Mitigate Ischemia-reperfusion Injury Research Articles

Ex-vivo lung perfusion: National trends and post-transplant outcomes.

Ex-vivo lung perfusion (EVLP) has potential to expand donor lung utilization, evaluate allograft viability, and mitigate ischemia-reperfusion injury. However, trends in EVLP use and recipient outcomes are unknown on a national scale. We examined trends in EVLP use and recipient outcomes in the United States. Adult patients undergoing lung transplant between 2013 and 2023 were identified in the Standard Transplant Analysis and Research-Organ Procurement and Transplantation Network database. Effects of EVLP use on center volume changes were assessed using difference-in-difference analysis. Multivariable logistic regression was used to evaluate associations between EVLP use and recipient 30-day mortality, post-operative length of stay, grade 3 primary graft dysfunction (PGD), and need for mechanical ventilation at 72hours. Of 23,807 lung transplants during the study period, 813 utilized EVLP. While transplant volume increased over time, this was not attributable to EVLP use. Recipients in the EVLP cohort demonstrated increased 30-day mortality [3.8% vs 2.4%; OR 1.57 (1.02-2.41); p=0.040], mechanical ventilation at 72hours [40.2% vs 31.2%; OR 1.58 (1.33-1.87); p<0.001], and longer postoperative length of stay (35.8 vs 30.0 days; IRR 1.19 (1.18-1.21); p<0.001) compared to the non-EVLP cohort. No difference in grade 3 PGD was found between groups [14.5% vs 14.1%; OR 1.04 (0.80-1.34); p=0.791]. Although annual transplant volume has increased, the upward trend cannot yet be attributed to EVLP use. In the largest study to date, our results suggest outcome differences between EVLP and non-EVLP recipient cohorts. This motivates future work to characterize how patient selection and institutional factors influence outcomes with EVLP use.

10°C static storage mitigates ischemia reperfusion injury through improved mitochondrial preservation in a porcine DCD liver model

10°C static storage mitigates ischemia reperfusion injury through improved mitochondrial preservation in a porcine DCD liver model

Phospholipid Nanoparticles: A Novel Colloid for Blood Volume Replacement, Reanimation, and Organ Protection in Hemorrhagic Shock.

Background/Objectives: Exsanguination is a leading cause of preventable death in military and civilian settings due to extensive blood loss and hemorrhagic shock, which trigger systemic effects such as impaired tissue perfusion, hypoxia, inflammation, and multi-organ dysfunction. Standard resuscitation restores blood volume but fails to address critical aspects of hemorrhagic shock, including inflammation, coagulopathy, and reperfusion injury. To address these limitations, novel phospholipid nanoparticle (PNP)-based resuscitative fluids, VBI-S and VBI-1, were developed to modulate nitric oxide (NO) levels, improving hemodynamic stability, tissue oxygenation, and reducing inflammatory injury. This study assessed the potential of novel phospholipid nanoparticle fluids, VBI-S and VBI-1, as resuscitative agents for severe hemorrhagic shock by evaluating their ability to regulate nitric oxide, restore blood pressure, and mitigate ischemia-reperfusion injury. Methods: This study involved two phases with Sprague Dawley rats (n = 6 per group). Phase one, lasting 4 h, included four groups: blood, Ringer's lactate, VBI-S, and VBI-1. Phase two, lasting 12 h, comprised sham, blood, and VBI-1 groups. Under anesthesia, one femoral artery was catheterized for blood pressure monitoring, and blood withdrawal from the other induced apnea. Reanimation was performed using an intra-arterial infusion of shed blood, Ringer's lactate, VBI-S, or VBI-1. Tissue samples were analyzed histologically and for oxidative DNA damage via immunofluorescence. Chemiluminescence and rheology assessed nitric oxide interactions and viscosity. Data were analyzed using ANOVA. Results: VBI-1 and shed blood increased mean arterial pressure (MAP) from <10 mmHg to survivable levels sustained for 12 h, with VBI-1 showing significantly higher MAP at 3-4 h. Rats treated with Ringer's lactate died within 30 min. Histology revealed reduced organ damage in VBI-1-treated rats compared to shed blood. Immunohistochemistry indicated significantly less oxidative DNA damage (p < 0.001) in VBI-1-treated rats. VBI-1 exhibited superior viscosity and nitric oxide binding. Conclusions: VBI-1 demonstrates strong potential as a resuscitative fluid, offering blood pressure restoration, reduced oxidative damage, and enhanced tissue perfusion, with significant implications for use in resource-limited and pre-hospital settings.

