Nitric oxide protects intestinal mucosal barrier function and prevents acute graft rejection after intestinal transplantation: A mini-review.

Intestinal transplantation is a complex technical procedure that provides patients suffering from end-stage intestinal failure an opportunity to enjoy improved quality of life, nutrition and survival. Compared to other types of organ transplants, it is a relatively new advancement in the field of organ transplantation. Nevertheless, great advances have been made over the past few decades to the present era, including the use of ischemic preconditioning, gene therapy, and addition of pharmacological supplements to preservation solutions. However, despite these strides, intestinal transplantation is still a challenging endeavor due to several factors. Notable among them is ischemia-reperfusion injury (IRI), which results in loss of cellular integrity and mucosal barrier function. In addition, IRI causes graft failure, delayed graft function, and decreased graft and recipient survival. This has necessitated the search for novel therapeutic avenues and improved transplantation protocols to prevent or attenuate intestinal IRI. Among the many candidate agents that are being investigated to combat IRI and its associated complications, nitric oxide (NO). NO is an endogenously produced gaseous signaling molecule with several therapeutic properties. The purpose of this mini-review is to discuss IRI and its related complications in intestinal transplantation, and NO as an emerging pharmacological tool against this challenging pathological condition. i.

Comparative Analysis of Ischemia-Reperfusion Injury in Heart Transplantation: A Single-Center Study Evaluating Conventional Ice-Cold Storage versus the Paragonix SherpaPak Cardiac Transport System.

BACKGROUND: Since the 2018 allocation system change in heart transplantation (HT), ischemic times have increased, which may be associated with peri-operative and post-operative complications. This study aimed to compare ischemia reperfusion injury (IRI) in hearts preserved using ice-cold storage (ICS) and the Paragonix SherpaPak TM Cardiac Transport System (CTS). METHODS: From January 2021 to June 2022, consecutive endomyocardial biopsies from 90 HT recipients were analyzed by a cardiac pathologist in a single-blinded manner: 33 ICS and 57 CTS. Endomyocardial biopsies were performed at three-time intervals post-HT, and the severity of IRI manifesting histologically as coagulative myocyte necrosis (CMN) was evaluated, along with graft rejection and graft function. RESULTS: The incidence of IRI at weeks 1, 4, and 8 post-HT were similar between the ICS and CTS groups. There was a 59.3% statistically significant reduction in CMN from week 1 to 4 with CTS, but not with ICS. By week 8, there were significant reductions in CMN in both groups. Only 1 out of 33 (3%) patients in the ICS group had an ischemic time >240 mins, compared to 10 out of 52 (19%) patients in the CTS group. During the follow-up period of 8 weeks to 12 months, there were no significant differences in rejection rates, formation of de novo donor-specific antibodies and overall survival between the groups. CONCLUSION: The CTS preservation system had similar rates of IRI and clinical outcomes compared to ICS despite longer overall ischemic times. There is significantly more recovery of IRI in the early post operative period with CTS. This study supports CTS as a viable option for preservation from remote locations, expanding the donor pool.

Cellular and molecular mechanisms of cell damage and cell death in ischemia-reperfusion injury in organ transplantation.

Ischemia-reperfusion injury (IRI) is a critical pathological condition in which cell death plays a major contributory role, and negatively impacts post-transplant outcomes. At the cellular level, hypoxia due to ischemia disturbs cellular metabolism and decreases cellular bioenergetics through dysfunction of mitochondrial electron transport chain, causing a switch from cellular respiration to anaerobic metabolism, and subsequent cascades of events that lead to increased intracellular concentrations of Na+, H+ and Ca2+ and consequently cellular edema. Restoration of blood supply after ischemia provides oxygen to the ischemic tissue in excess of its requirement, resulting in over-production of reactive oxygen species (ROS), which overwhelms the cells' antioxidant defence system, and thereby causing oxidative damage in addition to activating pro-inflammatory pathways to cause cell death. Moderate ischemia and reperfusion may result in cell dysfunction, which may not lead to cell death due to activation of recovery systems to control ROS production and to ensure cell survival. However, prolonged and severe ischemia and reperfusion induce cell death by apoptosis, mitoptosis, necrosis, necroptosis, autophagy, mitophagy, mitochondrial permeability transition (MPT)-driven necrosis, ferroptosis, pyroptosis, cuproptosis and parthanoptosis. This review discusses cellular and molecular mechanisms of these various forms of cell death in the context of organ transplantation, and their inhibition, which holds clinical promise in the quest to prevent IRI and improve allograft quality and function for a long-term success of organ transplantation.

