Modeling of ischemicreperfusion injury of the liver and kidneys in the experiment: working out the methodology
B. I. Yaremin,
E. Yu. Anosova,
B. I. Kazymov,
K. F. Alekberov,
M. S. Novruzbekov,
V. A. Zuykova,
F. R. Gyul'magomedova https://doi.org/10.20340/vmi-rvz.2024.6.TX.1
Abstract
Introduction. A significant shortage of high-quality donor organs remains one of the most pressing challenges, especially when it comes to extended criteria donors or asystolic donors. The solution to this problem arises at the intersection of surgical skill, advanced biomedical technologies and a deep understanding of the mechanisms of ischemia-reperfusion injury (IRI). Objective. This study was carried out to substantiate and refine the technique of extracorporeal ex-vivo perfusion of a liver graft on an animal model using the Ex-Stream perfusion apparatus for extracorporeal oxygenation according to TU 32.50.21-002-75538036-2020 (RU holder Transbiotek LLC, St. Petersburg, Russia, manufacturer Biosoft-M LLC, Moscow, Russia). Materials and methods. The study was conducted on male pigs weighing 15–30 kg (n = 5). The study is based on the analysis of the results of hypothermic oxygenated perfusion of the liver transplant in a vivarium using a cardiopulmonary bypass apparatus. The study was conducted according to the following protocol: the donor liver was removed from the animal with the formation of a temporary venovenous bypass, pharmaco-cold preservation of the organ using the Ex-Stream apparatus and its subsequent replantation. Results. The following results were obtained in a series of 5 observations. Tissue damage markers (AST, ALT, LDH, GGTP) showed a gradual increase in their level in the perfusate over the course of ischemia. The average values of AST and ALT increased by 2-3 times, LDH - by 1.5-2 times, and GGTP - by 1.2-1.5 times compared to the initial values. The level of malondialdehyde, reflecting oxidative stress, increased by an average of 30–40% by the end of the experiment, while the level of glutathione decreased by 20–25%. Concentrations of proinflammatory cytokines (TNF-α, IL-6, IL-1β) in the perfusate increased 2–4 times compared to baseline values, indicating the development of an inflammatory response. Microscopic examination with hematoxylin and eosin staining revealed signs of ischemic damage to hepatocytes, such as cytoplasmic vacuolization, nuclear pyknosis, and disruption of the beam structure. The degree of damage increased with increasing ischemia time. Mason staining showed a moderate increase in connective tissue in the portal tracts and pericentral zones, indicating initial fibrotic changes. Ultramicroscopic examination (transmission electron microscopy) revealed swelling of mitochondria, disruption of the integrity of their cristae, expansion of the endoplasmic reticulum and formation of autophagosomes in hepatocytes. Oxygen consumption by liver tissue gradually decreased during the experiment, reaching 60-70% of the initial level by the end of the observation. Carbon dioxide production also decreased, but to a lesser extent, amounting to 75-85% of the baseline values. Analysis of the perfusate using a potentiostat-galvanostat IPS showed a gradual decrease in the oxidation-reduction potential, indicating an increase in hypoxia and depletion of antioxidant reserves. The activity of superoxide dismutase and catalase, key antioxidant enzymes, decreased by 30-40% and 20- 30%, respectively, compared with the initial values, indicating a weakening of the antioxidant defense. Conclusion. The obtained results indicate that the developed model using the Ex-Stream device is reproducible and allows for effective study of the state of ischemia-reperfusion injury. This opens up opportunities for conducting a larger and more comprehensive series of experiments, the results of which will be the subject of our further research.
Keywords
Трансплантация печени / Liver Transplantation MeSH: D016092 / D016092,
Ишемически-реперфузионное повреждение / Ischemia-Reperfusion Injury MeSH: Д054058 / D015427,
Гипотермия / Hypothermia – Д006955 / D007035,
Перфузия / Perfusion – Д010490 / D010490,
Трансплантация органов / Organ Transplantation – Д016177 / D016177,
Периферическое сосудистое сопротивление / Peripheral Vascular Resistance MeSH: Д020293 / D020293,
Свиная модель / Porcine Model MeSH: Д053124 / D053124
Supporting agencies: This study was conducted with the support of a grant "Application of Various Protocols of Perfusion Preservation in Kidney and Liver Transplantation" (Grant No. 2312-15/22, dated March 25, 2022) from the non-profit organization "Moscow Center for Innovative Technologies in Healthcare".