Impact of Paired Remote Ischemic Preconditioning on Postreperfusion Syndrome in Living-Donor Liver Transplantation: A Propensity-Score Matching Analysis.

Background and Objectives: Postreperfusion syndrome (PRS) is a significant challenge in liver transplantation (LT), leading to severe circulatory and metabolic complications. Ischemic preconditioning (IPC), including remote IPC (RIPC), can mitigate ischemia-reperfusion injury, although its efficacy in LT remains unclear. This study evaluated the impact of paired RIPC, involving the application of RIPC to both the recipient and the living donor, on the incidence of PRS and the need for rescue epinephrine during living-donor LT (LDLT). Materials and Methods: This retrospective observational cohort analysis included 676 adult patients who had undergone elective LDLT between September 2012 and September 2022. After applying exclusion criteria and propensity score matching (PSM), 664 patients were categorized into the paired RIPC and non-RIPC groups. The primary outcomes were the occurrence of PRS and the need for rescue epinephrine during reperfusion. Results: The incidence of PRS and the need for rescue epinephrine were significantly lower in the paired RIPC group than in the non-RIPC group. Furthermore, the incidence of postoperative acute kidney injury was lower in the paired RIPC group. Multivariable logistic regression adjusted for propensity scores indicated that paired RIPC was significantly associated with a reduced occurrence of PRS (odds ratio: 0.672, 95% confidence interval: 0.479-0.953, p = 0.021). Conclusions: Paired RIPC, involving both the recipient and the living donor, effectively reduces the occurrence of PRS and the need for rescue epinephrine during LDLT. These findings suggest that paired RIPC protects against ischemia-reperfusion injury in LDLT. Future randomized controlled trials are needed to verify our results and to explore the underlying mechanisms of the protective effects of RIPC.

Exercise preconditioning mitigates Ischemia-Reperfusion injury in rats by enhancing mitochondrial respiration

Cerebral ischemia and subsequent reperfusion damage are prevalent in clinical practice, linked to numerous neurodegenerative diseases. Cerebral ischemia deprives brain tissue of essential oxygen and nutrients, disrupting energy metabolism and causing cellular dysfunction. Although reperfusion theoretically aids recovery, it instead initiates complex injury responses such as oxidative stress, apoptosis, and inflammation, worsening brain damage. Recent research suggests that enhancing neuronal energy status by modulating energy metabolism pathways can effectively counter these effects. For instance, boosting mitochondrial function, improving energy provision, and decreasing harmful metabolites can mitigate oxidative stress and cellular injury. This study investigated the protective effects of exercise preconditioning against ischemia–reperfusion injury in rats. It was observed that exercise enhances energy levels and mitochondrial respiration by upregulating the expression of COX4 and NAMPT proteins and activating AMPK and mitochondrial complex V. This process facilitates metabolic reprogramming characterized by the promotion of oxidative phosphorylation (OXPHOS) and the pentose phosphate pathway (PPP), alongside a reduction in glycolysis. Such reprogramming reduces harmful metabolites, mitigating apoptosis and oxidative stress, and is a key factor in alleviating acute ischemic hypoxia-induced brain damage. These findings introduce a novel therapeutic approach for ischemic brain reperfusion injury, underscoring the crucial role of ATP production and metabolic regulation in neuroprotection.

First-in-Human Phase 2a (ATMIRe) Trial of Ex Vivo Allograft Treatment with iCM012 to Mitigate Ischemia-Reperfusion Injury in Kidney Transplantation

First-in-Human Phase 2a (ATMIRe) Trial of Ex Vivo Allograft Treatment with iCM012 to Mitigate Ischemia-Reperfusion Injury in Kidney Transplantation

Comparison of the effects of axillary brachial plexus block, inhalation anesthesia, and total intravenous anesthesia on tourniquet-induced ischemia-reperfusion injury in upper extremity surgery.

