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Diodati NG, Qu G, Mehrad B, Schaller MA. Cryopreservation of human lung tissue for 3D ex vivo analysis. Respir Res 2025; 26:187. [PMID: 40375251 DOI: 10.1186/s12931-025-03265-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Accepted: 04/29/2025] [Indexed: 05/18/2025] Open
Abstract
Ex vivo culture techniques have assisted researchers in narrowing the translational gap between the lab and the clinic by allowing the study of biology in human tissues. In pulmonary biology, however, the availability of such tissues is a limiting factor in experimental design and constrains the reproducibility and replicability of these models as scientifically rigorous complements to in vitro or in vivo methods. Cryopreservation of human lung tissue is a strategy to address these limitations by generating cryopreserved biobanks of donors in the ex vivo study of pulmonary biology. Modern cryopreservation solutions, incorporating blends of cryoprotective extracellular macromolecules and cell-permeant non-toxic small molecules, have enabled the long-term storage of human lung tissue, allowing repeated experiments in the same donors and the simultaneous study of the same hypothesis across multiple donors, therefore granting the qualities of reproducibility and replicability to ex vivo systems. Specific considerations are required to properly maintain fundamental aspects of tissue structure, properties, and function throughout the cryopreservation process. The examples of existing cryopreservation systems successfully employed to amass cryobanks, and ex vivo culture techniques compatible with cryopreservation, are discussed herein, with the goal of indicating the potential of cryopreservation in ex vivo human lung tissue culture and highlighting opportunities for cryopreservation to expand the utility of ex vivo human lung culture systems in the pursuit of clinically relevant discoveries.
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Affiliation(s)
- Nickolas G Diodati
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida College of Medicine, 1200 Newell Drive, Room MSB-M440, Gainesville, FL, 32610, USA.
| | - Ganlin Qu
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida College of Medicine, 1200 Newell Drive, Room MSB-M440, Gainesville, FL, 32610, USA
| | - Borna Mehrad
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida College of Medicine, 1200 Newell Drive, Room MSB-M440, Gainesville, FL, 32610, USA
| | - Matthew A Schaller
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida College of Medicine, 1200 Newell Drive, Room MSB-M440, Gainesville, FL, 32610, USA
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Chen Z, Chen J, Lin D, Kang H, Luo Y, Wang X, Wang L, Liu D. Forming Single-Cell-Derived Colon Cancer Organoid Arrays on a Microfluidic Chip for High Throughput Tumor Heterogeneity Analysis. ACS Biomater Sci Eng 2024; 10:5265-5273. [PMID: 39087916 DOI: 10.1021/acsbiomaterials.4c00727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/02/2024]
Abstract
Single-cell-derived tumor organoids (STOs) possess a distinct genetic background, making them valuable tools for demonstrating tumor heterogeneity. In order to fulfill the high throughput demands of STO assays, we have developed a microfluidic chip containing 30 000 microwells, which is dedicated to a single cell culture approach for selective expansion and differential induction of cancer stem cells. The microwells are coated with a hydrophilic copolymer to eliminate cell adhesion, and the cell culture is supported by poly(ethylene glycol) (PEG) to establish a nonadhesive culture environment. By utilizing an input cell density of 7 × 103·mL-1, it is possible to construct a 4000 single cell culture system through stochastic cell occupation. We demonstrate that the addition of 15% PEG10000 in the cell culture medium effectively prevents cell loss while facilitating tumor stem cell expansion. As were demonstrated by HCT116, HT29, and SW480 colon cancer cells, the microfluidic approach achieved a STO formation rate of ∼20%, resulting in over 800 STOs generated from a single culture. Comprehensive analysis through histomorphology, immunohistochemistry, drug response evaluation, assessment of cell invasion, and biomarker detection reveals the heterogeneity among individual STOs. Specifically, the smaller STOs exhibited higher invasion and drug resistance capabilities compared with the larger ones. The developed microfluidic approach effectively facilitates STO formation and offers promising prospects for investigating tumor heterogeneity, as well as conducting personalized therapy-focused drug screening.
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Affiliation(s)
- Zihe Chen
- Department of Laboratory Medicine, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China
| | - Jueming Chen
- Department of Laboratory Medicine, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China
| | - Dongguo Lin
- Department of Laboratory Medicine, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China
- Guangdong Engineering Technology Research Center of Microfluidic Chip Medical Diagnosis, Guangzhou 510180, China
| | - Hui Kang
- Department of Pathology, School of Medicine, Jinan University, Guangzhou 510632, China
| | - Yanzhang Luo
- Department of Laboratory Medicine, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China
| | - Xiaogang Wang
- Department of Laboratory Medicine, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China
| | - Lihui Wang
- Department of Pathology, School of Medicine, Jinan University, Guangzhou 510632, China
| | - Dayu Liu
- Department of Laboratory Medicine, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China
- Guangdong Engineering Technology Research Center of Microfluidic Chip Medical Diagnosis, Guangzhou 510180, China
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Kervella D, Branchereau J, Prudhomme T, Nerrière-Daguin V, Renaudin K, Minault D, Hervouet J, Martinet B, Bruneau S, Le Bas-Bernardet S, Blancho G. MHC Class I Masking to Prevent AMR in a Porcine Kidney Transplantation Model in Alloimmunized Recipients. Transplant Direct 2023; 9:e1490. [PMID: 37250484 PMCID: PMC10219698 DOI: 10.1097/txd.0000000000001490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 03/30/2023] [Indexed: 05/31/2023] Open
Abstract
Presensitized patients awaiting a kidney transplant have a lower graft survival and a longer waiting time because of the limited number of potential donors and the higher risk of antibody-mediated rejection (AMR), particularly in the early posttransplant period, because of preformed donor-specific antibodies binding major histocompatibility complex (MHC) molecules expressed by the graft endothelium followed by the activation of the complement. Advances in kidney preservation techniques allow the development of ex vivo treatment of transplants. We hypothesized that masking MHC ex vivo before transplantation could help to prevent early AMR in presensitized recipients. We evaluated a strategy of MHC I masking by an antibody during ex vivo organ perfusion in a porcine model of kidney transplantation in alloimmunized recipients. Methods Through the in vitro calcein-release assay and flow cytometry, we evaluated the protective effect of a monoclonal anti-swine leukocyte antigen class I antibody (clone JM1E3) against alloreactive IgG complement-dependent cytotoxicity toward donor endothelial cells. Kidneys perfused ex vivo with JM1E3 during hypothermic machine perfusion were transplanted to alloimmunized recipients. Results In vitro incubation of endothelial cells with JM1E3 decreased alloreactive IgG cytotoxicity (mean complement-dependent cytotoxicity index [% of control condition] with 1 µg/mL 74.13% ± 35.26 [calcein assay] and 66.88% ± 33.46 [cytometry]), with high interindividual variability. After transplantation, acute AMR occurred in all recipients on day 1, with signs of complement activation (C5b-9 staining) as soon as 1 h after transplantation, despite effective JM1E3 binding on graft endothelium. Conclusions Despite a partial protective effect of swine leukocyte antigen I masking with JM1E3 in vitro, ex vivo perfusion of the kidney with JM1E3 before transplantation was not sufficient alone at preventing or delaying AMR in highly sensitized recipients.
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Affiliation(s)
- Delphine Kervella
- Center for Research in Transplantation and Translational Immunology, INSERM, Nantes Université, Centre Hospitalier Universitaire Nantes, UMR 1064, Institut Transplantation Urologie Néphrologie, Nantes, France
- Service de Néphrologie et Immunologie clinique, Centre Hospitalier Universitaire Nantes, Nantes Université, Institut Transplantation Urologie Néphrologie, Nantes, France
| | - Julien Branchereau
- Center for Research in Transplantation and Translational Immunology, INSERM, Nantes Université, Centre Hospitalier Universitaire Nantes, UMR 1064, Institut Transplantation Urologie Néphrologie, Nantes, France
- Service d'Urologie, Centre Hospitalier Universitaire Nantes, Nantes Université, Institut Transplantation Urologie Néphrologie, Nantes, France
| | - Thomas Prudhomme
- Center for Research in Transplantation and Translational Immunology, INSERM, Nantes Université, Centre Hospitalier Universitaire Nantes, UMR 1064, Institut Transplantation Urologie Néphrologie, Nantes, France
| | - Véronique Nerrière-Daguin
- Center for Research in Transplantation and Translational Immunology, INSERM, Nantes Université, Centre Hospitalier Universitaire Nantes, UMR 1064, Institut Transplantation Urologie Néphrologie, Nantes, France
| | - Karine Renaudin
- Service d'anatomopathologie, Centre Hospitalier Universitaire Nantes, Nantes Université, Nantes, France
| | - David Minault
- Center for Research in Transplantation and Translational Immunology, INSERM, Nantes Université, Centre Hospitalier Universitaire Nantes, UMR 1064, Institut Transplantation Urologie Néphrologie, Nantes, France
| | - Jérémy Hervouet
- Center for Research in Transplantation and Translational Immunology, INSERM, Nantes Université, Centre Hospitalier Universitaire Nantes, UMR 1064, Institut Transplantation Urologie Néphrologie, Nantes, France
| | - Bernard Martinet
- Center for Research in Transplantation and Translational Immunology, INSERM, Nantes Université, Centre Hospitalier Universitaire Nantes, UMR 1064, Institut Transplantation Urologie Néphrologie, Nantes, France
| | - Sarah Bruneau
- Center for Research in Transplantation and Translational Immunology, INSERM, Nantes Université, Centre Hospitalier Universitaire Nantes, UMR 1064, Institut Transplantation Urologie Néphrologie, Nantes, France
| | - Stéphanie Le Bas-Bernardet
- Center for Research in Transplantation and Translational Immunology, INSERM, Nantes Université, Centre Hospitalier Universitaire Nantes, UMR 1064, Institut Transplantation Urologie Néphrologie, Nantes, France
| | - Gilles Blancho
- Center for Research in Transplantation and Translational Immunology, INSERM, Nantes Université, Centre Hospitalier Universitaire Nantes, UMR 1064, Institut Transplantation Urologie Néphrologie, Nantes, France
- Service de Néphrologie et Immunologie clinique, Centre Hospitalier Universitaire Nantes, Nantes Université, Institut Transplantation Urologie Néphrologie, Nantes, France
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Yuce-Erarslan E, Domb AAJ, Kasem H, Uversky VN, Coskuner-Weber O. Intrinsically Disordered Synthetic Polymers in Biomedical Applications. Polymers (Basel) 2023; 15:polym15102406. [PMID: 37242981 DOI: 10.3390/polym15102406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 04/29/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
In biology and medicine, intrinsically disordered synthetic polymers bio-mimicking intrinsically disordered proteins, which lack stable three-dimensional structures, possess high structural/conformational flexibility. They are prone to self-organization and can be extremely useful in various biomedical applications. Among such applications, intrinsically disordered synthetic polymers can have potential usage in drug delivery, organ transplantation, artificial organ design, and immune compatibility. The designing of new syntheses and characterization mechanisms is currently required to provide the lacking intrinsically disordered synthetic polymers for biomedical applications bio-mimicked using intrinsically disordered proteins. Here, we present our strategies for designing intrinsically disordered synthetic polymers for biomedical applications based on bio-mimicking intrinsically disordered proteins.
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Affiliation(s)
- Elif Yuce-Erarslan
- Chemical Engineering, Istanbul University-Cerrahpasa, Avcilar, Istanbul 34320, Turkey
| | - Abraham Avi J Domb
- School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel
| | - Haytam Kasem
- Azrieli College of Engineering, 26 Ya'akov Schreiboim Street, Jerusalem 9103501, Israel
| | - Vladimir N Uversky
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Orkid Coskuner-Weber
- Molecular Biotechnology, Turkish-German University, Sahinkaya Caddesi, No. 106, Beykoz, Istanbul 34820, Turkey
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Teodoro JS, Da Silva RT, Machado IF, Panisello-Roselló A, Roselló-Catafau J, Rolo AP, Palmeira CM. Shaping of Hepatic Ischemia/Reperfusion Events: The Crucial Role of Mitochondria. Cells 2022; 11:688. [PMID: 35203337 PMCID: PMC8870414 DOI: 10.3390/cells11040688] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/09/2022] [Accepted: 02/11/2022] [Indexed: 12/10/2022] Open
Abstract
Hepatic ischemia reperfusion injury (HIRI) is a major hurdle in many clinical scenarios, including liver resection and transplantation. Various studies and countless surgical events have led to the observation of a strong correlation between HIRI induced by liver transplantation and early allograft-dysfunction development. The detrimental impact of HIRI has driven the pursuit of new ways to alleviate its adverse effects. At the core of HIRI lies mitochondrial dysfunction. Various studies, from both animal models and in clinical settings, have clearly shown that mitochondrial function is severely hampered by HIRI and that its preservation or restoration is a key indicator of successful organ recovery. Several strategies have been thus implemented throughout the years, targeting mitochondrial function. This work briefly discusses some the most utilized approaches, ranging from surgical practices to pharmacological interventions and highlights how novel strategies can be investigated and implemented by intricately discussing the way mitochondrial function is affected by HIRI.