About the Authors
B. I. Yaremin
N.V. Sklifosovsky Research Institute of Emergency Medicine;
Moscow Medical University "Reaviz"
Russian Federation
Competing Interests:
Russian Federation
Boris I. Yaremin, Cand. Sci. (Med.), Surgeon, Researcher at the Liver Transplantation Center; Associate Professor of the Department of Transplantology and Artificial Organs; Head of the Department of Surgical Diseases
3, Bolshaya Sukharevskaya Square, Moscow, 129090;
2, Krasnobogatyrskaya st., building 2, Moscow, 107564
Competing Interests:
The authors declare the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Boris Yaremin, who serves as the Executive Secretary of the Editorial Board, and Ekaterina Anosova, who acts as the Scientific Editor of the journal, are co-authors of this scientific work. To ensure an unbiased review process and maintain the integrity of the double-blind peer review, these authors were not involved in the evaluation, decision-making, or any other aspect of the manuscript handling process. The manuscript was independently reviewed by external experts who have no affiliation with the journal's editorial board or the authors of the work. The final decision regarding publication was made by the Editor-in-Chief based on the recommendations provided by the independent reviewers and in accordance with the journal's standard criteria for assessing scientific merit, originality, and quality of the submitted work.
E. Yu. Anosova
N.V. Sklifosovsky Research Institute of Emergency Medicine
Russian Federation
Competing Interests:
Russian Federation
Ekaterina Yu. Anosova, Clinical resident of the liver transplantation Center
3, Bolshaya Sukharevskaya Square, Moscow, 129090
Competing Interests:
The authors declare the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Boris Yaremin, who serves as the Executive Secretary of the Editorial Board, and Ekaterina Anosova, who acts as the Scientific Editor of the journal, are co-authors of this scientific work. To ensure an unbiased review process and maintain the integrity of the double-blind peer review, these authors were not involved in the evaluation, decision-making, or any other aspect of the manuscript handling process. The manuscript was independently reviewed by external experts who have no affiliation with the journal's editorial board or the authors of the work. The final decision regarding publication was made by the Editor-in-Chief based on the recommendations provided by the independent reviewers and in accordance with the journal's standard criteria for assessing scientific merit, originality, and quality of the submitted work.
B. I. Kazymov
N.V. Sklifosovsky Research Institute of Emergency Medicine;
Moscow Medical University "Reaviz"
Russian Federation
Competing Interests:
Russian Federation
Bakhtiyar I. Kazymov, Surgeon, researcher at the Liver Transplantation Center; Assistant of the Department of Surgical Diseases
3, Bolshaya Sukharevskaya Square, Moscow, 129090;
2, Krasnobogatyrskaya st., building 2, Moscow, 107564
Competing Interests:
The authors declare the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Boris Yaremin, who serves as the Executive Secretary of the Editorial Board, and Ekaterina Anosova, who acts as the Scientific Editor of the journal, are co-authors of this scientific work. To ensure an unbiased review process and maintain the integrity of the double-blind peer review, these authors were not involved in the evaluation, decision-making, or any other aspect of the manuscript handling process. The manuscript was independently reviewed by external experts who have no affiliation with the journal's editorial board or the authors of the work. The final decision regarding publication was made by the Editor-in-Chief based on the recommendations provided by the independent reviewers and in accordance with the journal's standard criteria for assessing scientific merit, originality, and quality of the submitted work.
K. F. Alekberov
N.V. Sklifosovsky Research Institute of Emergency Medicine
Russian Federation
Competing Interests:
Russian Federation
Kyamran F. Alekberov, Surgeon, researcher at the Liver Transplantation Center, N.V. Sklifosovsky Research Institute of Emergency MedicineKyamran F. Alekberov Surgeon, researcher at the Liver Transplantation Center
3, Bolshaya Sukharevskaya Square, Moscow, 129090
Competing Interests:
The authors declare the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Boris Yaremin, who serves as the Executive Secretary of the Editorial Board, and Ekaterina Anosova, who acts as the Scientific Editor of the journal, are co-authors of this scientific work. To ensure an unbiased review process and maintain the integrity of the double-blind peer review, these authors were not involved in the evaluation, decision-making, or any other aspect of the manuscript handling process. The manuscript was independently reviewed by external experts who have no affiliation with the journal's editorial board or the authors of the work. The final decision regarding publication was made by the Editor-in-Chief based on the recommendations provided by the independent reviewers and in accordance with the journal's standard criteria for assessing scientific merit, originality, and quality of the submitted work.