Evaluating the Effects of Kidney Preservation at 10 °C with Hemopure and Sodium Thiosulfate in a Rat Model of Syngeneic Orthotopic Kidney Transplantation.

Kidney transplantation is preferred for end-stage renal disease. The current gold standard for kidney preservation is static cold storage (SCS) at 4 °C. However, SCS contributes to renal graft damage through ischemia-reperfusion injury (IRI). We previously reported renal graft protection after SCS with a hydrogen sulfide donor, sodium thiosulfate (STS), at 4 °C. Therefore, this study aims to investigate whether SCS at 10 °C with STS and Hemopure (blood substitute), will provide similar protection. Using in vitro model of IRI, we subjected rat renal proximal tubular epithelial cells to hypoxia-reoxygenation for 24 h at 10 °C with or without STS and measured cell viability. In vivo, we preserved 36 donor kidneys of Lewis rats for 24 h in a preservation solution at 10 °C supplemented with STS, Hemopure, or both followed by transplantation. Tissue damage and recipient graft function parameters, including serum creatinine, blood urea nitrogen, urine osmolality, and glomerular filtration rate (GFR), were evaluated. STS-treated proximal tubular epithelial cells exhibited enhanced viability at 10 °C compared with untreated control cells (p < 0.05). Also, STS and Hemopure improved renal graft function compared with control grafts (p < 0.05) in the early time period after the transplant, but long-term function did not reach significance. Overall, renal graft preservation at 10 °C with STS and Hemopure supplementation has the potential to enhance graft function and reduce kidney damage, suggesting a novel approach to reducing IRI and post-transplant complications.

Empagliflozin activates JAK2/STAT3 signaling and protects cardiomyocytes from hypoxia/reoxygenation injury under high glucose conditions.

The morbidity and mortality rates of cardiovascular disease are markedly higher in patients with diabetes than in non-diabetic patients, including patients with ischemia-reperfusion injury (IRI). However, the cardiovascular protective effects of Empagliflozin (EMPA) on IRI in diabetes mellitus have rarely been studied. In this study, we established a cardiomyocyte hypoxia/reoxygenation (H/R) injury model to mimic myocardial I/R injuries that occur in vivo. H9C2 cells were subjected to high glucose (HG) treatment plus H/R injury to mimic myocardial I/R injuries that occur in diabetes mellitus. Next, different concentrations of EMPA were added to the H9C2 cells and its protective effect was detected. STAT3 knockdown with recombinant plasmids was used to determine its roles. Our results showed that H/R injury-induced cell apoptosis, necroptosis, oxidative stress, and endoplasmic reticulum stress were further promoted by HG conditions, and HG treatment plus an H/R injury inhibited the activation of JAK2/STAT3 signaling. EMPA was found to protect against H/R-induced cardiomyocyte injury under HG conditions and activate JAK2/STAT3 signaling, while down-regulation of STAT3 reversed the protective effect of EMPA. When taken together, these findings indicate that EMPA protects against I/R-induced cardiomyocyte injury by activating JAK2/STAT3 signaling under HG conditions. Our results clarified the mechanisms that underlie the cardiovascular protective effects of EMPA in diabetes mellitus and provide new therapeutic targets for IRI in diabetes mellitus.

Pre-Treatment of Transplant Donors with Hydrogen Sulfide to Protect against Warm and Cold Ischemia-Reperfusion Injury in Kidney and Other Transplantable Solid Organs.