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Affiliation(s)
- João S. Teodoro
- MitoLab, Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal; (J.S.T.); (A.P.R.)
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
- IIIUC–Institute of Interdisciplinary Research, University of Coimbra, Pólo II da Universidade de Coimbra, 3000 Coimbra, Portugal
| | - Rui T. Da Silva
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, 08036 Barcelona, Spain; (A.P.-R.); (J.R.-C.)
| | - Ivo F. Machado
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
- IIIUC–Institute of Interdisciplinary Research, University of Coimbra, Pólo II da Universidade de Coimbra, 3000 Coimbra, Portugal
| | - Arnau Panisello-Roselló
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, 08036 Barcelona, Spain; (A.P.-R.); (J.R.-C.)
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, 08036 Barcelona, Spain; (A.P.-R.); (J.R.-C.)
| | - Anabela P. Rolo
- MitoLab, Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal; (J.S.T.); (A.P.R.)
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
| | - Carlos M. Palmeira
- MitoLab, Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal; (J.S.T.); (A.P.R.)
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
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Huang J, Guo J, Zhou L, Zheng G, Cao J, Li Z, Zhou Z, Lei Q, Brinker CJ, Zhu W. Advanced Nanomaterials-Assisted Cell Cryopreservation: A Mini Review. ACS APPLIED BIO MATERIALS 2021; 4:2996-3014. [PMID: 35014388 DOI: 10.1021/acsabm.1c00105] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cell cryopreservation is of vital significance both for transporting and storing cells before experimental/clinical use. Cryoprotectants (CPAs) are necessary additives in the preserving medium in cryopreservation, preventing cells from freeze-thaw injuries. Traditional organic solvents have been widely used in cell cryopreservation for decades. Given the obvious damage to cells due to their undesirable cytotoxicity and the burdensome post-thaw washing cycles before use, traditional CPAs are more and more likely to be replaced by modern ones with lower toxicity, less processing, and higher efficiency. As materials science thrives, nanomaterials are emerging to serve as potent vehicles for delivering nontoxic CPAs or inherent CPAs comparable to or even superior to conventional ones. This review will introduce some advanced nanomaterials (e.g., organic/inorganic nanoCPAs, nanodelivery systems) utilized for cell cryopreservation, providing broader insights into this developing field.
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Affiliation(s)
- Junda Huang
- MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, P. R. China
| | - Jimin Guo
- Center for Micro-Engineered Materials, Department of Chemical and Biological Engineering, The University of New Mexico, Albuquerque, New Mexico 87131, United States.,Department of Internal Medicine, Molecular Medicine, The University of New Mexico, Albuquerque, New Mexico 87131, United States
| | - Liang Zhou
- MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, P. R. China
| | - Guansheng Zheng
- MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, P. R. China
| | - Jiangfan Cao
- MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, P. R. China
| | - Zeyu Li
- MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, P. R. China
| | - Zhuang Zhou
- MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, P. R. China
| | - Qi Lei
- MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, P. R. China
| | - C Jeffrey Brinker
- Center for Micro-Engineered Materials, Department of Chemical and Biological Engineering, The University of New Mexico, Albuquerque, New Mexico 87131, United States
| | - Wei Zhu
- MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, P. R. China
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Improved Normothermic Machine Perfusion After Short Oxygenated Hypothermic Machine Perfusion of Ischemically Injured Porcine Kidneys. Transplant Direct 2021; 7:e653. [PMID: 33490378 PMCID: PMC7817286 DOI: 10.1097/txd.0000000000001108] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 10/17/2020] [Accepted: 10/21/2020] [Indexed: 12/15/2022] Open
Abstract
Supplemental Digital Content is available in the text. Background. In an era where global kidney shortage has pushed the field of transplantation towards using more marginal donors, modified kidney preservation techniques are currently being reviewed. Some techniques require further optimization before implementation in full scale transplantation studies. Using a porcine donation after circulatory death kidney model, we investigated whether initial kidney hemodynamics improved during normothermic machine perfusion if this was preceded by a short period of oxygenated hypothermic machine perfusion (oxHMP) rather than static cold storage (SCS). Methods. Kidneys subjected to 75 minutes of warm ischemia were randomly assigned to either SCS (n = 4) or SCS + oxHMP (n = 4), with a total cold storage time of 240 minutes. Cold preservation was followed by 120 minutes of normothermic machine perfusion with continuous measurement of hemodynamic parameters and renal function. Results. oxHMP preserved kidneys maintained significantly lower renal resistance throughout the normothermic machine perfusion period compared to SCS kidneys (P < 0.001), reaching lowest levels at 60 minutes with means of 0.71 ± 0.35 mm Hg/mL/min/100 g (SCS) and 0.45 ± 0.15 mm Hg/mL/min/100 g (oxHMP). Accordingly, the oxHMP group had a higher mean renal blood flow versus SCS kidneys (P < 0.001). oxHMP kidneys had higher oxygen consumption during normothermic machine perfusion compared to SCS preserved kidneys (P < 0.001). Creatinine clearance remained similar between groups (P = 0.665). Conclusions. Preceding oxHMP significantly improved initial normothermic machine perfusion hemodynamics and increased total oxygen consumption. With the long period of warm ischemia, immediate kidney function was not observed, reflected by the findings of low creatinine clearance in both groups.
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Legeai C, Durand L, Savoye E, Macher MA, Bastien O. Effect of preservation solutions for static cold storage on kidney transplantation outcomes: A National Registry Study. Am J Transplant 2020; 20:3426-3442. [PMID: 32400921 DOI: 10.1111/ajt.15995] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 03/25/2020] [Accepted: 04/22/2020] [Indexed: 01/25/2023]
Abstract
This study aimed to evaluate how 5 preservation solutions for static cold storage affected kidney transplant outcomes. It included all first single kidney transplants during 2010-2014 from donations after brain death in the French national transplant registry, excluding preemptive transplants and transplants of kidneys preserved with a hypothermic perfusion machine. The effects of each preservation solution on delayed graft function (DGF) and 1-year transplant failure were evaluated with hierarchical multivariable logistic regression models. The study finally included 7640 transplanted kidneys: 3473 (45.5%) preserved with Institut Georges Lopez-1 solution (IGL-1), 773 (10.1%) with University of Wisconsin solution, 731 (9.6%) with Solution de Conservation des Organes et Tissus (SCOT, organ and tissue preservation solution), 2215 (29.0%) with Celsior, and 448 (5.9%) with histidine-tryptophan-ketoglutarate. Primary nonfunction rates did not differ by solution. After adjustment for donor, recipient, and transplant characteristics, the DGF risk was significantly lower with IGL-1 than with all other solutions (odds ratio [OR] 0.55, 95% confidence interval [CI] 0.48-0.64). Conversely, SCOT was associated with a DGF risk significantly higher than the other solutions (OR 2.69, 95% CI 2.21-3.27) and triple that of IGL-1 (OR 3.37, 95% CI 2.72-4.16). One year after transplantation, the transplant failure rate did not differ significantly by preservation solution. The difference between the groups for 1-year mean creatinine clearance was not clinically relevant.
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Affiliation(s)
- Camille Legeai
- Organ and Tissue Procurement and Transplantation Department, Agence de la Biomédecine, Saint Denis La Plaine, France
| | - Louise Durand
- Organ and Tissue Procurement and Transplantation Department, Agence de la Biomédecine, Saint Denis La Plaine, France
| | - Emilie Savoye
- Organ and Tissue Procurement and Transplantation Department, Agence de la Biomédecine, Saint Denis La Plaine, France
| | - Marie-Alice Macher
- Organ and Tissue Procurement and Transplantation Department, Agence de la Biomédecine, Saint Denis La Plaine, France
| | - Olivier Bastien
- Organ and Tissue Procurement and Transplantation Department, Agence de la Biomédecine, Saint Denis La Plaine, France
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Panisello Rosello A, Teixeira da Silva R, Castro C, G. Bardallo R, Calvo M, Folch-Puy E, Carbonell T, Palmeira C, Roselló Catafau J, Adam R. Polyethylene Glycol 35 as a Perfusate Additive for Mitochondrial and Glycocalyx Protection in HOPE Liver Preservation. Int J Mol Sci 2020; 21:5703. [PMID: 32784882 PMCID: PMC7461048 DOI: 10.3390/ijms21165703] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/03/2020] [Accepted: 08/04/2020] [Indexed: 02/08/2023] Open
Abstract
Organ transplantation is a multifactorial process in which proper graft preservation is a mandatory step for the success of the transplantation. Hypothermic preservation of abdominal organs is mostly based on the use of several commercial solutions, including UW, Celsior, HTK and IGL-1. The presence of the oncotic agents HES (in UW) and PEG35 (in IGL-1) characterize both solution compositions, while HTK and Celsior do not contain any type of oncotic agent. Polyethylene glycols (PEGs) are non-immunogenic, non-toxic and water-soluble polymers, which present a combination of properties of particular interest in the clinical context of ischemia-reperfusion injury (IRI): they limit edema and nitric oxide induction and modulate immunogenicity. Besides static cold storage (SCS), there are other strategies to preserve the organ, such as the use of machine perfusion (MP) in dynamic preservation strategies, which increase graft function and survival as compared to the conventional static hypothermic preservation. Here we report some considerations about using PEG35 as a component of perfusates for MP strategies (such as hypothermic oxygenated perfusion, HOPE) and its benefits for liver graft preservation. Improved liver preservation is closely related to mitochondria integrity, making this organelle a good target to increase graft viability, especially in marginal organs (e.g., steatotic livers). The final goal is to increase the pool of suitable organs, and thereby shorten patient waiting lists, a crucial problem in liver transplantation.
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Affiliation(s)
- Arnau Panisello Rosello
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC)-IDIBAPS, CIBEREHD, 08036 Barcelona, Catalonia, Spain; (A.P.R.); (R.T.d.S.); (E.F.-P.)
- Centre Hépato-Biliaire, AP-PH, Hôpital Paul Brousse, 94800 Villejuif, France; (C.C.); (R.A.)
| | - Rui Teixeira da Silva
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC)-IDIBAPS, CIBEREHD, 08036 Barcelona, Catalonia, Spain; (A.P.R.); (R.T.d.S.); (E.F.-P.)
- Center for Neuroscience and Cell Biology, Universidade Coimbra, 3000-370 Coimbra, Portugal;
| | - Carlos Castro
- Centre Hépato-Biliaire, AP-PH, Hôpital Paul Brousse, 94800 Villejuif, France; (C.C.); (R.A.)
| | - Raquel G. Bardallo
- Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain; (R.G.B.); (T.C.)
| | - Maria Calvo
- Serveis Cientifico Tècnics, 08036-Campus Hospital Clínic, Universitat de Barcelona, 08919 Barcelona, Catalonia, Spain;
| | - Emma Folch-Puy
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC)-IDIBAPS, CIBEREHD, 08036 Barcelona, Catalonia, Spain; (A.P.R.); (R.T.d.S.); (E.F.-P.)
| | - Teresa Carbonell
- Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain; (R.G.B.); (T.C.)
| | - Carlos Palmeira
- Center for Neuroscience and Cell Biology, Universidade Coimbra, 3000-370 Coimbra, Portugal;
| | - Joan Roselló Catafau
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC)-IDIBAPS, CIBEREHD, 08036 Barcelona, Catalonia, Spain; (A.P.R.); (R.T.d.S.); (E.F.-P.)
| | - René Adam
- Centre Hépato-Biliaire, AP-PH, Hôpital Paul Brousse, 94800 Villejuif, France; (C.C.); (R.A.)
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10
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Effects of a New Type of Shrinkage-Reducing Agent on Concrete Properties. MATERIALS 2020; 13:ma13133018. [PMID: 32640670 PMCID: PMC7372398 DOI: 10.3390/ma13133018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/02/2020] [Accepted: 07/02/2020] [Indexed: 11/17/2022]
Abstract
Shrinkage-reducing agents have been developed to mitigate shrinkage and to control cracks in concrete. This study aims to evaluate the impact of a newly developed shrinkage-reducing agent (N-SRA) on concrete properties and to compare its properties with a conventional shrinkage-reducing agent (C-SRA). The hydration rate, compressive strength, splitting tensile strength, shrinkage, occurrence of cracking, and freezing and thawing were investigated. N-SRA showed higher surface tension than C-SRA and reduced shrinkage to the same degree as C-SRA with half the dosage of C-SRA. The addition of N-SRA or C-SRA did not influence the early compressive strength but slightly reduced splitting tensile strength at seven days. Concrete with N-SRA showed higher compressive strength at 28 days than those of concrete with C-SRA or without SRA. Furthermore, concrete with N-SRA extended the period for the occurrence of shrinkage cracking under restrained conditions. It was found that N-SRA provided excellent freezing and thawing resistance because of the formation of good air voids, while C-SRA demonstrated inefficient behaviour in such an environment.