Post-ischemia reperfusion can lead to oxidative stress and an increase in oxidative markers. Employing preventive strategies and antioxidant agents may help mitigate ischemia-reperfusion injury (IRI). The use of a tourniquet in extremity surgery has been associated with IRI. This study aims to investigate the impact of three different approaches- brachial plexus block, total intravenous anesthesia (TIVA), and inhalation anesthesia-on IRI during upper extremity surgery using a tourniquet. Patients aged 18 to 45 with American Society of Anesthesiologists (ASA) I-II scores were randomly assigned to one of three groups: Group A received an axillary block with bupivacaine; Group I underwent inhalation anesthesia with sevoflurane; and Group T received TIVA with propofol and remifentanil infusion. Blood samples were collected to measure glucose, lactate, total anti-oxidant status (TAS), total oxidant status (TOS), and ischemia-modified albumin (IMA) levels at various time points: before anesthesia (t1), 1 minute before tourniquet release (t2), 20 minutes after tourniquet release (t3), and 4 hours after tourniquet release (t4). In Group I, lactate levels at t3, and glucose levels at t2 and t3, were higher compared to the other groups. Group A exhibited lower IMA levels at t2, t3, and t4 than the other groups. Additionally, Group I had lower IMA levels at t2, t3, and t4 compared to Group T. TAS levels were higher in Group I at t2, t3, and t4 compared to the other groups. TOS levels at t2 and t3 were lower in Group A than in Group I. Axillary anesthesia results in a sympathetic block, promoting better perfusion of the upper extremity. This study demonstrated lower levels of oxidative stress markers with axillary plexus block. Therefore, these results suggest that the axillary block has the potential to mitigate IRI.

The protective effects of Axitinib on blood-brain barrier dysfunction and ischemia-reperfusion injury in acute ischemic stroke

Background and purposeThe pathophysiological features of acute ischemic stroke (AIS) often involve dysfunction of the blood-brain barrier (BBB), characterized by the degradation of tight junction proteins (Tjs) leading to increased permeability. This dysfunction can exacerbate cerebral injury and contribute to severe complications. The permeability of the BBB fluctuates during different stages of AIS and is influenced by various factors. Developing effective therapies to restore BBB function remains a significant challenge in AIS treatment. High levels of vascular endothelial growth factor (VEGF) in the early stages of AIS have been shown to worsen BBB breakdown and stroke progression. Our study aimed to investigate the protective effects of the VEGF receptor inhibitor Axitinib on BBB dysfunction and cerebral ischemia/reperfusion-induced injury. MethodsBEnd3 cell exposed to oxygen–glucose deprivation (OGD) model was constructed to estimate pharmacological activity of Axitinib (400 ng/ml) on anti-apoptosis and pathological barrier function recovery. In vivo, rats were subjected to a 1 h transient middle cerebral artery occlusion and 23 h reperfusion (tMCAO/R) to investigate the permeability of BBB and cerebral tissue damage. Axitinib was administered through the tail vein at the beginning of reperfusion. BBB integrity was assessed by Evans blue leakage and the expression levels of Tjs claudin-5 and occludin. ResultsOur research revealed that co-incubation with Axitinib enhanced the cell viability of OGD-insulted bEnd3 cells, decreased LDH leakage rate, and suppressed the expression of apoptosis-related proteins cytochrome C and Bax. Axitinib also mitigated the damage to Tjs and facilitated the restoration of transepithelial electrical resistance in OGD-insulted bEnd.3 cells. In vivo, Axitinib administration reduced intracerebral Evans blue leakage and up-regulated the expression of Tjs in the penumbra brain tissue in tMCAO/R rats. Notably, 10 mg/kg Axitinib exerted a significant anti-ischemic effect by decreasing cerebral infarct volume and brain edema volume, improving neurological function, and reducing pro-inflammatory cytokines IL-6 and TNF-α in the brain. ConclusionsOur study highlights Axitinib as a potent protectant of blood-brain barrier function, capable of promoting pathological blood-brain barrier recovery through VEGF inhibition and increased expression of tight junction proteins in AIS. This suggests that VEGF antagonism within the first 24 h post-stroke could be a novel therapeutic approach to enhance blood-brain barrier function and mitigate ischemia-reperfusion injury.