Ischemia-reperfusion injury (IRI), a pathological condition resulting from prolonged cessation and subsequent restoration of blood flow to a tissue, is an inevitable consequence of solid organ transplantation. Current organ preservation strategies, such as static cold storage (SCS), are aimed at reducing IRI. However, prolonged SCS exacerbates IRI. Recent research has examined pre-treatment approaches to more effectively attenuate IRI. Hydrogen sulfide (H2S), the third established member of a family of gaseous signaling molecules, has been shown to target the pathophysiology of IRI and thus appears to be a viable candidate that can overcome the transplant surgeon's enemy. This review discusses pre-treatment of renal grafts and other transplantable organs with H2S to mitigate transplantation-induced IRI in animal models of transplantation. In addition, ethical principles of pre-treatment and potential applications of H2S pre-treatment in the prevention of other IRI-associated conditions are discussed.

Static Cold Storage with Mitochondria-Targeted Hydrogen Sulfide Donor Improves Renal Graft Function in an Ex Vivo Porcine Model of Controlled Donation-after-Cardiac-Death Kidney Transplantation.

The global donor kidney shortage crisis has necessitated the use of suboptimal kidneys from donors-after-cardiac-death (DCD). Using an ex vivo porcine model of DCD kidney transplantation, the present study investigates whether the addition of hydrogen sulfide donor, AP39, to University of Wisconsin (UW) solution improves graft quality. Renal pedicles of male pigs were clamped in situ for 30 min and the ureters and arteries were cannulated to mimic DCD. Next, both donor kidneys were nephrectomized and preserved by static cold storage in UW solution with or without AP39 (200 nM) at 4 °C for 4 h followed by reperfusion with stressed autologous blood for 4 h at 37 °C using ex vivo pulsatile perfusion apparatus. Urine and arterial blood samples were collected hourly during reperfusion. After 4 h of reperfusion, kidneys were collected for histopathological analysis. Compared to the UW-only group, UW+AP39 group showed significantly higher pO2 (p < 0.01) and tissue oxygenation (p < 0.05). Also, there were significant increases in urine production and blood flow rate, and reduced levels of urine protein, serum creatinine, blood urea nitrogen, plasma Na+ and K+, as well as reduced intrarenal resistance in the UW+AP39 group compared to the UW-only group. Histologically, AP39 preserved renal structure by reducing the apoptosis of renal tubular cells and immune cell infiltration. Our finding could lay the foundation for improved graft preservation and reduce the increasingly poor outcomes associated with DCD kidney transplantation.

Connexins in endothelial cells as a therapeutic target for solid organ transplantation.

Connexins are a class of membrane proteins widely distributed throughout the body and have various functions based on their location and levels of expression. More specifically, connexin proteins expressed in endothelial cells (ECs) have unique roles in maintaining EC barrier integrity and function-a highly regulated process that is critical for pro-inflammatory and pro-coagulant reactions. In this minireview, we discuss the regulatory influence connexin proteins have in maintaining EC barrier integrity and their role in ischemia-reperfusion injury as it relates to organ transplantation. It is evident that certain isoforms of the connexin protein family are uniquely positioned to have far-reaching effects on preserving organ function; however, there is still much to be learned of their roles in transplant immunology and the application of this knowledge to the development of targeted therapeutics.

A biocompatible nanoparticle-based approach to inhibiting renal ischemia reperfusion injury in mice by blocking thrombospondin-1 activity.

Thrombospondin-1 (TSP-1) is a key mediator of renal ischemia-reperfusion injury (IRI), a major cause of kidney dysfunction under various disease conditions and a risk factor of renal allograft rejection. In this study, we developed a nanotechnology-based therapy targeting TSP-1 to prevent renal IRI. A biocompatible nanoparticle (NP) capable of specific binding to TSP-1 was prepared by conjugating NPs with TSP-1-binding (LSKL) peptides. LSKL/NPs not only effectively adsorbed recombinant TSP-1 proteins in vitro, but also efficiently neutralized TSP-1 in mice undergoing renal IRI. IRI-induced elevation of TSP-1 in the kidney was significantly inhibited by post-IR treatment with LSKL/NPs, but not free LSKL or NPs. Furthermore, TSP-1 proteins adsorbed on LSKL/NPs were functionally inactive and unable to induce apoptosis in renal tubular epithelial cells. Importantly, LSKL/NPs induced strong protection against renal IRI, as shown by markedly diminished serum creatinine levels and improved histological lesions of the kidney. Thus, LSKL/NPs provide a useful means of depleting and inactivating TSP-1 and a potential therapy for renal IRI.