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11
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Qi H, Ma B, Tan H, Li C, Zhi Z, Wang H, Liu X, Yang Q. Effect of sodium gluconate on molecular conformation of polycarboxylate superplasticizer studied by the molecular dynamics simulation. J Mol Model 2020; 26:45. [PMID: 32009188 DOI: 10.1007/s00894-020-4309-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 01/23/2020] [Indexed: 11/26/2022]
Abstract
Sodium gluconate (SG) has been accepted as one of the main additional components in polycarboxylate superplasticizer (PCE) system, due to its excellent retarding effect. While the negative effect on dispersion of PCE was reported in the literature, the reason was not completely revealed. In this study, molecular dynamics simulation was used to investigate the mutual influence between SG and PCE in calcium hydroxide (CH) solution. Radial distribution function (RDF) was used to analyze the effects of SG on the complexation of PCE with Ca2+. Radius of gyration (Rg) was adopted to characterize the conformations of the backbone and side chains of PCE in CH solution. Finally, several adsorption and dispersion models were proposed. The results showed that the presence of SG would perturb adsorption of PCE, which was one of the main reasons that affected the dispersion ability of PCE. SG could preferentially combine with Ca2+ so that less amount of Ca2+ is available for combination of PCE, and this could extend the main chain of PCE and show advantage for PCE adsorption. Besides, adding SG could squeeze the side chains of PCE, which would put a negative effect on the dispersion. These findings gave deeper insight into understanding the dispersion mechanism of PCE-SG system.
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Affiliation(s)
- Huahui Qi
- State Key Laboratory of Silicate Materials for Architectures, Wuhan University of Technology, Wuhan, 430070, Hubei, China
| | - Baoguo Ma
- State Key Laboratory of Silicate Materials for Architectures, Wuhan University of Technology, Wuhan, 430070, Hubei, China
| | - Hongbo Tan
- State Key Laboratory of Silicate Materials for Architectures, Wuhan University of Technology, Wuhan, 430070, Hubei, China.
| | - Chunbao Li
- State Key Laboratory of Silicate Materials for Architectures, Wuhan University of Technology, Wuhan, 430070, Hubei, China
| | - Zhenzhen Zhi
- School of materials science and engineering, Luoyang Institute of Science and Technology, Luoyang, 471023, Henan, China
| | - Hui Wang
- Faculty of Architectural, Civil Engineering and Environment, Ningbo University, Ningbo, 315000, China
| | - Xiaohai Liu
- State Key Laboratory of Silicate Materials for Architectures, Wuhan University of Technology, Wuhan, 430070, Hubei, China
| | - Qi Yang
- State Key Laboratory of Silicate Materials for Architectures, Wuhan University of Technology, Wuhan, 430070, Hubei, China
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12
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Acute resuscitation with polyethylene glycol-20k: A thromboelastographic analysis. J Trauma Acute Care Surg 2020; 87:322-330. [PMID: 31033892 DOI: 10.1097/ta.0000000000002332] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Previous ex vivo studies have shown that polyethylene glycol-20,000 Da (PEG-20k), a novel synthetic polymer that is highly effective for resuscitation, has a hypocoagulable effect on human blood. This study's objective was to determine the in vivo effects of PEG-20k-based resuscitation solutions on coagulation and platelet function in a porcine model of hemorrhagic shock. METHODS Anesthetized pigs underwent controlled hemorrhage until the lactate reached 7 mmol/L or 50% to 55% of their estimated blood volume was removed. A laparotomy was performed to simulate tissue injury. Low volume resuscitation (LVR) was given with fluorescein isothiocyanate-labeled 10% PEG-20k solution (100 mg/mL) or Lactated Ringers, both delivered at volumes equal to 10% of the estimated blood volume (n = 5). Thromboelastography was performed after surgery (baseline), after hemorrhage, and 15 minutes, 120 minutes, and 240 minutes postresuscitation. Hemoglobin was measured to determine changes in plasma volume. Plasma PEG-20k concentration was measured by indicator dilution. RESULTS Pigs given PEG-20k survived 2.6-fold longer than controls (p < 0.001) and had a significant increase in plasma volume demonstrated by the sustained drop in hemoglobin, relative to controls. Pigs resuscitated with LR died from hypotension an average of 90 minutes after resuscitation compared to the PEG-20k pigs, which all survived 240 minutes and were then euthanized with normal blood pressure and lactate. Administration of PEG-20k primarily decreased the thromboelastograph maximum amplitude, however this began to return toward baseline by 240 minutes. Peak plasma concentration of PEG-20k after LVR were 40% lower than predicted, based on simple dilution (5.7 mg/mL vs. 10 mg/mL) and the half-life was 59.6 minutes. CONCLUSION These data demonstrate that acute resuscitation with PEG-20k significantly improves tolerance to hypovolemia but also decreases platelet function in the coagulation cascade, which was due, in part, to its volume expanding effects.
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13
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Immunological and Toxicological Considerations for the Design of Liposomes. NANOMATERIALS 2020; 10:nano10020190. [PMID: 31978968 PMCID: PMC7074910 DOI: 10.3390/nano10020190] [Citation(s) in RCA: 200] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 01/14/2020] [Accepted: 01/15/2020] [Indexed: 12/25/2022]
Abstract
Liposomes hold great potential as gene and drug delivery vehicles due to their biocompatibility and modular properties, coupled with the major advantage of attenuating the risk of systemic toxicity from the encapsulated therapeutic agent. Decades of research have been dedicated to studying and optimizing liposomal formulations for a variety of medical applications, ranging from cancer therapeutics to analgesics. Some effort has also been made to elucidate the toxicities and immune responses that these drug formulations may elicit. Notably, intravenously injected liposomes can interact with plasma proteins, leading to opsonization, thereby altering the healthy cells they come into contact with during circulation and removal. Additionally, due to the pharmacokinetics of liposomes in circulation, drugs can end up sequestered in organs of the mononuclear phagocyte system, affecting liver and spleen function. Importantly, liposomal agents can also stimulate or suppress the immune system depending on their physiochemical properties, such as size, lipid composition, pegylation, and surface charge. Despite the surge in the clinical use of liposomal agents since 1995, there are still several drawbacks that limit their range of applications. This review presents a focused analysis of these limitations, with an emphasis on toxicity to healthy tissues and unfavorable immune responses, to shed light on key considerations that should be factored into the design and clinical use of liposomal formulations.
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14
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Suzuki T, Ota C, Fujino N, Tando Y, Suzuki S, Yamada M, Kondo T, Okada Y, Kubo H. Improving the viability of tissue-resident stem cells using an organ-preservation solution. FEBS Open Bio 2019; 9:2093-2104. [PMID: 31642604 PMCID: PMC6886303 DOI: 10.1002/2211-5463.12748] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 09/02/2019] [Accepted: 10/22/2019] [Indexed: 12/24/2022] Open
Abstract
Human clinical specimens are a valuable source of tissue‐resident stem cells, but such cells need to be collected immediately after tissue collection. To extend the timescale for collection from fresh human samples, we developed a new extracellular fluid (ECF)‐type preservation solution based on a high‐sodium and low‐potassium solution containing low‐molecular‐weight dextran and glucose, which is used for preservation of organs for transplantation. In this study, we compared the preservation of tissue‐resident stem cells using our ECF solution with that using three other solutions: PBS, Dulbecco’s modified Eagle’s medium and Euro‐Collins solution. These solutions represent a common buffer, a common culture medium and a benchmark organ‐preservation solution, respectively. Lung tissues were removed from mice and preserved for 72 h under low‐temperature conditions. Of the solutions tested, only preservation in the ECF‐type solution could maintain the proliferation and differentiation capacity of mouse lung tissue‐resident stem cells. In addition, the ECF solution could preserve the viability and proliferation of human alveolar epithelial progenitor cells when stored for more than 7 days at 4 °C. The mean viability of human alveolar type II cells at 2, 5, 8 and 14 days of low‐temperature preservation was 90.9%, 84.8%, 85.7% and 66.3%, respectively, with no significant differences up to 8 days. Overall, our findings show that use of our ECF‐type preservation solution may maintain the viability and function of tissue‐resident stem cells. Use of this preservation solution may facilitate the investigation of currently unobtainable human tissue specimens for human stem cell biology. Here, we describe a newly developed extracellular fluid‐type organ preservation solution that maintained the viability of human lung stem/progenitor cells, such as alveolar type II cells, during 7‐day refrigerated preservation after the collection of lung specimens in local hospitals. This ready‐to‐use solution may be suitable for the transport of human clinical specimens from hospitals to scientific and bioengineering laboratories.![]()
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Affiliation(s)
- Takaya Suzuki
- Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Chiharu Ota
- Department of Pediatrics, Tohoku University Hospital, Sendai, Japan
| | - Naoya Fujino
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yukiko Tando
- Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Satoshi Suzuki
- Department of Thoracic Surgery, Japanese Red Cross Ishinomaki Hospital, Ishinomaki, Japan
| | - Mitsuhiro Yamada
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Kondo
- Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Yoshinori Okada
- Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Hiroshi Kubo
- Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, Sendai, Japan
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15
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Carnevale ME, Lausada N, Juan de Paz L, Stringa P, Machuca M, Rumbo M, Guibert EE, Tiribelli C, Gondolesi GE, Rodriguez JV. The Novel N,N-bis-2-Hydroxyethyl-2-Aminoethanesulfonic Acid-Gluconate-Polyethylene Glycol-Hypothermic Machine Perfusion Solution Improves Static Cold Storage and Reduces Ischemia/Reperfusion Injury in Rat Liver Transplant. Liver Transpl 2019; 25:1375-1386. [PMID: 31121085 DOI: 10.1002/lt.25573] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 05/16/2019] [Indexed: 01/19/2023]
Abstract
Organ transplantation is the treatment of choice against terminal and irreversible organ failure. Optimal preservation of the graft is crucial to counteract cold ischemia effects. As we developed an N,N-bis-2-hydroxyethyl-2-aminoethanesulfonic acid-gluconate-polyethylene glycol (BGP)-based solution (hypothermic machine perfusion [HMP]), we aimed to analyze the use of this solution on static cold storage (SCS) of rat livers for transplantation as compared with the histidine tryptophan ketoglutarate (HTK) preservation solution. Livers procured from adult male Sprague Dawley rats were preserved with BGP-HMP or HTK solutions. Liver total water content and metabolites were measured during the SCS at 0°C for 24 hours. The function and viability of the preserved rat livers were first assessed ex vivo after rewarming (90 minutes at 37°C) and in vivo using the experimental model of reduced-size heterotopic liver transplantation. After SCS, the water and glycogen content in both groups remained unchanged as well as the tissue glutathione concentration. In the ex vivo studies, livers preserved with the BGP-HMP solution were hemodynamically more efficient and the O2 consumption rate was higher than in livers from the HTK group. Bile production and glycogen content after 90 minutes of normothermic reperfusion was diminished in both groups compared with the control group. Cellular integrity of the BGP-HMP group was better, and the histological damage was reversible. In the in vivo model, HTK-preserved livers showed a greater degree of histological injury and higher apoptosis compared with the BGP-HMP group. In conclusion, our results suggest a better role of the BGP-HMP solution compared with HTK in preventing ischemia/reperfusion injury in the rat liver model.
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Affiliation(s)
- Matías E Carnevale
- Centro Binacional (Argentina-Italia) de Investigaciones en Criobiología Clínica y Aplicada, Universidad Nacional de Rosario, Rosario, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de la Plata, La Plata, Argentina
| | - Natalia Lausada
- Cátedra de Trasplante, Facultad de Ciencias Médicas, Universidad Nacional de la Plata, La Plata, Argentina
| | - Leonardo Juan de Paz
- Centro Binacional (Argentina-Italia) de Investigaciones en Criobiología Clínica y Aplicada, Universidad Nacional de Rosario, Rosario, Argentina
| | - Pablo Stringa
- Cátedra de Trasplante, Facultad de Ciencias Médicas, Universidad Nacional de la Plata, La Plata, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de la Plata, La Plata, Argentina
| | - Mariana Machuca
- Laboratorio de Patología Especial, Facultad de Ciencias Veterinarias, Universidad Nacional de la Plata, La Plata, Argentina
| | - Martin Rumbo
- Instituto de Estudios Inmunológicos y Fisiopatológicos, Universidad Nacional de la Plata, La Plata, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de la Plata, La Plata, Argentina
| | - Edgardo E Guibert
- Centro Binacional (Argentina-Italia) de Investigaciones en Criobiología Clínica y Aplicada, Universidad Nacional de Rosario, Rosario, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de la Plata, La Plata, Argentina
| | | | - Gabriel E Gondolesi
- Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de la Plata, La Plata, Argentina.,Servicio de Cirugía General, Trasplante Hepático, Pancreático e Intestinal, Hospital Universitario Fundación Favaloro, Laboratorio de Microcirugía Experimental, Instituto de Medicina Traslacional, Trasplante y Bioengeniería, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Favaloro, Buenos Aires, Argentina
| | - Joaquin V Rodriguez
- Centro Binacional (Argentina-Italia) de Investigaciones en Criobiología Clínica y Aplicada, Universidad Nacional de Rosario, Rosario, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de la Plata, La Plata, Argentina
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16
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Chen Y, Shi J, Xia TC, Xu R, He X, Xia Y. Preservation Solutions for Kidney Transplantation: History, Advances and Mechanisms. Cell Transplant 2019; 28:1472-1489. [PMID: 31450971 PMCID: PMC6923544 DOI: 10.1177/0963689719872699] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Solid organ transplantation was one of the greatest medical advances during the past few
decades. Organ preservation solutions have been applied to diminish ischemic/hypoxic
injury during cold storage and improve graft survival. In this article, we provide a
general review of the history and advances of preservation solutions for kidney
transplantation. Key components of commonly used solutions are listed, and effective
supplementations for current available preservation solutions are discussed. At cellular
and molecular levels, further insights were provided into the pathophysiological
mechanisms of effective ingredients against ischemic/hypoxic renal injury during cold
storage. We pay special attention to the cellular and molecular events during
transplantation, including ATP depletion, acidosis, mitochondrial dysfunction, oxidative
stress, inflammation, and other intracellular mechanisms.