Acupuncture Extended the Thrombolysis Window by Suppressing Blood-Brain Barrier Disruption and Regulating Autophagy-Apoptosis Balance after Ischemic Stroke.

Ischemic stroke (IS) is one of the leading causes of death and disability worldwide. The narrow therapeutic window (within 4.5 h) and severe hemorrhagic potential limits therapeutic efficacy of recombinant tissue type plasminogen activator (rt-PA) intravenous thrombolysis for patients. Xingnao Kaiqiao (XNKQ) acupuncture is an integral part of traditional Chinese medicine, specifically designed to address acute ischemic stroke by targeting key acupoints such as Shuigou (GV26) and Neiguan (PC6). In this study, we explored the therapeutic potential of XNKQ acupuncture in extending the time window for thrombolysis and interrogated the molecular mechanisms responsible for this effect. The effect of extending the thrombolysis window by acupuncture was evaluated via TTC staining, neuronal score evaluation, hemorrhagic transformation assay, and H&E staining. RNA sequencing (RNA-seq) technology was performed to identify the therapeutic targets and intervention mechanisms of acupuncture. Evans blue staining and transmission electron microscopy were used to assess blood-brain barrier (BBB) integrity. Immunofluorescence staining and co-immunoprecipitation were performed to evaluate the level of autophagy and apoptosis and validate their interactions with BBB endothelial cells. Acupuncture alleviated infarction and neurological deficits and extended the thrombolysis window to 6 h. The RNA-seq revealed 16 potential therapeutic predictors for acupuncture intervention, which related to suppressing inflammation and restoring the function of BBB and blood vessels. Furthermore, acupuncture suppressed BBB leakage and preserved tight junction protein expression. The protective effect was associated with regulation of the autophagy-apoptosis balance in BBB endothelial cells. Acupuncture intervention dissociated the Beclin1/Bcl-2 complex, thereby promoting autophagy and reducing apoptosis. XNKQ acupuncture could serve as an adjunctive therapy for rt-PA thrombolysis, aiming to extend the therapeutic time window and mitigate ischemia-reperfusion injury. Acupuncture suppressed BBB disruption by regulating the autophagy-apoptosis balance, which in turn extended the therapeutic window of rt-PA in IS. These findings provide a rationale for further exploration of acupuncture as a complementary candidate co-administered with rt-PA.

Beating Heart Transplant Procedures Using Organs From Donors With Circulatory Death

The use of ex vivo normothermic organ perfusion has enabled the use of deceased after circulatory death (DCD) donors for heart transplants. However, compared with conventional brain death donation, DCD heart transplantation performed with ex vivo organ perfusion involves an additional period of warm and cold ischemia, exposing the allograft to multiple bouts of ischemia reperfusion injury and may contribute to the high rates of extracorporeal membrane oxygenation usage after DCD heart transplantation. To assess whether the beating heart method of DCD heart transplantation is safe and whether it has an acceptable rate of extracorporeal membrane oxygenation use postoperatively. This case series includes 10 patients with end-stage heart failure undergoing DCD heart transplantation at a single academic medical center from October 1, 2022, to August 3, 2023. Data were analyzed from October 2022 to August 2023. Using a beating heart method of implantation of the donor allograft. The main outcome was primary graft dysfunction necessitating postoperative initiation of mechanical circulatory support. Survival and initiation of mechanical circulatory support were secondary outcomes. In this case series, 10 consecutive patients underwent DCD heart transplantation via the beating heart method. Ten of 10 recipients were male (100%), the mean (SD) age was 51.2 (13.8) years, and 7 (70%) had idiopathic dilated cardiomyopathy. Ten patients (100%) survived, and 0 patients had initiation of extracorporeal membrane oxygenation postoperatively. No other mechanical circulatory support, including intra-aortic balloon pump, was initiated postoperatively. Graft survival was 100% (10 of 10 patients), and, at the time of publication, no patients have been listed for retransplantation. In this study of 10 patients undergoing heart transplantation, the beating heart implantation method for DCD heart transplantation was safe and may mitigate ischemia reperfusion injury, which may lead to lower rates of primary graft dysfunction necessitating extracorporeal membrane oxygenation. These results are relevant to institutions using DCD donors for heart transplantation.

