scholarly journals Characterizing Autophagy in the Cold Ischemic Injury of Small Bowel Grafts: Evidence from Rat Jejunum

Metabolites ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 396
Author(s):  
Ibitamuno Caleb ◽  
Luca Erlitz ◽  
Vivien Telek ◽  
Mónika Vecsernyés ◽  
György Sétáló ◽  
...  
Keyword(s):  
Cold Storage ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Degradation Pathway ◽  
Metabolic Adaptation ◽  
Cold Ischemia ◽  
Cold Preservation ◽  
Opposite Trend ◽  
Preservation Injury ◽  
Apoptotic Damage

Cold ischemic injury to the intestine during preservation remains an unresolved issue in transplantation medicine. Autophagy, a cytoplasmic protein degradation pathway, is essential for metabolic adaptation to starvation, hypoxia, and ischemia. It has been implicated in the cold ischemia (CI) of other transplantable organs. This study determines the changes in intestinal autophagy evoked by cold storage and explores the effects of autophagy on ischemic grafts. Cold preservation was simulated by placing the small intestines of Wistar rats in an IGL-1 (Institute George Lopez) solution at 4 °C for varying periods (3, 6, 9, and 12 h). The extent of graft preservation injury (mucosal and cellular injury) and changes in autophagy were measured after each CI time. Subsequently, we determined the differences in apoptosis and preservation injury after activating autophagy with rapamycin or inhibiting it with 3-methyladenine. The results revealed that ischemic injury and autophagy were induced by cold storage. Autophagy peaked at 3 h and subsequently declined. After 12 h of storage, autophagic expression was reduced significantly. Additionally, enhanced intestinal autophagy by rapamycin was associated with less tissue, cellular, and apoptotic damage during and after the 12-h long preservation. After reperfusion, grafts with enhanced autophagy still presented with less injury. Inhibiting autophagy exhibited the opposite trend. These findings demonstrate intestinal autophagy changes in cold preservation. Furthermore, enhanced autophagy was protective against cold ischemia–reperfusion damage of the small bowels.

scholarly journals Custodiol-N Is Superior to Custodiol® Solution in Experimental Rat Uterus Preservation

2020 ◽  
Vol 21 (21) ◽  
pp. 8015
Author(s):  
Viktorija Zitkute ◽  
Mindaugas Kvietkauskas ◽  
Vygante Maskoliunaite ◽  
Bettina Leber ◽  
Diana Ramasauskaite ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Protective Role ◽  
Sprague Dawley ◽  
Cold Ischemia ◽  
Tissue Samples ◽  
Cold Preservation ◽  
Uterus Transplantation ◽  
Tissue Edema

Uterus transplantation (UTx) is the first and only available treatment for women with absolute uterine factor infertility. However, clinical application is limited by the lack of organs, ischemia/reperfusion injury, as well as immunosuppression after UTx. Several different preservation solutions are used in experimental and clinical UTx, including Custodiol® solution. Recently, the novel Custodiol-N solution was developed with superior results in organ preservation. However, the solution was not tested yet in UTx. Therefore, the aims of this study were to evaluate the effect of Custodiol-N in uterus prolonged cold preservation time (8 and 24 h), compared to Custodiol® solution. Uterus tissue samples were obtained from adult Sprague Dawley rats (n = 10/group). Cold ischemic injury was estimated by histology, including immunohistochemistry, and biochemical tissue analyses. After 8 h of cold ischemia, higher percentage of tissue edema, necrosis signs and myeloperoxidase expression, as well as lower superoxide dismutase activity were found in Custodiol® compared to Custodiol-N (p < 0.05). These differences were more pronounced after 24 h of cold preservation time (p < 0.05). This study demonstrated that Custodiol-N protects uterus grafts from cold ischemic injury better than standard Custodiol® most likely via inhibition of oxidative stress and tissue edema. It seems that iron chelators in the composition of Custodiol-N play an important protective role against cold ischemia.