Prolonged preservation by hypothermic machine perfusion facilitates logistics in liver transplantation: A European observational cohort study.

A short period (1-2 h) of hypothermic oxygenated machine perfusion (HOPE) after static cold storage is safe and reduces ischemia-reperfusion injury-related complications after liver transplantation. Machine perfusion time is occasionally prolonged for logistical reasons, but it is unknown if prolonged HOPE is safe and compromises outcomes. We conducted a multicenter, observational cohort study of patients transplanted with a liver preserved by prolonged (≥4 h) HOPE. Postoperative biochemistry, complications, and survival were evaluated. The cohort included 93 recipients from 12 European transplant centers between 2014-2021. The most common reason to prolong HOPE was the lack of an available operating room to start the transplant procedure. Grafts underwent HOPE for a median (range) of 4:42 h (4:00-8:35 h) with a total preservation time of 10:50 h (5:50-20:50 h). Postoperative peak ALT was 675 IU/L (interquartile range 419-1378 IU/L). The incidence of postoperative complications was low, and 1-year graft and patient survival were 94% and 88%, respectively. To conclude, good outcomes are achieved after transplantation of donor livers preserved with prolonged (median 4:42 h) HOPE, leading to a total preservation time of almost 21 h. These results suggest that simple, end-ischemic HOPE may be utilized for safe extension of the preservation time to ease transplantation logistics.

The current status of stem cell-based therapies during ex vivo graft perfusion: An integrated review of four organs.

The use of extended criteria donor grafts is a promising strategy to increase the number of organ transplantations and reduce waitlist mortality. However, these organs are often compromised and/or damaged, are more susceptible to preservation injury, and are at risk for developing post-transplant complications. Ex vivo organ perfusion is a novel technology to preserve donor organs while providing oxygen and nutrients at distinct perfusion temperatures. This preservation method allows to resuscitate grafts and optimize function with therapeutic interventions prior to solid organ transplantation. Stem cell-based therapies are increasingly explored for their ability to promote regeneration and reduce the inflammatory response associated with in vivo reperfusion. The aim of this review is to describe the current state of stem cell-based therapies during ex vivo organ perfusion for the kidney, liver, lung, and heart. We discuss different strategies, including type of cells, route of administration, mechanisms of action, efficacy, and safety. The progress made within lung transplantation justifies the initiation of clinical trials, whereas more research is likely required for the kidney, liver, and heart to progress into clinical application. We emphasize the need for standardization of methodology to increase comparability between future (clinical) studies.

Abdominal normothermic regional perfusion in controlled donation after circulatory determination of death liver transplantation: Outcomes and risk factors for graft loss.

Postmortem normothermic regional perfusion (NRP) is a rising preservation strategy in controlled donation after circulatory determination of death (cDCD). Herein, we present results for cDCD liver transplants performed in Spain 2012-2019, with outcomes evaluated through December 31, 2020. Results were analyzed retrospectively and according to recovery technique (abdominal NRP [A-NRP] or standard rapid recovery [SRR]). During the study period, 545 cDCD liver transplants were performed with A-NRP and 258 with SRR. Median donor age was 59 years (interquartile range 49-67 years). Adjusted risk estimates were improved with A-NRP for overall biliary complications (OR 0.300, 95% CI 0.197-0.459, p < .001), ischemic type biliary lesions (OR 0.112, 95% CI 0.042-0.299, p < .001), graft loss (HR 0.371, 95% CI 0.267-0.516, p < .001), and patient death (HR 0.540, 95% CI 0.373-0.781, p = .001). Cold ischemia time (HR 1.004, 95% CI 1.001-1.007, p = .021) and re-transplantation indication (HR 9.552, 95% CI 3.519-25.930, p < .001) were significant independent predictors for graft loss among cDCD livers with A-NRP. While use of A-NRP helps overcome traditional limitations in cDCD liver transplantation, opportunity for improvement remains for cases with prolonged cold ischemia and/or technically complex recipients, indicating a potential role for complimentary ex situ perfusion preservation techniques.