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Affiliation(s)
- Yimeng Chen
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Jian Shi
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Terry C Xia
- The University of Connecticut, Storrs, CT, USA
| | - Renfang Xu
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Xiaozhou He
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Ying Xia
- Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China
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17
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Vectisol Formulation Enhances Solubility of Resveratrol and Brings Its Benefits to Kidney Transplantation in a Preclinical Porcine Model. Int J Mol Sci 2019; 20:ijms20092268. [PMID: 31071925 PMCID: PMC6540035 DOI: 10.3390/ijms20092268] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/03/2019] [Accepted: 05/05/2019] [Indexed: 02/07/2023] Open
Abstract
Current organ shortages have led centers to extend the acceptance criteria for organs, increasing the risk for adverse outcomes. Current preservation protocols have not been adapted so as to efficiently protect these organs. Herein, we target oxidative stress, the key mechanism of ischemia reperfusion injury. Vectisol® is a novel antioxidant strategy based on the encapsulation of resveratrol into a cyclodextrin, increasing its bioavailability. We tested this compound as an additive to the most popular static preservation solutions and machine perfusion (LifePort) in a preclinical pig model of kidney autotransplantation. In regard to static preservation, supplementation improved glomerular filtration and proximal tubular function early recovery. Extended follow-up confirmed the higher level of protection, slowing chronic loss of function (creatininemia and proteinuria) and the onset of histological lesions. Regarding machine perfusion, the use of Vectisol® decreased oxidative stress and apoptosis at the onset of reperfusion (30 min post declamping). Improved quality was confirmed with decreased early levels of circulating SOD (Superoxide Dismutase) and ASAT (asparagine amino transferase). Supplementation slowed the onset of chronic loss of function, as well as interstitial fibrosis and tubular atrophy. The simple addition of Vectisol® to the preservation solution significantly improved the performance of organ preservation, with long-term effects on the outcome. This strategy is thus a key player for future multi-drug therapy aimed at ischemia reperfusion in transplantation.
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18
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La-Beck NM, Liu X, Wood LM. Harnessing Liposome Interactions With the Immune System for the Next Breakthrough in Cancer Drug Delivery. Front Pharmacol 2019; 10:220. [PMID: 30914953 PMCID: PMC6422978 DOI: 10.3389/fphar.2019.00220] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 02/22/2019] [Indexed: 01/03/2023] Open
Abstract
Liposomal nanoparticles are a heterogeneous group of engineered drug carriers that have tremendous therapeutic potential in the treatment of cancer. They increase tumor drug delivery, significantly attenuate drug toxicity, and protect the drug from degradation. However, two decades after approval of the first nanoparticle-mediated anticancer drug, pegylated liposomal doxorubicin (Doxil), there has yet to be a major shift in cancer treatment paradigms. Only two anticancer nanoparticles are used in the first-line treatment of cancer patients, with all others relegated to the refractory or salvage setting. Herein, we discuss new insights into the mechanisms underlying in vivo interactions between liposomes and the tumor immunologic milieu, and the knowledge gaps that need to be addressed in order to realize the full clinical potential of cancer nanomedicines. We also discuss immunopharmacology insights from a parallel field, Cancer Immunotherapy, which have the potential to generate breakthroughs in Cancer Nanomedicine.
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Affiliation(s)
- Ninh M. La-Beck
- Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, United States
- Department of Pharmacy Practice, School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, United States
| | - Xinli Liu
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX, United States
| | - Laurence M. Wood
- Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, United States
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19
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Pereira J, Ferraretto X, Patrat C, Meddahi-Pellé A. Dextran-Based Hydrogel as a New Tool for BALB/c 3T3 Cell Cryopreservation Without Dimethyl Sulfoxide. Biopreserv Biobank 2019; 17:2-10. [DOI: 10.1089/bio.2018.0034] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Affiliation(s)
- Jessica Pereira
- INSERM, UMR S-1148, LVTS, CHU Xavier Bichat, Paris, France
- Université Paris 13, Sorbonne Paris Cité, Villetaneuse, France
| | - Xavier Ferraretto
- INSERM, UMR S-1148, LVTS, CHU Xavier Bichat, Paris, France
- Université Paris 13, Sorbonne Paris Cité, Villetaneuse, France
- Department of Reproductive Biology, AP-HP, Bichat-Claude Bernard Hospital, Paris, France
| | - Catherine Patrat
- Department of Reproductive Biology, AP-HP, Bichat-Claude Bernard Hospital, Paris, France
- Université Paris-Diderot, Paris, France
| | - Anne Meddahi-Pellé
- INSERM, UMR S-1148, LVTS, CHU Xavier Bichat, Paris, France
- Université Paris 13, Sorbonne Paris Cité, Villetaneuse, France
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20
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Coskun A, Baykal AT, Oztug M, Kazan D, Kaya E, Emiroglu R, Yılmaz S, Dundar HZ, Akgoz M, Berber I, Aktas H, Bilsel G, Karaosmanoglu K, Çetiner B, Arslan C, Yurtsever I, Yazıcı C. Proteomic Analysis of Liver Preservation Solutions Prior to Liver Transplantation. CURR PROTEOMICS 2019. [DOI: 10.2174/1570164615666180905104543] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Objective: Transplantation is the preferred treatment for patients with end-stage liver diseases. However, in clinical practice, functional preservation of the liver is a major concern before the transplantation. Although various protective solutions are used (in combination with hypothermia), the functional preservation time for liver is still limited to hours. We analyzed the preservation medium to detect the proteins released from the liver during storage period.
Material/Methods:
Samples were collected from the pre-transplant preservation mediums of 23 liver donors. For all donors, the cases involved Donation after Brain Death (DBD). 2D-PAGE and LCMSMS methodologies were used to detect the proteins and peptides from the preservation mediums.
Results:
A total of 198 proteins originating from the liver were detected.
Conclusion:
The data provide valuable insights into biomarkers that may be used to evaluate organ injury, functional status, and suitability for transplantation. Additionally, the findings could be valuable for the development of new strategies for effective preservation of solid organs prior to transplantation.
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Affiliation(s)
- Abdurrahman Coskun
- Department of Medical Biochemistry, School of Medicine, Acibadem University, Istanbul, Turkey
| | - Ahmet Tarik Baykal
- Department of Medical Biochemistry, School of Medicine, Acibadem University, Istanbul, Turkey
| | - Merve Oztug
- TUBITAK UME (National Metrology Institute), Gebze, Turkey
| | - Dilek Kazan
- Department of Bioengineering, Engineering Faculty, Marmara University, Istanbul, Turkey
| | - Ekrem Kaya
- Department of General Surgery, School of Medicine, Uludag University, Bursa, Turkey
| | - Remzi Emiroglu
- Department of General Surgery, School of Medicine,Acibadem University, Istanbul, Turkey
| | - Sezai Yılmaz
- Department of General Surgery, School of Medicine, Inonu University, Malatya, Turkey
| | - Halit Ziya Dundar
- Department of General Surgery, School of Medicine, Uludag University, Bursa, Turkey
| | - Muslum Akgoz
- TUBITAK UME (National Metrology Institute), Gebze, Turkey
| | - Ibrahim Berber
- Department of General Surgery, School of Medicine,Acibadem University, Istanbul, Turkey
| | - Hikmet Aktas
- Vocational School of Health Services, Acibadem University Istanbul, Turkey
| | - Gokhan Bilsel
- TUBITAK UME (National Metrology Institute), Gebze, Turkey
| | - Kubra Karaosmanoglu
- Department of Bioengineering, Engineering Faculty, Marmara University, Istanbul, Turkey
| | - Banu Çetiner
- Department of Medical Biochemistry, School of Medicine, Acibadem University, Istanbul, Turkey
| | - Cansu Arslan
- Department of Medical Biochemistry, School of Medicine, Acibadem University, Istanbul, Turkey
| | - Ilknur Yurtsever
- Regenerative and Restorative Medicine Research Center, Medipol University, Istanbul, Turkey
| | - Cevat Yazıcı
- Department of Medical Biochemistry, School of Medicine, Erciyes University, Kayseri, Turkey
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21
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Barriers and Advances in Kidney Preservation. BIOMED RESEARCH INTERNATIONAL 2018; 2018:9206257. [PMID: 30643824 PMCID: PMC6311271 DOI: 10.1155/2018/9206257] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 10/15/2018] [Accepted: 11/14/2018] [Indexed: 12/16/2022]
Abstract
Despite the fact that a significant fraction of kidney graft dysfunctions observed after transplantation is due to ischemia-reperfusion injuries, there is still no clear consensus regarding optimal kidney preservation strategy. This stems directly from the fact that as of yet, the mechanisms underlying ischemia-reperfusion injury are poorly defined, and the role of each preservation parameter is not clearly outlined. In the meantime, as donor demography changes, organ quality is decreasing which directly increases the rate of poor outcome. This situation has an impact on clinical guidelines and impedes their possible harmonization in the transplant community, which has to move towards changing organ preservation paradigms: new concepts must emerge and the definition of a new range of adapted preservation method is of paramount importance. This review presents existing barriers in transplantation (e.g., temperature adjustment and adequate protocol, interest for oxygen addition during preservation, and clear procedure for organ perfusion during machine preservation), discusses the development of novel strategies to overcome them, and exposes the importance of identifying reliable biomarkers to monitor graft quality and predict short and long-term outcomes. Finally, perspectives in therapeutic strategies will also be presented, such as those based on stem cells and their derivatives and innovative models on which they would need to be properly tested.
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22
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Liebrecht LK, Newton J, Martin EJ, Wickramaratne N, Jayaraman S, Han J, Aboutanos M, Brophy DF, Mangino MJ. Thromboelastographic analysis of novel polyethylene glycol based low volume resuscitation solutions. PLoS One 2018; 13:e0207147. [PMID: 30439979 PMCID: PMC6237338 DOI: 10.1371/journal.pone.0207147] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 10/25/2018] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Low volume resuscitation (LVR) in shock prevents deleterious effects of crystalloid loading in pre-hospital settings. Polyethylene glycol 20,000 (PEG-20k) based LVR solutions are 20-fold more effective at maintaining perfusion and survival in shock compared to conventional crystalloids. The aim of this study was to determine coagulation and platelet function of whole blood treated with 10% PEG-20k. METHODS Citrated blood from volunteers (n = 25) or early admission severely injured trauma patients (n = 9) were diluted 10% with various LVR solutions in a matched design with a paired volume control (saline), and studied using thromboelastography (TEG). FINDINGS In healthy volunteers and patients, 10% PEG-20k significantly increased clot amplification time (k), decreased propagation (angle), maximal clot size and strength (MA), and the overall coagulation index (CI), but not clot initiation (R) or fibrinolysis (Ly30), relative to paired saline dilutional controls. Clinically, K, angle, and MA were just outside of the normal limits in volunteers but not in patients. No statistical differences existed between PEG-20k and Hextend (HES) in either patient population. In a dose response series using volunteer blood, all effects of 10% PEG-20k on TEG were reversed and normalized by lower concentrations (7.5% and 5%). Furthermore, 7.5% PEG-20k produced similar resuscitation effects as 10% PEG in rodent hemorrhagic shock models (n = 5). CONCLUSIONS In conclusion, PEG-20k based LVR solutions produced a dose-dependent minor hypocoagulative state, possibly associated with changes in clot propagation and platelet function, which can be reversed by dose reduction in concentration while providing superior LVR, microvascular rescue, and lactate clearance compared to saline or starch.