M. S. Novruzbekov
N.V. Sklifosovsky Research Institute of Emergency Medicine;
Moscow Medical University "Reaviz"
Russian Federation
Competing Interests:
Russian Federation
Murad S. Novruzbekov, Dr. Sci. (Med.), Professor, Scientific Director of the Liver Transplantation Center; Head of the Department of Transplantology and Artificial Organs; Professor of the Department of Surgical Diseases
3, Bolshaya Sukharevskaya Square, Moscow, 129090;
2, Krasnobogatyrskaya st., building 2, Moscow, 107564
Competing Interests:
The authors declare the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Boris Yaremin, who serves as the Executive Secretary of the Editorial Board, and Ekaterina Anosova, who acts as the Scientific Editor of the journal, are co-authors of this scientific work. To ensure an unbiased review process and maintain the integrity of the double-blind peer review, these authors were not involved in the evaluation, decision-making, or any other aspect of the manuscript handling process. The manuscript was independently reviewed by external experts who have no affiliation with the journal's editorial board or the authors of the work. The final decision regarding publication was made by the Editor-in-Chief based on the recommendations provided by the independent reviewers and in accordance with the journal's standard criteria for assessing scientific merit, originality, and quality of the submitted work.
V. A. Zuykova
Pirogov Russian National Research Medical University
Russian Federation
Competing Interests:
Russian Federation
Victoriya A. Zuykova, 6th year student of the medical faculty
1 Ostrovityanova St., Moscow, 117513
Competing Interests:
The authors declare the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Boris Yaremin, who serves as the Executive Secretary of the Editorial Board, and Ekaterina Anosova, who acts as the Scientific Editor of the journal, are co-authors of this scientific work. To ensure an unbiased review process and maintain the integrity of the double-blind peer review, these authors were not involved in the evaluation, decision-making, or any other aspect of the manuscript handling process. The manuscript was independently reviewed by external experts who have no affiliation with the journal's editorial board or the authors of the work. The final decision regarding publication was made by the Editor-in-Chief based on the recommendations provided by the independent reviewers and in accordance with the journal's standard criteria for assessing scientific merit, originality, and quality of the submitted work.
F. R. Gyul'magomedova
Sechenov First Moscow State Medical University (Sechenov University)
Russian Federation
Competing Interests:
Russian Federation
Fatimat Ruslanovna Gyulmagomedov, 6th year student of the medical faculty of the N.V. Sklifosovsky Institute of Clinical Medicine
8 Trubetskaya St., Bldg. 2, Moscow, 11904
Competing Interests:
The authors declare the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Boris Yaremin, who serves as the Executive Secretary of the Editorial Board, and Ekaterina Anosova, who acts as the Scientific Editor of the journal, are co-authors of this scientific work. To ensure an unbiased review process and maintain the integrity of the double-blind peer review, these authors were not involved in the evaluation, decision-making, or any other aspect of the manuscript handling process. The manuscript was independently reviewed by external experts who have no affiliation with the journal's editorial board or the authors of the work. The final decision regarding publication was made by the Editor-in-Chief based on the recommendations provided by the independent reviewers and in accordance with the journal's standard criteria for assessing scientific merit, originality, and quality of the submitted work.
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For citations:
Yaremin B.I., Anosova E.Yu., Kazymov B.I., Alekberov K.F., Novruzbekov M.S., Zuykova V.A., Gyul'magomedova F.R. Modeling of ischemicreperfusion injury of the liver and kidneys in the experiment: working out the methodology. Bulletin of the Medical Institute "REAVIZ" (REHABILITATION, DOCTOR AND HEALTH). 2024;14(6):159-170. (In Russ.) https://doi.org/10.20340/vmi-rvz.2024.6.TX.1
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