MicroRNA antagonist therapy during normothermic machine perfusion of donor kidneys.

Normothermic machine perfusion (NMP) is a novel clinical approach to overcome the limitations of traditional hypothermic organ preservation. NMP can be used to assess and recondition organs prior to transplant and is the subject of clinical trials in solid organ transplantation. In addition, NMP provides an opportunity to deliver therapeutic agents directly to the organ, thus avoiding many limitations associated with systemic treatment of the recipient. We report the delivery of oligonucleotide-based therapy to human kidneys during NMP, in this case to target microRNA function (antagomir). An antagomir targeting mir-24-3p localized to the endothelium and proximal tubular epithelium. Endosomal uptake during NMP conditions facilitated antagomir co-localization with proteins involved in the RNA-induced silencing complex (RISC) and demonstrated engagement of the miRNA target. This pattern of uptake was not seen during cold perfusion. Targeting mir-24-3p action increased expression of genes controlled by this microRNA, including heme oxygenase-1 and sphingosine-1-phosphate receptor 1. The expression of genes not under the control of mir-24-3p was unchanged, indicating specificity of the antagomir effect. In summary, this is the first report of ex vivo gymnotic delivery of oligonucleotide to the human kidney and demonstrates that NMP provides the platform to bind and block detrimental microRNAs in donor kidneys prior to transplantation.

Modulating donor mitochondrial fusion/fission delivers immunoprotective effects in cardiac transplantation.

Early insults associated with cardiac transplantation increase the immunogenicity of donor microvascular endothelial cells (ECs), which interact with recipient alloreactive memory T cells and promote responses leading to allograft rejection. Thus, modulating EC immunogenicity could potentially alter T cell responses. Recent studies have shown modulating mitochondrial fusion/fission alters immune cell phenotype. Here, we assess whether modulating mitochondrial fusion/fission reduces EC immunogenicity and alters EC-T cell interactions. By knocking down DRP1, a mitochondrial fission protein, or by using the small molecules M1, a fusion promoter, and Mdivi1, a fission inhibitor, we demonstrate that promoting mitochondrial fusion reduced EC immunogenicity to allogeneic CD8+ T cells, shown by decreased T cell cytotoxic proteins, decreased EC VCAM-1, MHC-I expression, and increased PD-L1 expression. Co-cultured T cells also displayed decreased memory frequencies and Ki-67 proliferative index. For in vivo significance, we used a novel murine brain-dead donor transplant model. Balb/c hearts pretreated with M1/Mdivi1 after brain-death induction were heterotopically transplanted into C57BL/6 recipients. We demonstrate that, in line with our in vitro studies, M1/Mdivi1 pretreatment protected cardiac allografts from injury, decreased infiltrating T cell production of cytotoxic proteins, and prolonged allograft survival. Collectively, our data show promoting mitochondrial fusion in donor ECs mitigates recipient T cell responses and leads to significantly improved cardiac transplant survival.

Augmenter of liver regeneration-mediated mitophagy protects against hepatic ischemia/reperfusion injury.

Augmenter of liver regeneration (ALR) is an anti-apoptotic protein found mainly in mitochondria. It protects hepatocytes from ischemia-reperfusion (I/R) injury, but the underlying mechanism is not clear. We found that in rats, delivery of the ALR gene alleviated hepatic I/R injury during orthotopic liver transplantation as evidenced by reduced serum aminotransferase, oxidative stress and apoptosis, and increased expression of autophagy markers. In an in vitro hypoxia/reoxygenation (H/R) model, overexpression of the ALR gene activated autophagy and relieved defective mitophagy via the PINK1/Parkin pathway. Mechanistically, ALR transfection induced the expression of mitofusin 2 (Mfn2) in the H/R model, which led to PINK1 accumulation and mitochondrial translocation of Parkin. Deletion of Mfn2 abolished mitophagy activation induced by ALR transfection, promoted mitochondrial dysfunction, and eventually increased cell apoptosis. Mfn2 administration prevented the inhibition of mitophagy in ALR-knockout (KO) cells, thus attenuated mitochondrial dysfunction and cell apoptosis. In heterozygous ALR-knockout mice treated with a warm I/R injury, marked aggravation of liver injury was associated with mitophagy inhibition and reduction in Mfn2 expression. Taken together, our results confirm that ALR accelerated Parkin translocation and mitophagy via Mfn2, and protected hepatocytes from I/R-induced injury. Our findings provide a novel rationale for the treatment of hepatic I/R injury.