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Affiliation(s)
- Loren K. Liebrecht
- Department of Surgery, Division of Acute Care Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
| | - Jason Newton
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
| | - Erika J. Martin
- Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University School of Pharmacy, Richmond, Virginia, United States of America
| | - Nina Wickramaratne
- Department of Surgery, Division of Acute Care Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
| | - Sudha Jayaraman
- Department of Surgery, Division of Acute Care Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
| | - Jinfeng Han
- Department of Surgery, Division of Acute Care Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
| | - Michel Aboutanos
- Department of Surgery, Division of Acute Care Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
| | - Donald F. Brophy
- Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University School of Pharmacy, Richmond, Virginia, United States of America
| | - Martin J. Mangino
- Department of Surgery, Division of Acute Care Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
- Department of Emergency Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
- * E-mail:
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23
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Tian Y, Zhu H, Wu J, Wang S. Effect of improved preservation solution with methoxy polyethylene glycol succinimidyl propionate on rat cornea. Cell Tissue Bank 2018; 19:667-679. [PMID: 30069708 DOI: 10.1007/s10561-018-9719-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 07/28/2018] [Indexed: 11/30/2022]
Abstract
To observe the effect of DMEM/F12 pegylated with methoxy polyethylene glycol succinimidyl propionate (mPEG-SPA) on the biophysical and immune characteristics of the rat cornea preserved in it. Corneal grafts were harvested from Wistar rat and preserved in the DMEM/F12 plus mPEG-SPA, DMEM/F12 without mPEG-SPA, and standard Optisol-GS solution at 4 °C for 14 days, referred as plus-PEG, minus-PEG, and Optisol grafts, respectively. The biophysical properties of those grafts, including transmittance, thickness, water content, and biomechanics were investigated. The survival of those grafts was observed in the high-risk corneal transplantation model. Transmittance and biomechanics did not show any differences among those grafts. Thickness and water content of plus-PEG grafts were slightly improved. Proliferation and activation of lymphocytes were lower while they were incubated with plus-PEG grafts, compared with minus-PEG grafts and Optisol grafts. The mean survival time was significantly prolonged in plus-PEG grafts. DMEM/F12 solution plus mPEG-SPA improved the survival of corneal grafts and maintained the comparative biophysical characteristics of them, compared with the standard preservation solution.
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Affiliation(s)
- Ying Tian
- The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510150, People's Republic of China
| | - Haifeng Zhu
- The First Hospital of Xi'an, Xi'an, 710000, People's Republic of China.,Shaanxi Provincial Institute of Ophthalmology, Xi'an, 710000, People's Republic of China.,Shaanxi Provincial Key Laboratory of Ophthalmology, Xi'an, 710000, People's Republic of China.,Clinical Research Center for Ophthalmologic Diseases of Shaanxi, Xi'an, 710000, People's Republic of China
| | - Jie Wu
- The First Hospital of Xi'an, Xi'an, 710000, People's Republic of China.,Shaanxi Provincial Institute of Ophthalmology, Xi'an, 710000, People's Republic of China.,Shaanxi Provincial Key Laboratory of Ophthalmology, Xi'an, 710000, People's Republic of China.,Clinical Research Center for Ophthalmologic Diseases of Shaanxi, Xi'an, 710000, People's Republic of China
| | - Shuangyong Wang
- The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510150, People's Republic of China.
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24
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Casselbrant A, Söfteland JM, Hellström M, Malinauskas M, Oltean M. Luminal Polyethylene Glycol Alleviates Intestinal Preservation Injury Irrespective of Molecular Size. J Pharmacol Exp Ther 2018; 366:29-36. [PMID: 29739826 DOI: 10.1124/jpet.117.247023] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 04/26/2018] [Indexed: 08/30/2023] Open
Abstract
Intestinal preservation injury (IPI) and the resulting mucosa injury raise several serious challenges early after intestinal transplantation. The current clinical approach using only vascular perfusion allows the shortest preservation period among the abdominal organs. The experimental addition of luminal polyethylene glycol (PEG) solutions has been repeatedly suggested to alleviate preservation injury, improve graft quality, and prolong the preservation time. We investigated whether the molecular mass of PEG in solution influences the development of intestinal preservation injury. Small intestines of Sprague-Dawley rats were perfused with University of Wisconsin solution. Group 1 underwent vascular perfusion only (clinical control), group 2 received additional luminal PEG3350 Da, group 3 received luminal PEG10000 Da, and group 4 received luminal PEG20000 Da (n = 8/group). Tissue samples were obtained after 4, 8, and 14 hours. We studied the tissue damage (Chiu/Park score, Goblet cells, apoptosis, tight junctions), activation of c-Jun NH2-terminal kinase (JNK), and p38-mitogen-activated protein kinase (MAPK), and we performed Ussing chamber assessments. Mucosal morphologic and electrophysiologic parameters were significantly improved in the groups receiving luminal PEG. There was significantly less apoptotic activity in groups 2, 3, and 4. Both MAPKs revealed an activation peak after 4 hours with group 3 showing lesser p38-MAPK activation. PEG 20 kDa interfered with protein immunodetection. The results indicate that luminal solutions of PEG of medium and large molecular mass significantly delay the onset and development of IPI, providing further evidence that luminal interventions may allow for longer cold storage intervals of intestinal grafts.
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Affiliation(s)
- Anna Casselbrant
- Institute of Clinical Sciences, Department of Gastrosurgical Research and Education (A.C.) and Institute of Clinical Sciences, Laboratory for Transplantation and Regenerative Medicine (J.M.S., M.H., M.O.), Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania (M.M.); and The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden (J.M.S., M.O.)
| | - John M Söfteland
- Institute of Clinical Sciences, Department of Gastrosurgical Research and Education (A.C.) and Institute of Clinical Sciences, Laboratory for Transplantation and Regenerative Medicine (J.M.S., M.H., M.O.), Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania (M.M.); and The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden (J.M.S., M.O.)
| | - Mats Hellström
- Institute of Clinical Sciences, Department of Gastrosurgical Research and Education (A.C.) and Institute of Clinical Sciences, Laboratory for Transplantation and Regenerative Medicine (J.M.S., M.H., M.O.), Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania (M.M.); and The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden (J.M.S., M.O.)
| | - Mantas Malinauskas
- Institute of Clinical Sciences, Department of Gastrosurgical Research and Education (A.C.) and Institute of Clinical Sciences, Laboratory for Transplantation and Regenerative Medicine (J.M.S., M.H., M.O.), Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania (M.M.); and The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden (J.M.S., M.O.)
| | - Mihai Oltean
- Institute of Clinical Sciences, Department of Gastrosurgical Research and Education (A.C.) and Institute of Clinical Sciences, Laboratory for Transplantation and Regenerative Medicine (J.M.S., M.H., M.O.), Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania (M.M.); and The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden (J.M.S., M.O.)
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25
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Tessier SN, Weng L, Moyo WD, Au SH, Wong KHK, Angpraseuth C, Stoddard AE, Lu C, Nieman LT, Sandlin RD, Uygun K, Stott SL, Toner M. Effect of Ice Nucleation and Cryoprotectants during High Subzero-Preservation in Endothelialized Microchannels. ACS Biomater Sci Eng 2018; 4:3006-3015. [PMID: 31544149 DOI: 10.1021/acsbiomaterials.8b00648] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Cryopreservation is of significance in areas including tissue engineering, regenerative medicine, and organ transplantation. We investigated endothelial cell attachment and membrane integrity in a microvasculature model at high subzero temperatures in the presence of extracellular ice. The results show that in the presence of heterogeneous extracellular ice formation induced by ice nucleating bacteria, endothelial cells showed improved attachment at temperature minimums of -6 °C. However, as temperatures decreased below -6 °C, endothelial cells required additional cryoprotectants. The glucose analog, 3-O-methyl-D-glucose (3-OMG), rescued cell attachment optimally at 100 mM (cells/lane was 34, as compared to 36 for controls), while 2% and 5% polyethylene glycol (PEG) were equally effective at -10 °C (88% and 86.4% intact membranes). Finally, endothelialized microchannels were stored for 72 h at -10 °C in a preservation solution consisting of the University of Wisconsin (UW) solution, Snomax, 3-OMG, PEG, glycerol, and trehalose, whereby cell attachment was not significantly different from unfrozen controls, although membrane integrity was compromised. These findings enrich our knowledge about the direct impact of extracellular ice on endothelial cells. Specifically, we show that, by controlling the ice nucleation temperature and uniformity, we can preserve cell attachment and membrane integrity. Further, we demonstrate the strength of leveraging endothelialized microchannels to fuel discoveries in cryopreservation of thick tissues and solid organs.
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Affiliation(s)
- Shannon N Tessier
- Center for Engineering in Medicine and BioMEMS Resource Center, Surgical Services, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, United States.,Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, United States.,Shriners Hospital for Children, 51 Blossom Street, Boston, Massachusetts 02114, United States
| | - Lindong Weng
- Center for Engineering in Medicine and BioMEMS Resource Center, Surgical Services, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, United States.,Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, United States
| | - Will D Moyo
- Center for Engineering in Medicine and BioMEMS Resource Center, Surgical Services, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, United States.,Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, United States
| | - Sam H Au
- Center for Engineering in Medicine and BioMEMS Resource Center, Surgical Services, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, United States.,Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, United States
| | - Keith H K Wong
- Center for Engineering in Medicine and BioMEMS Resource Center, Surgical Services, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, United States.,Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, United States.,Shriners Hospital for Children, 51 Blossom Street, Boston, Massachusetts 02114, United States
| | - Cindy Angpraseuth
- Center for Engineering in Medicine and BioMEMS Resource Center, Surgical Services, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, United States.,Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, United States
| | - Amy E Stoddard
- Center for Engineering in Medicine and BioMEMS Resource Center, Surgical Services, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, United States.,Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, United States
| | - Chenyue Lu
- Massachusetts General Hospital Cancer Center, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, United States
| | - Linda T Nieman
- Massachusetts General Hospital Cancer Center, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, United States
| | - Rebecca D Sandlin
- Center for Engineering in Medicine and BioMEMS Resource Center, Surgical Services, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, United States.,Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, United States.,Shriners Hospital for Children, 51 Blossom Street, Boston, Massachusetts 02114, United States
| | - Korkut Uygun
- Center for Engineering in Medicine and BioMEMS Resource Center, Surgical Services, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, United States.,Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, United States.,Shriners Hospital for Children, 51 Blossom Street, Boston, Massachusetts 02114, United States
| | - Shannon L Stott
- Center for Engineering in Medicine and BioMEMS Resource Center, Surgical Services, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, United States.,Massachusetts General Hospital Cancer Center, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, United States.,Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, United States
| | - Mehmet Toner
- Center for Engineering in Medicine and BioMEMS Resource Center, Surgical Services, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, United States.,Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, United States.,Shriners Hospital for Children, 51 Blossom Street, Boston, Massachusetts 02114, United States
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26
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The Optimal PEG for Kidney Preservation: A Preclinical Porcine Study. Int J Mol Sci 2018; 19:ijms19020454. [PMID: 29401654 PMCID: PMC5855676 DOI: 10.3390/ijms19020454] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 12/26/2017] [Accepted: 01/29/2018] [Indexed: 01/12/2023] Open
Abstract
University of Wisconsin (UW) solution is not optimal for preservation of marginal organs. Polyethylene glycol (PEG) could improve protection. Similarly formulated solutions containing either 15 or 20 g/L PEG 20 kDa or 5, 15 and 30 g/L PEG 35 kDa were tested in vitro on kidney endothelial cells, ex vivo on preserved kidneys, and in vivo in a pig kidney autograft model. In vitro, all PEGs provided superior preservation than UW in terms of cell survival, adenosine triphosphate (ATP) production, and activation of survival pathways. Ex vivo, tissue injury was lower with PEG 20 kDa compared to UW or PEG 35 kDa. In vivo, function recovery was identical between UW and PEG 35 kDa groups, while PEG 20 kDa displayed swifter recovery. At three months, PEG 35 kDa 15 and 30 g/L animals had worse outcomes than UW, while 5 g/L PEG 35 kDa was similar. PEG 20 kDa was superior to both UW and PEG 35 kDa in terms of function and fibrosis development, with low activation of damage pathways. PEG 20 kDa at 15 g/L was superior to 20 g/L. While in vitro models did not discriminate between PEGs, in large animal models of transplantation we showed that PEG 20 kDa offers a higher level of protection than UW and that longer chains such as PEG 35 kDa must be used at low doses, such as found in Institut George Lopez (IGL1, 1g/L).