Poly(ADP-ribose) polymerase and renal hypothermic preservation injury

2004 ◽  
Vol 286 (5) ◽  
pp. F838-F847 ◽  
Author(s):  
Martin J. Mangino ◽  
Mary Ametani ◽  
Csaba Szabó ◽  
James H. Southard
Keyword(s):  
Enzyme Activity ◽  
Reperfusion Injury ◽  
Cold Storage ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Synthesis Rate ◽  
Renal Tubules ◽  
Hypothermic Preservation ◽  
Preservation Injury ◽  
Parp Activity

The nuclear enzyme poly(ADP-ribose) polymerase (PARP) has been implicated in ischemia-reperfusion injury in many tissues under normothermic conditions. The purpose of this study was to determine whether PARP contributes to mechanisms of the hypothermic ischemia-reperfusion injury that occurs when kidneys are cold stored for transplantation. Cortical tissue slice PARP enzyme activity rose significantly with prolonged cold storage and was dependent on both reperfusion and preservation quality. However, prior exposure to warm ischemia abrogated this increase. PARP protein increased with cold storage but was not dependent on reperfusion. PARP enzyme activity rose quickly after reperfusion in buffer and was not different when whole blood was used. Addition of exogenous hydrogen peroxide (3 mM) to normal renal slices significantly increased PARP activity over 4 h in the cortex but not in the medulla, but the medullary basal PARP synthesis rate was five times higher than that in the cortex. However, the reactive oxygen species (ROS) inhibitors catalase (2,000 U/ml), Trolox (200 μM), and DMSO (15 mM) did not reduce reperfusion-induced PARP activity in cold-stored cortical slices. Finally, PARP inhibitors potentiated preservation injury in isolated canine proximal renal tubules. In conclusion, canine renal PARP enzyme activity rises with prolonged cold storage after reperfusion and may play a protective rather than an injurious role in hypothermic preservation for transplantation. ROS are sufficient but not necessary to activate PARP under these conditions.

Renal NG2-expressing cells have macrophage-like phenotype and facilitate renal recovery after ischemic injury

2021 ◽  
Author(s):  
Wararat Kittikulsuth ◽  
Daisuke Nakano ◽  
Kento Kitada ◽  
Norio Suzuki ◽  
Masayuki Yamamoto ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Recovery Process ◽  
Mannose Receptor ◽  
M2 Macrophage ◽  
Debris Accumulation ◽  
Cellular Debris ◽  
Brain Pericytes ◽  
Anti Inflammatory Cytokine

Pericytes play an important role in the recovery process after ischemic injury of many tissues. Brain pericytes in the peri-infarct area express macrophage markers in response to injury stimuli and are involved in neovascularization. In the kidney, nerve/glial antigen 2 (NG2)+ pericytes have been found to accumulate after renal injury. These accumulated NG2+ cells are not involved in scar formation. However, the role of accumulated NG2+ cells in injured kidneys remains unknown. Here, using a reversible ischemic reperfusion model, we found that renal NG2+ cells were increased in injured kidneys and expressed macrophage markers (CD11b or F4/80) on day 3 after reperfusion. Isolated NG2+ cells from ischemia/reperfusion (I/R) kidneys also had phagocytic activity and expressed anti-inflammatory cytokine genes, including mannose receptor and IL-10. These macrophage-like NG2+ cells did not likely differentiate into myofibroblasts because they did not increase α-SMA expression. Intravenous transfusion of renal NG2+ cells isolated from donor mice on day 3 after reperfusion into recipient mice on day 1 after I/R surgery revealed that NG2+ cell-injected mice had lower plasma blood urea nitrogen, reduced KIM-1 mRNA expression, ameliorated renal damage, and reduced cellular debris accumulation than PBS-injected mice on day 5 after reperfusion. In conclusion, these data suggest that renal NG2+ cells have an M2 macrophage-like ability and play a novel role in facilitating the recovery process after renal I/R injury.