The application of nanotechnology in kidney transplantation.

Kidney transplantation is a crucial treatment option for end-stage renal disease patients, but challenges related to graft function, rejection and immunosuppressant side effects persist. This review highlights the potential of nanotechnology in addressing these challenges. Nanotechnology offers innovative solutions to enhance organ preservation, evaluate graft function, mitigate ischemia-reperfusion injury and improve drug delivery for immunosuppressants. The integration of nanotechnology holds promise for improving outcomes in kidney transplantation.

Effect of multiorgan abdominal ischemic preconditioning on experimental kidney transplantation.

To mitigate ischemia-reperfusion injury (IRI) triggered in solid organ transplant procedures, we aimed to evaluate the effects of multi-organ abdominal ischemic preconditioning (MAIP) in the context of renal IRI. An experimental kidney transplant model was conducted. Rats were divided into three groups: an intervention free basal group from which physiological data was collected; a control group (CT), which consisted of transplanted animals without MAIP; and a treated group, in which a MAIP protocol was implemented in the donor during the procurement of the left kidney, monitoring the recipient for 24 hours. Urea, creatinine, and lactate dehydrogenase, as well as histopathological analysis (Banff: CT 1,66 ± 0,57 vs. basal 0, and MAIP 1), showed a clear trend in favor of MAIP group. Similar results were observed for tumor necrosis factor-α, interleukin-6 and CXCL10, as well as indicators of oxidative stress, with statistically significant levels for CXCL10 [0,295 ± 0,0074 arbitrary units (AU) CT and 0,0057 ± 0,0065 AU MAIP] and TBARS (2,93 ± 0,08 nmol/μg CT; and 2,49 ± 0,23 nmol/μg MAIP; p 0.05). The findings indicated that the MAIP exerts a protective influence on the transplanted kidneys, functioning as an IRI-protective strategy and enhancing the parameters associated with renal graft functionality.

Cardioprotective effect of Interleukin-11 against warm ischemia-reperfusion injury in a rat heart donor model

Shortage of donor organs for heart transplantation is a worldwide problem. Donation after circulatory death (DCD) has been proposed to expand the donor pool. However, in contrast to the donation after brain death that undergoes immediate cold preservation, warm ischemia and subsequent reperfusion injury are inevitable in DCD. It has been reported that interleukin-11 (IL-11) mitigates ischemia-reperfusion injury in rodent models of myocardial infarction and donation after brain death heart transplantation. We hypothesized that IL-11 also offers benefit to warm ischemia in an experimental model of cardiac transplantation that resembles DCD. The hearts of naïve male Sprague Dawley rats (n = 15/group) were procured, subjected to 25-min warm ischemia, and reperfused for 60 min using Langendorff apparatus. IL-11 or saline was administered intravenously before the procurement, added to maintenance buffer, and infused via perfusion during reperfusion. IL-11 group exhibited significantly better cardiac function post-reperfusion. Severely damaged mitochondria was found in the electron microscopic analysis of control hearts whereas the mitochondrial structure was better preserved in the IL-11 treated hearts. Immunoblot analysis using neonatal rat cardiomyocytes revealed increased signal transducer and activator of transcription 3 (STAT3) phosphorylation at Ser727 after IL-11 treatment, suggesting its role in mitochondrial protection. Consistent with expected activation of mitochondrial respiration by mitochondrial STAT3, immunohistochemical staining demonstrated a higher mitochondrial cytochrome c oxidase subunit 2 expression. In summary, IL-11 protects the heart from warm ischemia reperfusion injury by alleviating mitochondrial injury and could be a viable therapeutic option for DCD heart transplantation.

MicroRNA-specific therapeutic targets and biomarkers of apoptosis following myocardial ischemia-reperfusion injury.