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27
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Barin-Le Guellec C, Largeau B, Bon D, Marquet P, Hauet T. Ischemia/reperfusion-associated tubular cells injury in renal transplantation: Can metabolomics inform about mechanisms and help identify new therapeutic targets? Pharmacol Res 2018; 129:34-43. [PMID: 29309901 DOI: 10.1016/j.phrs.2017.12.032] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 12/29/2017] [Accepted: 12/29/2017] [Indexed: 12/31/2022]
Abstract
Tubular cells are central targets of ischemia-reperfusion (I/R) injury in kidney transplantation. Inflammation and metabolic disturbances occurring within these cells are deleterious by themselves but also favor secondary events, such as activation of immune response. It is critical to have an in depth understanding of the mechanisms governing tubular cells response to I/R if one wants to define pertinent biomarkers or to elaborate targeted therapeutic interventions. As oxidative damage was shown to be central in the patho-physiological mechanisms, the impact of I/R on proximal tubular cells metabolism has been widely studied, contrary to its effects on expression and activity of membrane transporters of the proximal tubular cells. Yet, temporal modulation of transporters over ischemia and reperfusion periods appears to play a central role, not only in the induction of cells injury but also in graft function recovery. Metabolomics in cell models or diverse biofluids has the potential to provide large pictures of biochemical consequences of I/R. Metabolomic studies conducted in experimental models of I/R or in transplanted patients indeed retrieved metabolites belonging to the pathways known to be particularly affected. Interestingly, they also revealed that metabolic disturbances and transporters activities are in very close mutual interplay. As well as helping to select diagnostic biomarkers, such analyses could also contribute to identify new pharmacological targets and to set up innovative nephroprotective strategies for the future. Even if various therapeutic approaches have been evaluated for a long time to prevent or treat I/R injuries, metabolomics has helped identifying new ones, those related to membrane transporters seeming to be of particular interest. However, considering the very complex and multifactorial effects of I/R in the context of kidney transplantation, all tracks must be followed if one wants to prevent or limit its deleterious consequences.
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Affiliation(s)
- Chantal Barin-Le Guellec
- INSERM UMR 1248, IPPRITT, Limoges, France; CHU Tours, Laboratory of Biochemistry and Molecular Biology, Tours, France; FHU SUPORT, Limoges, Poitiers, Tours, France.
| | - Bérenger Largeau
- CHU Tours, Laboratory of Biochemistry and Molecular Biology, Tours, France
| | - Delphine Bon
- FHU SUPORT, Limoges, Poitiers, Tours, France; University of Poitiers, Poitiers, France; INSERM UMR 1082, IRTOMIT, Poitiers, France; CHU Poitiers, Laboratory of Biochemistry, Poitiers, France
| | - Pierre Marquet
- INSERM UMR 1248, IPPRITT, Limoges, France; FHU SUPORT, Limoges, Poitiers, Tours, France; University of Limoges, Faculty of Medicine, Limoges, France; CHU Limoges, Department of Pharmacology, Toxicology & Pharmacovigilance, Limoges, France
| | - Thierry Hauet
- FHU SUPORT, Limoges, Poitiers, Tours, France; University of Poitiers, Poitiers, France; INSERM UMR 1082, IRTOMIT, Poitiers, France; CHU Poitiers, Laboratory of Biochemistry, Poitiers, France
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28
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Fang C, Yang K, Zhou Q, Peng K, Yang H. A monolithic anti-freezing hydro/organo Janus actuator with sensitivity to the polarity of solvents. RSC Adv 2018; 8:35094-35101. [PMID: 35547062 PMCID: PMC9087327 DOI: 10.1039/c8ra06719h] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 09/27/2018] [Indexed: 11/21/2022] Open
Abstract
A monolithic anti-freezing hydro/organo Janus actuator which was synthesized by a one-step interfacial copolymerization shows various deformation patterns with solvent polarity.
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Affiliation(s)
- Chao Fang
- CAS Key Laboratory of Soft Matter Chemistry
- School of Chemistry and Materials Science
- University of Science and Technology of China
- Hefei 230026
- P. R. China
| | - Kaixiang Yang
- CAS Key Laboratory of Soft Matter Chemistry
- School of Chemistry and Materials Science
- University of Science and Technology of China
- Hefei 230026
- P. R. China
| | - Qiang Zhou
- CAS Key Laboratory of Soft Matter Chemistry
- School of Chemistry and Materials Science
- University of Science and Technology of China
- Hefei 230026
- P. R. China
| | - Kang Peng
- CAS Key Laboratory of Soft Matter Chemistry
- School of Chemistry and Materials Science
- University of Science and Technology of China
- Hefei 230026
- P. R. China
| | - Haiyang Yang
- CAS Key Laboratory of Soft Matter Chemistry
- School of Chemistry and Materials Science
- University of Science and Technology of China
- Hefei 230026
- P. R. China
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29
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Liposome-induced immunosuppression and tumor growth is mediated by macrophages and mitigated by liposome-encapsulated alendronate. J Control Release 2017; 271:139-148. [PMID: 29277680 DOI: 10.1016/j.jconrel.2017.12.023] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 12/20/2017] [Accepted: 12/21/2017] [Indexed: 12/13/2022]
Abstract
Liposomal nanoparticles are the most commonly used drug nano-delivery platforms. However, recent reports show that certain pegylated liposomal nanoparticles (PLNs) and polymeric nanoparticles have the potential to enhance tumor growth and inhibit antitumor immunity in murine cancer models. We sought herein to identify the mechanisms and determine whether PLN-associated immunosuppression and tumor growth can be reversed using alendronate, an immune modulatory drug. By conducting in vivo and ex vivo experiments with the immunocompetent TC-1 murine tumor model, we found that macrophages were the primary cells that internalized PLN in the tumor microenvironment and that PLN-induced tumor growth was dependent on macrophages. Treatment with PLN increased immunosuppression as evidenced by increased expression of arginase-1 in CD11b+Gr1+ cells, diminished M1 functionality in macrophages, and globally suppressed T-cell cytokine production. Encapsulating alendronate in PLN reversed these effects on myeloid cells and shifted the profile of multi-cytokine producing T-cells towards an IFNγ+ perforin+ response, suggesting increased cytotoxic functionality. Importantly, we also found that PLN-encapsulated alendronate (PLN-alen), but not free alendronate, abrogated PLN-induced tumor growth and increased progression-free survival. In summary, we have identified a novel mechanism of PLN-induced tumor growth through macrophage polarization and immunosuppression that can be targeted and inactivated to improve the anticancer efficacy of PLN-delivered drugs. Importantly, we also determined that PLN-alen not only reversed protumoral effects of the PLN carrier, but also had moderate antitumor activity. Our findings strongly support the inclusion of immune-responsive tumor models and in-depth immune functional studies in the preclinical drug development paradigm for cancer nanomedicines, and the further development of chemo-immunotherapy strategies to co-deliver alendronate and chemotherapy for the treatment of cancer.
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30
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Adsorbed Conformations of PCE Superplasticizers in Cement Pore Solution Unraveled by Molecular Dynamics Simulations. Sci Rep 2017; 7:16599. [PMID: 29192244 PMCID: PMC5709394 DOI: 10.1038/s41598-017-16048-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 11/06/2017] [Indexed: 11/21/2022] Open
Abstract
The conformations of polycarboxylate ether (PCE) type superplasticizer polymers adsorbed on the surface of MgO in cement pore solution are simulated by molecular dynamics (MD). Three types of PCEs commonly applied to concrete are simulated, namely a methacrylate type PCE (PCEM-P), an allyl ether type PCE (PCEA-P), and an isoprenyl ether type PCE (PCEI-P) with ethylene oxide (EO) unit numbers (P) of 25, 34 and 25, respectively. It is observed that the adsorbed layer thickness is inversely proportional to the experimentally measured adsorbed amount at the initial paste flow of 26 ± 0.5 cm. Simulation results indicate that the adsorbed layer thickness is sensitive to the initial polymer orientations against the model MgO surface. I.e., polymer molecules initially placed parallel/perpendicularly against the MgO surface gradually forms a train shaped or a loop and tail adsorption profile, respectively. As a result, the loop and tail shaped conformation gives a higher layer thickness.
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31
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Continuous Normothermic Ex Vivo Kidney Perfusion Improves Graft Function in Donation After Circulatory Death Pig Kidney Transplantation. Transplantation 2017; 101:754-763. [PMID: 27467537 DOI: 10.1097/tp.0000000000001343] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Donation after circulatory death (DCD) is current clinical practice to increase the donor pool. Deleterious effects on renal graft function are described for hypothermic preservation. Therefore, current research focuses on investigating alternative preservation techniques, such as normothermic perfusion. METHODS We compared continuous pressure-controlled normothermic ex vivo kidney perfusion (NEVKP) with static cold storage (SCS) in a porcine model of DCD autotransplantation. After 30 minutes of warm ischemia, right kidneys were removed from 30-kg Yorkshire pigs and preserved with 8-hour NEVKP or in 4°C histidine-tryptophan-ketoglutarate solution (SCS), followed by kidney autotransplantation. RESULTS Throughout NEVKP, electrolytes and pH values were maintained. Intrarenal resistance decreased over the course of perfusion (0 hour, 1.6 ± 0.51 mm per minute vs 7 hours, 0.34 ± 0.05 mm Hg/mL per minute, P = 0.005). Perfusate lactate concentration also decreased (0 hour, 10.5 ± 0.8 vs 7 hours, 1.4 ± 0.3 mmol/L, P < 0.001). Cellular injury markers lactate dehydrogenase and aspartate aminotransferase were persistently low (lactate dehydrogenase < 100 U/L, below analyzer range; aspartate aminotransferase 0 hour, 15.6 ± 9.3 U/L vs 7 hours, 24.8 ± 14.6 U/L, P = 0.298). After autotransplantation, renal grafts preserved with NEVKP demonstrated lower serum creatinine on days 1 to 7 (P < 0.05) and lower peak values (NEVKP, 5.5 ± 1.7 mg/dL vs SCS, 11.1 ± 2.1 mg/dL, P = 0.002). The creatinine clearance on day 4 was increased in NEVKP-preserved kidneys (NEVKP, 39 ± 6.4 vs SCS, 18 ± 10.6 mL/min; P = 0.012). Serum neutrophil gelatinase-associated lipocalin at day 3 was lower in the NEVKP group (1267 ± 372 vs 2697 ± 1145 ng/mL, P = 0.029). CONCLUSIONS Continuous pressure-controlled NEVKP improves renal function in DCD kidney transplantation. Normothermic ex vivo kidney perfusion might help to decrease posttransplant delayed graft function rates and to increase the donor pool.
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Eight-Hour Continuous Normothermic Ex Vivo Kidney Perfusion Is a Safe Preservation Technique for Kidney Transplantation: A New Opportunity for the Storage, Assessment, and Repair of Kidney Grafts. Transplantation 2017; 100:1862-70. [PMID: 27479157 DOI: 10.1097/tp.0000000000001299] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Hypothermic kidney storage causes preservation injury and is poorly tolerated by renal grafts. We investigated whether static cold storage (SCS) can be safely replaced with a novel technique of pressure-controlled normothermic ex vivo kidney perfusion (NEVKP) in heart-beating donor kidney transplantation. METHODS Right kidneys were removed from 30 kg Yorkshire pigs in a model of heart-beating donation and either preserved in cold histidine-tryptophan-ketoglutarate solution for 8 hours (n = 5), or subjected to 8 hours of pressure-controlled NEVKP (n = 5) followed by renal heterotopic autotransplantation. RESULTS During NEVKP, physiologic perfusion conditions were maintained with low intrarenal resistance and normal electrolyte and pH parameters. Aspartate aminotransferase and lactate dehydrogenase as injury markers were below the detectable analyzer range (<4 and <100 U/L, respectively). Perfusate lactate concentration decreased from baseline until the end of perfusion (10.38 ± 0.76 mmol/L vs 1.22 ± 0.26 mmol/L; P < 0.001). Posttransplantation, animals transplanted with NEVKP versus SCS grafts demonstrated similar serum creatinine peak levels (NEVKP, 2.0 ± 0.5 vs SCS 2.7 ± 0.7 mg/dL; P = 0.11) and creatinine clearance on day 10 (NEVKP, 65.9 ± 18.8 mL/min vs SCS 61.2 ± 15.6 mL/min; P = 0.74). After 10 days of follow-up, animals transplanted with NEVKP grafts had serum creatinine and blood urea nitrogen values comparable to their basal levels (P = 0.49 and P = 0.59), whereas animals transplanted with SCS grafts had persistently elevated serum creatinine and blood urea nitrogen when compared with basal levels (P = 0.01 and P = 0.03). CONCLUSIONS Continuous pressure-controlled NEVKP is feasible and safe in good quality heart-beating donor kidney grafts. It maintains a physiologic environment and excellent graft function ex vivo during preservation without causing graft injury.