Prolonged Mouse Cardiac Graft Cold Storage via Attenuating Ischemia-Reperfusion Injury Using a New Antioxidant-Based Preservation Solution

2016 ◽  
Vol 100 (5) ◽  
pp. 1032-1040 ◽  
Author(s):  
Songjie Cai ◽  
Naotsugu Ichimaru ◽  
Mingyi Zhao ◽  
Masayuki Fujino ◽  
Hidenori Ito ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Cold Storage ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Preservation Solution ◽  
Cardiac Graft

scholarly journals Transplantation-Induced Ischemia-Reperfusion Injury Modulates Antigen Presentation by Donor Renal CD11c+F4/80+ Macrophages through IL-1R8 Regulation

2020 ◽  
Vol 31 (3) ◽  
pp. 517-531 ◽  
Author(s):  
Sistiana Aiello ◽  
Manuel Alfredo Podestà ◽  
Pamela Y. Rodriguez-Ordonez ◽  
Francesca Pezzuto ◽  
Nadia Azzollini ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Antigen Presentation ◽  
Kidney Transplant ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cold Ischemia ◽  
Reversible Ischemia ◽  
Antigen Presenting

BackgroundIn donor kidneys subjected to ischemia-reperfusion injury during kidney transplant, phagocytes coexpressing the F4/80 and CD11c molecules mediate proinflammatory responses and trigger adaptive immunity in transplantation through antigen presentation. After injury, however, resident renal macrophages coexpressing these surface markers acquire a proreparative phenotype, which is pivotal in controlling inflammation and fibrosis. No data are currently available regarding the effects of transplant-induced ischemia-reperfusion injury on the ability of donor-derived resident renal macrophages to act as professional antigen-presenting cells.MethodsWe evaluated the phenotype and function of intragraft CD11c+F4/80+ renal macrophages after cold ischemia. We also assessed the modifications of donor renal macrophages after reversible ischemia-reperfusion injury in a mouse model of congeneic renal transplantation. To investigate the role played by IL-1R8, we conducted in vitro and in vivo studies comparing cells and grafts from wild-type and IL-R8–deficient donors.ResultsCold ischemia and reversible ischemia-reperfusion injury dampened antigen presentation by renal macrophages, skewed their polarization toward the M2 phenotype, and increased surface expression of IL-1R8, diminishing activation mediated by toll-like receptor 4. Ischemic IL-1R8–deficient donor renal macrophages acquired an M1 phenotype, effectively induced IFNγ and IL-17 responses, and failed to orchestrate tissue repair, resulting in severe graft fibrosis and aberrant humoral immune responses.ConclusionsIL-1R8 is a key regulator of donor renal macrophage functions after ischemia-reperfusion injury, crucial to guiding the phenotype and antigen-presenting role of these cells. It may therefore represent an intriguing pathway to explore with respect to modulating responses against autoantigens and alloantigens after kidney transplant.

scholarly journals A Novel Oxygen Carrier (M101) Attenuates Ischemia-Reperfusion Injuries during Static Cold Storage in Steatotic Livers

2021 ◽  
Vol 22 (16) ◽  
pp. 8542
Author(s):  
Njikem Asong-Fontem ◽  
Arnau Panisello-Rosello ◽  
Alexandre Lopez ◽  
Katsunori Imai ◽  
Franck Zal ◽  
...  
Keyword(s):  
Cold Storage ◽  
Organ Preservation ◽  
Marine Invertebrate ◽  
Ischemia Reperfusion ◽  
Oxygen Carrier ◽  
Graft Function ◽  
Ex Situ ◽  
Zucker Rats ◽  
Innovative Strategies ◽  
Lactate Levels