NRF2 assessment in discarded liver allografts: A role in allograft function and salvage.

Antioxidant defence mechanisms, such as the nuclear factor-erythroid 2-related-factor-2 (NRF2) axis, are integral to oxidative stress responses and ischemic injury. Hepatic antioxidant capacity is contingent on parenchymal quality, and there is a need to develop new insights into key molecular mechanisms in marginal liver allografts that might provide therapeutic targets. This study examines the clinical relevance of NRF2 in donor livers and its response to normothermic machine perfusion (NMP). Discarded donor livers (n = 40) were stratified into a high NRF2 and low NRF2 group by quantifying NRF2 expression. High NRF2 livers had significantly lower transaminase levels, hepatic vascular inflammation and peri-portal CD3+ T cell infiltration. Human liver allografts (n = 8) were then exposed to 6-h of NMP and high NRF2 livers had significantly reduced liver enzyme alterations and improved lactate clearance. To investigate these findings further, we used a rat fatty-liver model, treating livers with an NRF2 agonist during NMP. Treated livers had increased NRF2 expression and reduced transaminase derangements following NMP compared to vehicle control. These results support the association of elevated NRF2 expression with improved liver function. Targeting this axis could have a rationale in future studies and NRF2 agonists may represent a supplemental treatment strategy for rescuing marginal donor livers.

Single cell sequencing coupled with bioinformatics reveals PHYH as a potential biomarker in kidney ischemia reperfusion injury.

Ischemia reperfusion injury(IRI) is an important factor affecting the early function and long-term survival of transplanted kidney. Single cell RNA sequencing (scRNA-seq) is a powerful method for investigating cell-specific transcriptome changes in the kidney. This study aimed to identify the significant cell type and potential biomarkers in IRI. First, we downloaded the IRI related scRNA dataset GSE139506 from the GEO database. Then, classification of cell type was characterized and proximal tubule cell (PTC) was identified as a significant cell type. The functional enrichment analysis indicated that PTC were related to kidney function and is significant in the ferroptosis of IRI. Analyses of three-dimensional structure and iron binding substructure of protein was carried out basing on SWISS-MODEL database. Finally, we constructed the murine model with IRI and verify the higher expression of PHYH in IRI by PCR, Western blot (WB) and Immunohistochemistry (IHC) experiments. In conclusion, this study provided novel insights on the cell-type-specific expression gene biomarker in IRI pathogenesis.

Decay-Accelerating Factor Creates an Organ-Protective Phenotype after Hemorrhage in Conscious Rats.