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Plant V, Parrish DW, Limkemann A, Ferrada P, Aboutanos M, Mangino MJ. Low-Volume Resuscitation for Hemorrhagic Shock: Understanding the Mechanism of PEG-20k. J Pharmacol Exp Ther 2017; 361:334-340. [PMID: 28275202 DOI: 10.1124/jpet.116.239822] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 03/06/2017] [Indexed: 08/30/2023] Open
Abstract
Hemorrhagic shock leads to cell and tissue swelling and no reflow from compressed capillaries. Cell impermeants, including polyethylene glycol-20,000 (PEG-20k), reverse ischemia-induced cell swelling, extend low-volume resuscitation (LVR) time after shock, and increase tolerance to the low-volume state. The purpose of this study was to explore the mechanisms of action of PEG-20k containing LVR solutions. We hypothesized that PEG-20k acts as both an oncotic agent and an impermeant in the microcirculation, which moves water out of the space and into the capillaries to affect peripheral capillary filling and enhanced perfusion during the low-volume state. Rats were hemorrhaged until arterial lactate reached 9-10 mM/liter. Then, saline-based LVR solutions containing various impermeant materials were administered (10% blood volume). The LVR times for these solutions were determined by measuring the amount of time required for plasma lactate to climb back to 9 to 10 mM after LVR administration (low-volume tolerance). Capillary blood flow was measured by colored microspheres, and blood volume was measured by fluorescein isothiocyanate-labeled albumin dilution. Gluconate (impermeant), albumin (colloid), and PEG-20k (hybrid) increased LVR time over saline by 4-, 3-, and 8-fold, respectively. The combination of impermeant + albumin produced a biologic effect that was similar to PEG-20k alone. Capillary blood flow and plasma volume were decreased after shock with saline LVR but increased with PEG-20k, relative to saline. These data are consistent with the hypothesis that PEG-20k may act by establishing multiple osmotic gradients in the microcirculation to drive cell-to-capillary water transfer during hypovolemic shock.
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Affiliation(s)
- Valerie Plant
- Organ Preservation Laboratory, Department of Surgery, Division of Acute Care Surgical Services (V.P., D.W.P., P.F., M.A., M.J.M.), Department of Physiology and Biophysics (M.J.M.), and Department of Emergency Medicine (M.J.M.), Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Dan W Parrish
- Organ Preservation Laboratory, Department of Surgery, Division of Acute Care Surgical Services (V.P., D.W.P., P.F., M.A., M.J.M.), Department of Physiology and Biophysics (M.J.M.), and Department of Emergency Medicine (M.J.M.), Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Ashley Limkemann
- Organ Preservation Laboratory, Department of Surgery, Division of Acute Care Surgical Services (V.P., D.W.P., P.F., M.A., M.J.M.), Department of Physiology and Biophysics (M.J.M.), and Department of Emergency Medicine (M.J.M.), Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Paula Ferrada
- Organ Preservation Laboratory, Department of Surgery, Division of Acute Care Surgical Services (V.P., D.W.P., P.F., M.A., M.J.M.), Department of Physiology and Biophysics (M.J.M.), and Department of Emergency Medicine (M.J.M.), Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Michel Aboutanos
- Organ Preservation Laboratory, Department of Surgery, Division of Acute Care Surgical Services (V.P., D.W.P., P.F., M.A., M.J.M.), Department of Physiology and Biophysics (M.J.M.), and Department of Emergency Medicine (M.J.M.), Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Martin J Mangino
- Organ Preservation Laboratory, Department of Surgery, Division of Acute Care Surgical Services (V.P., D.W.P., P.F., M.A., M.J.M.), Department of Physiology and Biophysics (M.J.M.), and Department of Emergency Medicine (M.J.M.), Virginia Commonwealth University, School of Medicine, Richmond, Virginia
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Kaths JM, Cen JY, Chun YM, Echeverri J, Linares I, Ganesh S, Yip P, John R, Bagli D, Mucsi I, Ghanekar A, Grant DR, Robinson LA, Selzner M. Continuous Normothermic Ex Vivo Kidney Perfusion Is Superior to Brief Normothermic Perfusion Following Static Cold Storage in Donation After Circulatory Death Pig Kidney Transplantation. Am J Transplant 2017; 17:957-969. [PMID: 27647696 DOI: 10.1111/ajt.14059] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 09/07/2016] [Indexed: 01/25/2023]
Abstract
Hypothermic preservation is known to cause renal graft injury, especially in donation after circulatory death (DCD) kidney transplantation. We investigated the impact of cold storage (SCS) versus short periods of normothermic ex vivo kidney perfusion (NEVKP) after SCS versus prolonged, continuous NEVKP with near avoidance of SCS on kidney function after transplantation. Following 30 min of warm ischemia, kidneys were removed from 30-kg Yorkshire pigs and preserved for 16 h with (A) 16 h SCS, (B) 15 h SCS + 1 h NEVKP, (C) 8 h SCS + 8 h NEVKP, and (D) 16 h NEVKP. After contralateral kidney resection, grafts were autotransplanted and pigs followed up for 8 days. Perfusate injury markers such as aspartate aminotransferase and lactate dehydrogenase remained low; lactate decreased significantly until end of perfusion in groups C and D (p < 0.001 and p = 0.002). Grafts in group D demonstrated significantly lower serum creatinine peak when compared to all other groups (p < 0.001) and 24-h creatinine clearance at day 3 after surgery was significantly higher (63.4 ± 19.0 mL/min) versus all other groups (p < 0.001). Histological assessment on day 8 demonstrated fewer apoptotic cells in group D (p = 0.008). In conclusion, prolonged, continuous NEVKP provides superior short-term outcomes following DCD kidney transplantation versus SCS or short additional NEVKP following SCS.
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Affiliation(s)
- J M Kaths
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.,Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of General, Visceral, and Transplant Surgery, University Medical Center Mainz, Mainz, Germany
| | - J Y Cen
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Y M Chun
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - J Echeverri
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - I Linares
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - S Ganesh
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - P Yip
- Laboratory Medicine & Pathobiology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - R John
- Laboratory Medicine & Pathobiology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - D Bagli
- Departments of Surgery (Urology) & Physiology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - I Mucsi
- Multi Organ Transplant Program, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - A Ghanekar
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - D R Grant
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - L A Robinson
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - M Selzner
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
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Coskun A, Baykal AT, Kazan D, Akgoz M, Senal MO, Berber I, Titiz I, Bilsel G, Kilercik H, Karaosmanoglu K, Cicek M, Yurtsever I, Yazıcı C. Proteomic Analysis of Kidney Preservation Solutions Prior to Renal Transplantation. PLoS One 2016; 11:e0168755. [PMID: 28036361 PMCID: PMC5201308 DOI: 10.1371/journal.pone.0168755] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Accepted: 12/06/2016] [Indexed: 12/01/2022] Open
Abstract
One of the main issues in kidney transplantation is the optimal functional preservation of the organ until its transplantation into the appropriate recipient. Despite intensive efforts, the functional preservation period remains limited to hours. During this time, as a result of cellular injury, various proteins, peptides, and other molecules are released by the organ into the preservation medium. In this study, we used proteomic techniques to analyze the protein profiles of preservation solutions in which organs had been preserved prior to their transplantation. Samples were obtained from the preservation solutions of 25 deceased donor kidneys scheduled for transplantation. The protein profiles of the solutions were analyzed using 2D gel electrophoresis/MALDI-TOF and LC-MS/MS. We identified and quantified 206 proteins and peptides belonging to 139 different groups. Of these, 111 proteins groups were belonging to kidney tissues. This study used proteomic techniques to analyze the protein profiles of organ preservation solutions. These findings will contribute to the development of improved preservation solutions to effectively protect organs for transplantation.
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Affiliation(s)
- Abdurrahman Coskun
- Acibadem University School of Medicine, Department of Medical Biochemistry, Istanbul, Turkey
- * E-mail:
| | - Ahmet Tarik Baykal
- Acibadem University School of Medicine, Department of Medical Biochemistry, Istanbul, Turkey
| | - Dilek Kazan
- Marmara University Engineering Faculty, Department of Bioengineering, Istanbul, Turkey
| | | | | | - Ibrahim Berber
- Acibadem University School of Medicine Department of General Surgery, Istanbul, Turkey
| | - Izzet Titiz
- Haydarpasa Numune Research and Training Hospital, Department of General Surgery, Istanbul, Turkey
| | | | - Hakan Kilercik
- Yeni Yuzyil University, Gaziosmanpasa Hospital, Department of Anesthesiology, Istanbul, Turkey
| | - Kubra Karaosmanoglu
- Marmara University Engineering Faculty, Department of Bioengineering, Istanbul, Turkey
| | - Muslum Cicek
- Yeni Yuzyil University, Gaziosmanpasa Hospital, Department of Anesthesiology, Istanbul, Turkey
| | - Ilknur Yurtsever
- Istanbul Medipol University, Regenerative and Restorative Medicine Research Center, Beykoz/Istanbul, Turkey
| | - Cevat Yazıcı
- Erciyes University, School of Medicine, Department of Medical Biochemistry, Kayseri, Turkey
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Ischémie–reperfusion. Liquides de conservation et machines de perfusion en transplantation rénale. Prog Urol 2016; 26:964-976. [DOI: 10.1016/j.purol.2016.08.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 08/20/2016] [Accepted: 08/22/2016] [Indexed: 12/12/2022]
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Lifor Solution: An Alternative Preservation Solution in Small Bowel Transplantation. Gastroenterol Res Pract 2016; 2016:3925751. [PMID: 26880888 PMCID: PMC4737444 DOI: 10.1155/2016/3925751] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 08/04/2015] [Accepted: 08/11/2015] [Indexed: 01/30/2023] Open
Abstract
Background and Objectives. The intestinal mucosa is extremely sensitive to ischemia. Better intestinal preservation is the first step to improve the results of intestinal transplantation. The aim of the study is to investigate the effect of cold Lifor solution on preservation of swine small bowel. Methods. Swine ileum segments (200 cm) were allotransplanted heterotopically after 9-hour cold storage with UW solution (group 1, n = 6), with Lifor solution (group 2, n = 6), or without storage (group 3, n = 6), respectively. After cold storage, mucosal adenosine triphosphate (ATP) concentrations and histopathologic analysis after preservation were performed. At day 7 after the transplantation, intestinal absorptive function was also observed. Results. After 9 h cold preservation, pathological changes, the content of ATP in the intestinal mucosa, and the intestinal absorptive function after transplantation in group 2 were similar to those of group 1. Conclusion. The effect of cold storage of swine small bowel with Lifor solution is similar to that of UW solution. It may provide additional rationale for further exploration of Lifor as an alternative preservation solution in small bowel transplantation.
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Inhibition of High Mobility Group Box 1–Toll-Like Receptor-4 Signaling by Glycyrrhizin Contributes to the Attenuation of Cold Ischemic Injury of Liver in a Rat Model. Transplant Proc 2016; 48:191-8. [DOI: 10.1016/j.transproceed.2015.12.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 12/07/2015] [Indexed: 12/30/2022]
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Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation. Pediatr Nephrol 2015; 30:1243-54. [PMID: 25185880 DOI: 10.1007/s00467-014-2924-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 07/09/2014] [Accepted: 07/21/2014] [Indexed: 01/08/2023]
Abstract
In renal transplantation, live donor kidney grafts are associated with optimum success rates due to the shorter period of ischemia during the surgical procedure. The current shortage of donor organs for adult patients has caused a shift towards deceased donors, often with co-morbidity factors, whose organs are more sensitive to ischemia-reperfusion injury, which is unavoidable during transplantation. Donor management is pivotal to kidney graft survival through the control of the ischemia-reperfusion sequence, which is known to stimulate numerous deleterious or regenerative pathways. Although the key role of endothelial cells has been established, the complexity of the injury, associated with stimulation of different cell signaling pathways, such as unfolded protein response and cell death, prevents the definition of a unique therapeutic target. Preclinical transplant models in large animals are necessary to establish relationships and kinetics and have already contributed to the improvement of organ preservation. Therapeutic strategies using mesenchymal stem cells to induce allograft tolerance are promising advances in the treatment of the pediatric recipient in terms of reducing/withdrawing immunosuppressive therapy. In this review we focus on the different donor management strategies in kidney graft conditioning and on graft preservation consequences by highlighting the role of endothelial cells. We also propose strategies for preventing ischemia-reperfusion, such as cell therapy.
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40
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Bejaoui M, Pantazi E, Folch-Puy E, Baptista PM, García-Gil A, Adam R, Roselló-Catafau J. Emerging concepts in liver graft preservation. World J Gastroenterol 2015; 21:396-407. [PMID: 25593455 PMCID: PMC4292271 DOI: 10.3748/wjg.v21.i2.396] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 10/24/2014] [Accepted: 12/08/2014] [Indexed: 02/06/2023] Open
Abstract
The urgent need to expand the donor pool in order to attend to the growing demand for liver transplantation has obliged physicians to consider the use of suboptimal liver grafts and also to redefine the preservation strategies. This review examines the different methods of liver graft preservation, focusing on the latest advances in both static cold storage and machine perfusion (MP). The new strategies for static cold storage are mainly designed to increase the fatty liver graft preservation via the supplementation of commercial organ preservation solutions with additives. In this paper we stress the importance of carrying out effective graft washout after static cold preservation, and present a detailed discussion of the future perspectives for dynamic graft preservation using MP at different temperatures (hypothermia at 4 °C, normothermia at 37 °C and subnormothermia at 20 °C-25 °C). Finally, we highlight some emerging applications of regenerative medicine in liver graft preservation. In conclusion, this review discusses the "state of the art" and future perspectives in static and dynamic liver graft preservation in order to improve graft viability.