The combined impact of an increasing demand for liver transplantation and a growing incidence of nonalcoholic liver disease has provided the impetus for the development of innovative strategies to preserve steatotic livers. A natural oxygen carrier, HEMO2life®, which contains M101 that is extracted from a marine invertebrate, has been used for static cold storage (SCS) and has shown superior results in organ preservation. A total of 36 livers were procured from obese Zucker rats and randomly divided into three groups, i.e., control, SCS-24H and SCS-24H + M101 (M101 at 1 g/L), mimicking the gold standard of organ preservation. Ex situ machine perfusion for 2 h was used to evaluate the quality of the livers. Perfusates were sampled for functional assessment, biochemical analysis and subsequent biopsies were performed for assessment of ischemia-reperfusion markers. Transaminases, GDH and lactate levels at the end of reperfusion were significantly lower in the group preserved with M101 (p < 0.05). Protection from reactive oxygen species (low MDA and higher production of NO2-NO3) and less inflammation (HMGB1) were also observed in this group (p < 0.05). Bcl-1 and caspase-3 were higher in the SCS-24H group (p < 0.05) and presented more histological damage than those preserved with HEMO2life®. These data demonstrate, for the first time, that the addition of HEMO2life® to the preservation solution significantly protects steatotic livers during SCS by decreasing reperfusion injury and improving graft function.

scholarly journals In vitro modeling of nonhypoxic cold ischemia–reperfusion simulating lung transplantation

2009 ◽  
Vol 138 (3) ◽  
pp. 760-767 ◽  
Author(s):  
Monica Casiraghi ◽  
Jason R. Tatreau ◽  
John B. Abano ◽  
John W. Blackwell ◽  
Larry Watson ◽  
...  
Keyword(s):  
Lung Transplantation ◽  
Ischemia Reperfusion ◽  
Cold Ischemia ◽  
In Vitro Modeling

Abstract 14045: Reperfusion Therapy With Recombinant Human Relaxin (Serelaxin) Attenuates Myocardial Inflammasome Formation and Ischemic Injury in Mice via eNOS-dependent Mechanism

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Juan Valle Raleigh ◽  
Adolfo G Mauro ◽  
Carlo Marchetti ◽  
Jun He ◽  
Stefano Toldo ◽  
...  
Keyword(s):  
Infarct Size ◽  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Reperfusion Therapy ◽  
Coronary Artery Ligation ◽  
Myocardial Infarct Size ◽  
Caspase 1 ◽  
Anti Inflammatory ◽  
Dependent Mechanism

Background: The preconditioning-like infarct-sparing and anti-inflammatory effects of the peptide hormone relaxin following ischemic injury have been studied in the heart. Whether reperfusion therapy with recombinant human relaxin (serelaxin, SRLX) reduces myocardial infarct size and attenuates NLRP3 inflammasome formation/caspase-1 activation and subsequent loss of functional myocardium following ischemia/reperfusion (I/R) injury is unknown. Methods and Results: After baseline echocardiography, adult male C57BL (WT) or eNOS knockout (KO) mice underwent myocardial infarction (MI) by coronary artery ligation for 30 minutes followed by 24 h reperfusion. Mice were treated with either SRLX (10 μg/Kg; sc) or saline 5 minutes before reperfusion. SRLX improved survival at 24 h post MI in WT mice (79%) as compared with controls (42%), whereas there was no difference in survival between SRLX- and saline-treated eNOS KO mice. Moreover, SRLX significantly reduced infarct size, measured with TTC staining, and preserved LV fractional shortening (FS) and end-systolic diameter (LVESD) in WT mice as compared with controls. Interestingly, cardiac caspase-1 activity was markedly reduced in SRLX-treated mice compared with controls at 24 h post MI (Figure A-D). Genetic deletion of eNOS abolished the infarct-sparing and anti-inflammatory effects of SRLX as well as functional preservation. SRLX plasma levels were assessed 5 min. after treatment using ELISA and the results demonstrate therapeutic levels comparable to plasma relaxin during the first trimester of pregnancy (Figure E). Conclusion: Reperfusion therapy with SRLX attenuates myocardial I/R injury and NLRP3 inflammasome formation via eNOS-dependent mechanism. We propose that SRLX possesses an anti-inflammatory effect preventing caspase-1 activation and inflammatory complications following MI, which may shed some light on the mechanism behind the survival benefit observed in the RELAX-AHF trial.

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