 1.2 cells/acinus, P < 0.01). The number of KCs in sinusoids was significantly less in the S group than in the N group throughout the observation periods (before ischemia, 19.6 ± 3.3 cells/acinus vs 28.2 ± 4.1 cells/acinus, P < 0.01 and 120 min after reperfusion, 29.0 ± 4.3 cells/acinus vs 40.2 ± 3.3 cells/acinus, P < 0.01). The blood perfusion of sinusoids 120 min after reperfusion was maintained in the S group more than in the N group. Furthermore, elevation of serum alanine aminotransferase was lower in the S group than in the N group 120 min after reperfusion (99.7 ± 19.8 IU/L vs 166.3 ± 61.1 IU/L, P = 0.041), and histological impairment of hepatocyte structure was prevented in the S group.
CONCLUSION: Ischemia-reperfusion injury in mild steatotic liver was attenuated compared with normal liver due to the decreased number of KCs and the reduction of the KC-platelet interaction.
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Pratschke S, Eder M, Heise M, Nadalin S, Pascher A, Schemmer P, Scherer MN, Ulrich F, Wolters H, Jauch KW, Wöhling D, Angele MK. Protocol TOP-Study (tacrolimus organ perfusion): a prospective randomized multicenter trial to reduce ischemia reperfusion injury in transplantation of marginal liver grafts with an ex vivo tacrolimus perfusion. Transplant Res 2013; 2:3. [PMID: 23497558 PMCID: PMC3626672 DOI: 10.1186/2047-1440-2-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Accepted: 02/13/2013] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Critical organ shortage results in the utilization of extended donor criteria (EDC) liver grafts. These marginal liver grafts are prone to increased ischemia reperfusion injury (IRI) which may contribute to deteriorated graft function and survival. Experimental data have shown that the calcineurin inhibitor tacrolimus exerts protective effects on hepatic IRI when applied intravenously or directly as a hepatic rinse. Therefore, the aim of the present study is to examine the effects of an ex vivo tacrolimus perfusion on IRI in transplantation of EDC liver grafts. METHODS/DESIGN The TOP-Study (tacrolimus organ perfusion) is a randomized multicenter trial comparing the ex vivo tacrolimus perfusion of marginal liver grafts with placebo. We hypothesize that a tacrolimus rinse reduces IRI, potentially improving organ survival following transplantation of EDC livers. The study includes livers with two or more EDC, according to Eurotransplant International Foundation's definition of EDC livers. Prior to implantation, livers randomized to the treatment group are rinsed with tacrolimus at a concentration of 20 ng/ml in 1000 ml Custodiol solution and in the placebo group with Custodiol alone. The primary endpoint is the maximum serum alanine transamninase (ALT) level within the first 48 hours after surgery; however, the study design also includes a 1-year observation period following transplantation. The TOP-Study is an investigator-initiated trial sponsored by the University of Munich Hospital. Seven other German transplant centers are participating (Berlin, Frankfurt, Heidelberg, Mainz, Münster, Regensburg, Tübingen) and aim to include a total of 86 patients. DISCUSSION Tacrolimus organ perfusion represents a promising strategy to reduce hepatic IRI following the transplantation of marginal liver grafts. This treatment may help to improve the function of EDC grafts and therefore safely expand the donor pool in light of critical organ shortage. TRIAL REGISTER EudraCT number: 2010-021333-31, ClinicalTrials.gov identifier: NCT01564095.
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Affiliation(s)
- Sebastian Pratschke
- Department of Surgery, University of Munich Hospital, Campus Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 15, 81377 Munich, Germany
| | - Michael Eder
- Department of Surgery, University of Munich Hospital, Campus Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 15, 81377 Munich, Germany
| | - Michael Heise
- Department of Transplantation Surgery, University Medical Center, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Silvio Nadalin
- Department of General, Visceral and Transplantation Surgery, University Hospital Tübingen, Eberhard Karls University, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany
| | - Andreas Pascher
- Department of General, Visceral and Transplantation Surgery, Charité Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Peter Schemmer
- Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Marcus N Scherer
- Department of Surgery, University Hospital Regensburg, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | - Frank Ulrich
- Department of General and Visceral Surgery, Johann Wolfgang Goethe-University Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Heiner Wolters
- Department of General and Visceral Surgery, University Hospital Münster, Westphalian Wilhelms-University, Waldeyerstrasse 1, 48149 Münster, Germany
| | - Karl-Walter Jauch
- Department of Surgery, University of Munich Hospital, Campus Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 15, 81377 Munich, Germany
| | - Dirk Wöhling
- DABIO Gesellschaft für Auftragsforschung mbH, Altlaufstrasse 40, 85635 Höhenkirchen, Germany
| | - Martin K Angele
- Department of Surgery, University of Munich Hospital, Campus Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 15, 81377 Munich, Germany
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