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Zaouali MA, Bejaoui M, Calvo M, Folch-Puy E, Pantazi E, Pasut G, Rimola A, Ben Abdennebi H, Adam R, Roselló-Catafau J. Polyethylene glycol rinse solution: an effective way to prevent ischemia-reperfusion injury. World J Gastroenterol 2014; 20:16203-16214. [PMID: 25473175 PMCID: PMC4239509 DOI: 10.3748/wjg.v20.i43.16203] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Revised: 05/02/2014] [Accepted: 06/12/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To test whether a new rinse solution containing polyethylene glycol 35 (PEG-35) could prevent ischemia-reperfusion injury (IRI) in liver grafts. METHODS Sprague-Dawley rat livers were stored in University of Wisconsin preservation solution and then washed with different rinse solutions (Ringer's lactate solution and a new rinse solution enriched with PEG-35 at either 1 or 5 g/L) before ex vivo perfusion with Krebs-Heinseleit buffer solution. We assessed the following: liver injury (transaminase levels), mitochondrial damage (glutamate dehydrogenase activity), liver function (bile output and vascular resistance), oxidative stress (malondialdehyde), nitric oxide, liver autophagy (Beclin-1 and LCB3) and cytoskeleton integrity (filament and globular actin fraction); as well as levels of metalloproteinases (MMP2 and MMP9), adenosine monophosphate-activated protein kinase (AMPK), heat shock protein 70 (HSP70) and heme oxygenase 1 (HO-1). RESULTS When we used the PEG-35 rinse solution, reduced hepatic injury and improved liver function were noted after reperfusion. The PEG-35 rinse solution prevented oxidative stress, mitochondrial damage, and liver autophagy. Further, it increased the expression of cytoprotective heat shock proteins such as HO-1 and HSP70, activated AMPK, and contributed to the restoration of cytoskeleton integrity after IRI. CONCLUSION Using the rinse solution containing PEG-35 was effective for decreasing liver graft vulnerability to IRI.
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Savier E, Granger B, Charlotte F, Cormillot N, Siksik JM, Vaillant JC, Hannoun L. Liver preservation with SCOT 15 solution decreases posttransplantation cholestasis compared with University of Wisconsin solution: a retrospective study. Transplant Proc 2014; 43:3402-7. [PMID: 22099807 DOI: 10.1016/j.transproceed.2011.09.054] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND SCOT 15 is a new solution to preserve abdominal organs for transplantation. Its principal characteristic is the use of polyethylene glycol. Herein We report our experience using SCOT 15 compared with the reference University of Wisconsin (UW) solution for hepatic transplantation. METHODS We compared 2 groups: SCOT 15 (n = 33; 2009-2010) versus UW (n = 34; 2008-2010), which were paired for cold and warm ischemic times, donor ages, and graft weights. Endpoints were biologic tests in the first 2 months after the operation. A linear mixed model was used to evaluate longitudinal changes and influences of each solution. RESULTS No primary failure was observed. At postoperative day 0, transaminase values were higher in the SCOT 15 than in the UW group: aspartate transaminase: 2,435 ± 399 vs 589 ± 83 IU/L (P < .01); alanine transaminase: ALT: 1,207 ± 191 vs 484 ± 64 IU/L (P < .05), then returned to low levels in both groups. From day 0 to 8, coagulation factors reached normal values; there was no difference between the 2 groups. Total bilirubin decreased similarly in the 2 groups. However, from the second postoperative week (W1) to W8, the SCOT 15 group showed a slow decrease in the mean values of gamma-glutamyltranspeptidase (gGT) from 233 ± 125 to 130 ± 161 IU/L, which were significantly lower than those in the UW group, where the gGT remained around 300 IU/L (P < .01). The End-Stage Liver Disease, Child-Pugh, or United Network for Organ Sharing scores, primary liver diseases, hepatitic C virus status, arterial or biliary complications, and male/female ratio, which was different in the 2 groups, did not statistically influence these results. CONCLUSIONS The main effect of cold storage of human liver using SCOT 15 compared with UW solution was to decrease cholestasis following transplantation.
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Affiliation(s)
- E Savier
- Service de Chirurgie Digestive et Hépato-Bilio-Pancréatique-Transplantation Hépatique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
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Giraud S, Codas R, Hauet T, Eugene M, Badet L. Polyethylene glycols and organ protection against I/R injury. Prog Urol 2014; 24 Suppl 1:S37-43. [DOI: 10.1016/s1166-7087(14)70062-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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García-Gil FA, Fuentes-Broto L, Albendea CD, Serrano MT, Roselló-Catafau J, Lampreave F, López-Pingarrón L, Escartín J, Soria J, Garcia JJ, Fernández-Cruz L. Evaluation of Institut Georges Lopez-1 preservation solution in pig pancreas transplantation: a pilot study. Transplantation 2014; 97:901-907. [PMID: 24646772 DOI: 10.1097/tp.0000000000000050] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Institut Georges Lopez-1 preservation solution (IGL-1) is an emerging extracellular-type electrolyte solution, low in viscosity, containing polyethylene glycol 35 as a colloid. Although IGL-1 has shown beneficial outcomes in kidney and liver preservation, this pilot study is the first to evaluate the efficacy of IGL-1 in pancreas transplantation (PT) compared with the University of Wisconsin solution (UW). METHODS Sixteen Landrace pigs underwent allogeneic PT with 16 hr of cold ischemia. Grafts were preserved with IGL-1 (n=8) or UW (n=8). No immunosuppression was administered. We analyzed graft function, the acute-phase response, and oxidative stress in the pancreatic graft monitoring membrane fluidity and lipid peroxidation. RESULTS All eight grafts with IGL-1, but only six with UW, were functioning. Graft failures with UW resulted from graft thrombosis. There were no differences between the two solutions in the number of normoglycemic days (IGL-1: 11.5 ± 6.2 versus UW: 8.5 ± 4.4 days, P=0.1357), nor in lipid peroxidation during 16-hr cold ischemia (P=0.672), or reperfusion (P=0.185), but IGL-1 prevented changes in membrane fluidity after reperfusion when compared with UW (P=0.026). CONCLUSION IGL-1 offered the same degree of safety and effectiveness as UW in our model of pig PT with 16 hr of cold ischemia.
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Affiliation(s)
- Francisco A García-Gil
- 1 Department of Surgery, University of Zaragoza, Zaragoza, Spain. 2 Department of Pharmacology and Physiology, University of Zaragoza, Zaragoza, Spain. 3 Gastroenterology and Hepatology Department, HCU Lozano Blesa, Zaragoza, Spain. 4 Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research, Spanish National Research Council, Barcelona, Spain. 5 Department of Biochemistry and Molecular Cell Biology, University of Zaragoza, Zaragoza, Spain. 6 Department of Human Anatomy and Histology, University of Zaragoza, Zaragoza, Spain. 7 Department of Pathology, HCU Lozano Blesa, Zaragoza, Spain. 8 Department of Surgery, ICMDM, Hospital Clinic, University of Barcelona, Barcelona, Spain. 9 Address correspondence to: Prof. Francisco A. García-Gil, M.D., Ph.D., Department of Surgery, University of Zaragoza, Domingo Miral, s/n, 50009, Zaragoza, Spain
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Katayama M, Tsuchiaka S, Motegi T, Miyazaki M, Yamashita T, Shimamura S, Okamura Y, Uzuka Y. High-molecular-weight polyethylene glycol enhances hypothermic storage of feline kidney cells. J Vet Med Sci 2014; 76:923-6. [PMID: 24599064 PMCID: PMC4108781 DOI: 10.1292/jvms.13-0565] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Phosphate-buffered sucrose
(PBSc) solution is effective for short-term hypothermic preservation of tissue during
feline kidney transplantation. A high-molecular-weight polyethylene glycol (35,000 Da,
PEG35) reportedly enhanced the protective effects against cold-induced tubular injuries in
animal kidney transplantation models. We investigated the ability of PBSc solution
containing PEG35 to preserve cultured feline kidney cells using in vitro
WST-8 cell proliferation assays. PEG35 significantly improved cell viability during 24 hr
of cold preservation. PBSc containing 20 g/l PEG35 achieved an effect
almost equal to that of University of Wisconsin (UW) solution, the gold standard
preservation solution used in human clinical kidney transplantation, for up to 24 hr of
preservation. Our results suggest that PBSc containing PEG35 provides an excellent medium
for graft cold storage during feline kidney transplantation.
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Affiliation(s)
- Masaaki Katayama
- Division of Small Animal Surgery, Co-Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, 3-18-8 Ueda, Morioka, Iwate 020-8550, Japan
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Zhao H, Perez JS, Lu K, George AJT, Ma D. Role of Toll-like receptor-4 in renal graft ischemia-reperfusion injury. Am J Physiol Renal Physiol 2014; 306:F801-11. [PMID: 24523386 DOI: 10.1152/ajprenal.00469.2013] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Toll-like receptor-4 (TLR-4) has been increasingly recognized as playing a critical role in the pathogenesis of ischemia-reperfusion injury (IRI) of renal grafts. This review provides a detailed overview of the new understanding of the involvement of TLR-4 in ischemia-reperfusion injury of renal grafts and its clinical significance in renal transplantation. TLR-4 not only responds to exogenous microbial motifs but can also recognize molecules which are released by stressed and necrotic cells, as well as degraded products of endogenous macromolecules. Upregulation of TLR-4 is found in tubular epithelial cells, vascular endothelial cells, and infiltrating leukocytes during renal ischemia-reperfusion injury, which is induced by massive release of endogenous damage-associated molecular pattern molecules such as high-mobility group box chromosomal protein 1. Activation of TLR-4 promotes the release of proinflammatory mediators, facilitates leukocyte migration and infiltration, activates the innate and adaptive immune system, and potentiates renal fibrosis. TLR-4 inhibition serves as the target of pharmacological agents, which could attenuate ischemia-reperfusion injury and associated delayed graft function and allograft rejection. There is evidence in the literature showing that targeting TLR-4 could improve long-term transplantation outcomes. Given the pivotal role of TLR-4 in ischemia-reperfusion injury and associated delayed graft function and allograft rejection, inhibition of TLR-4 using pharmacological agents could be beneficial for long-term graft survival.
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Affiliation(s)
- Hailin Zhao
- Anaesthetics, Pain Medicine, and Intensive Care, Dept. of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.
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Tsoulfas G, Agorastou P. Ischemia reperfusion injury and the immune system. J Surg Res 2014; 186:114-115. [PMID: 23809153 DOI: 10.1016/j.jss.2013.05.094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2013] [Revised: 05/19/2013] [Accepted: 05/24/2013] [Indexed: 02/05/2023]
Affiliation(s)
- Georgios Tsoulfas
- Department of Surgery, Aristoteleion University of Thessaloniki, Thessaloniki, Greece.
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Liparoti S, Adami R, Reverchon E. PEG micronization by supercritical assisted atomization, operated under reduced pressure. J Supercrit Fluids 2012. [DOI: 10.1016/j.supflu.2012.08.009] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Bon D, Chatauret N, Giraud S, Thuillier R, Favreau F, Hauet T. New strategies to optimize kidney recovery and preservation in transplantation. Nat Rev Nephrol 2012; 8:339-47. [DOI: 10.1038/nrneph.2012.83] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Tian T, Lindell SL, Lam M, Mangino MJ. Ezrin functionality and hypothermic preservation injury in LLC-PK1 cells. Cryobiology 2012; 65:60-7. [PMID: 22554620 DOI: 10.1016/j.cryobiol.2012.04.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2011] [Revised: 02/06/2012] [Accepted: 04/12/2012] [Indexed: 12/21/2022]
Abstract
Renal epithelial cells from donor kidneys are susceptible to hypothermic preservation injury, which is attenuated when they over express the cytoskeletal linker protein ezrin. This study was designed to characterize the mechanisms of this protection. Renal epithelial cell lines were created from LLC-PK1 cells, which expressed mutant forms of ezrin with site directed alterations in membrane binding functionality. The study used cells expressing wild type ezrin, T567A, and T567D ezrin point mutants. The A and D mutants have constitutively inactive and active membrane binding conformations, respectively. Cells were cold stored (4 °C) for 6-24 h and reperfused for 1h to simulate transplant preservation injury. Preservation injury was assessed by mitochondrial activity (WST-1) and LDH release. Cells expressing the active ezrin mutant (T567D) showed significantly less preservation injury compared to wild type or the inactive mutant (T567A), while ezrin-specific siRNA knockdown and the inactive mutant potentiated preservation injury. Ezrin was extracted and identified from purified mitochondria. Furthermore, isolated mitochondria specifically bound anti-ezrin antibodies, which were reversed with the addition of exogenous recombinant ezrin. Recombinant wild type ezrin significantly reduced the sensitivity of the mitochondrial permeability transition pore (mPTP) to calcium, suggesting ezrin may modify mitochondrial function. In conclusion, the cytoskeletal linker protein ezrin plays a significant role in hypothermic preservation injury in renal epithelia. The mechanisms appear dependent on the molecule's open configuration (traditional linker functionality) and possibly a novel mitochondrial specific role, which may include modulation of mPTP function or calcium sensitivity.
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Affiliation(s)
- Tao Tian
- Department of Surgery, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298, USA
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