Preclinical and clinical studies have shown that traumatic hemorrhage (TH) induces early complement cascade activation, leading to inflammation-associated multiple-organ dysfunction syndrome (MODS). Several previous studies have demonstrated the beneficial effects of complement inhibition in anesthetized (unconscious) animal models of hemorrhage. Anesthetic agents profoundly affect the immune response, microcirculation response, and coagulation patterns and thereby may confound the TH research data acquired. However, no studies have addressed the effect of complement inhibition on inflammation-driven MODS in a conscious model of hemorrhage. This study investigated whether early administration of decay-accelerating factor (CD55/DAF, a complement C3/C5 inhibitor) alleviates hemorrhage-induced organ damage and how DAF modulates hemorrhage-induced organ damage. DAF was administered to unanesthetized male Sprague Dawley rats subjected to pressure-controlled hemorrhage followed by a prolonged (4 h) hypotensive resuscitation with or without lactated Ringer's (LR). We assessed DAF effects on organ protection, tissue levels of complement synthesis and activation, T lymphocyte infiltration, fluid resuscitation requirements, and metabolic acidosis. Hemorrhage with (HR) or without (H) LR resuscitation resulted in significantly increased C3, C5a, and C5b-9 deposition in the lung and intestinal tissues. HR rats had significantly higher tissue levels of complement activation/deposition (particularly C5a and C5b-9 in the lung tissues), a higher but not significant amount of C3 and C5b-9 pulmonary microvascular deposition, and relatively severe injury in the lung and intestinal tissues compared to H rats. DAF treatment significantly reduced tissue C5b-9 formation and C3 deposition in the H or HR rats and decreased tissue levels of C5a and C3 mRNA in the HR rats. This treatment prevented the injury of these organs, improved metabolic acidosis, reduced fluid resuscitation requirements, and decreased T-cell infiltration in lung tissues. These findings suggest that DAF has the potential as an organ-protective adjuvant treatment for TH during prolonged damage control resuscitation.

Indoleamine 2,3 Dioxygenase 1-The Potential Link between the Innate Immunity and the Ischemia-Reperfusion-Induced Acute Kidney Injury?

Ischemia-reperfusion injury (IRI) is of the most common causes of acute kidney injury (AKI); nevertheless, the mechanisms responsible for both early kidney injury and the reparative phase are not fully recognised. The inflammatory response following ischemia is characterised by the crosstalk between cells belonging to the innate immune system-dendritic cells (DCs), macrophages, neutrophils, natural killer (NK) cells, and renal tubular epithelial cells (RTECs). A tough inflammatory response can damage the renal tissue; it may also have a protective effect leading to the repair after IRI. Indoleamine 2,3 dioxygenase 1 (IDO1), the principal enzyme of the kynurenine pathway (KP), has a broad spectrum of immunological activity from stimulation to immunosuppressive activity in inflamed areas. IDO1 expression occurs in cells of the innate immunity and RTECs during IRI, resulting in local tryptophan (TRP) depletion and generation of kynurenines, and both of these mechanisms contribute to the immunosuppressive effect. Nonetheless, it is unknown if the above mechanism can play a harmful or preventive role in IRI-induced AKI. Despite the scarcity of literature in this field, the current review attempts to present a possible role of IDO1 activation in the regulation of the innate immune system in IRI-induced AKI.

Postconditioning by Delayed Administration of Ciclosporin A: Implication for Donation after Circulatory Death (DCD).

Heart transplantation is facing a shortage of grafts. Donation after Circulatory Death (DCD) would constitute a new potential of available organs. In the present work, we aimed to evaluate whether Postconditioning (ischemic or with ciclosporin-A (CsA)) could reduce ischemia-reperfusion injury in a cardiac arrest model when applied at the start of reperfusion or after a delay. An isolated rat heart model was used as a model of DCD. Hearts were submitted to a cardiac arrest of 40 min of global warm ischemia (37 °C) followed by 3 h of 4 °C-cold preservation, then 60 min reperfusion. Hearts were randomly allocated into the following groups: control, ischemic postconditioning (POST, consisting of two episodes each of 30 s ischemia and 30 s reperfusion at the onset of reperfusion), and CsA group (CsA was perfused at 250 nM for 10 min at reperfusion). In respective subgroups, POST and CsA were applied after a delay of 3, 10, and 20 min. Necrosis was lower in CsA and POST versus controls (p < 0.01) whereas heart functions were improved (p < 0.01). However, while the POST lost its efficacy if delayed beyond 3 min of reperfusion, CsA treatment surprisingly showed a reduction of necrosis even if applied after a delay of 3 and 10 min of reperfusion (p < 0.01). This cardioprotection by delayed CsA application correlated with better functional recovery and higher mitochondrial respiratory index. Furthermore, calcium overload necessary to induce mitochondrial permeability transition pore (MPTP) opening was similar in all cardioprotection groups, suggesting a crucial role of MPTP in this delayed protection of DCD hearts.