MicroRNAs are single-stranded non-coding RNAs that participate in post-transcriptional regulation of gene expression, it is involved in the regulation of apoptosis after myocardial ischemia-reperfusion injury. For example, the alteration of mitochondrial structure is facilitated by MicroRNA-1 through the regulation of apoptosis-related proteins, such as Bax and Bcl-2, thereby mitigating cardiomyocyte apoptosis. MicroRNA-21 not only modulates the expression of NF-κB to suppress inflammatory signals but also activates the PI3K/AKT pathway to mitigate ischemia-reperfusion injury. Overexpression of MicroRNA-133 attenuates reactive oxygen species (ROS) production and suppressed the oxidative stress response, thereby mitigating cellular apoptosis. MicroRNA-139 modulates the extrinsic death signal of Fas, while MicroRNA-145 regulates endoplasmic reticulum calcium overload, both of which exert regulatory effects on cardiomyocyte apoptosis. Therefore, the article categorizes the molecular mechanisms based on the three classical pathways and multiple signaling pathways of apoptosis. It summarizes the targets and pathways of MicroRNA therapy for ischemia-reperfusion injury and analyzes future research directions.

Mitsugumin 53 mitigation of ischemia–reperfusion injury in a mouse model

ObjectivePrimary graft dysfunction is often attributed to ischemia–reperfusion injury, and prevention would be a therapeutic approach to mitigate injury. Mitsugumin 53, a myokine, is a component of the endogenous cell membrane repair machinery. Previously, exogenous administration of recombinant human (recombinant human mitsugumin 53) protein has been shown to mitigate acute lung injury. In this study, we aimed to quantify a therapeutic benefit of recombinant human mitsugumin 53 to mitigate a transplant-relevant model of ischemia–reperfusion injury. MethodsC57BL/6J mice were subjected to 1 hour of ischemia (via left lung hilar clamp), followed by 24 hours of reperfusion. mg53−/− mice were administered exogenous recombinant human mitsugumin 53 or saline before reperfusion. Tissue, bronchoalveolar lavage, and blood samples were collected at death and used to quantify the extent of lung injury via histology and biochemical assays. ResultsAdministration of recombinant human mitsugumin 53 showed a significant decrease in an established biometric profile of lung injury as measured by lactate dehydrogenase and endothelin-1 in the bronchoalveolar lavage and plasma. Biochemical markers of apoptosis and pyroptosis (interleukin-1β and tumor necrosis factor-α) were also significantly mitigated, overall demonstrating recombinant human mitsugumin 53's ability to decrease the inflammatory response of ischemia–reperfusion injury. Exogenous recombinant human mitsugumin 53 administration showed a trend toward decreasing overall cellular infiltrate and neutrophil response. Fluorescent colocalization imaging revealed recombinant human mitsugumin 53 was effectively delivered to the endothelium. ConclusionsThese data demonstrate that recombinant human mitsugumin 53 has the potential to prevent or reverse ischemia–reperfusion injury–mediated lung damage. Although additional studies are needed in wild-type mice to demonstrate efficacy, this work serves as proof-of-concept to indicate the potential therapeutic benefit of mitsugumin 53 administration to mitigate ischemia–reperfusion injury.

Effect of valproic acid upon skeletal muscle subjected to prolonged tourniquet application

BackgroundValproic acid (VPA), a histone deacetylase inhibitor, has shown improved outcomes when used as a pharmaceutical intervention in animal studies of hemorrhage, septic shock, and combined injuries. This study was...

Can Hypothermic Oxygenated Perfusion Mitigate Ischemia-Reperfusion Injury in Ex-Situ Split Grafts? – A Comparative Study with Living Donation in Pediatric Liver Transplantation

Abstract Background The gold standard in pediatric split liver transplantation (SLT) is living donation (LD) providing high-quality grafts with short static cold storage (SCS). Aims This study investigates the protective effect of hypothermic oxygenated perfusion (HOPE) on ex-situ partial grafts from deceased donors in comparison to standard ex-situ Static-Split and LD SLT. Methods We included all consecutive HOPE-Split, Static-Split and LD SLT performed from 2018-2022 at a single center. The primary endpoint was early ischemia-reperfusion injury (IRI) based on reperfusion biopsy (graded from none/0 to severe/4), the occurrence of post reperfusion syndrome (PRS, drop≥30% of systolic arterial pressure) and post-LT transaminase release. Results A total of 46 SLT (14 HOPE-Split, 17 Static-Split, and 15 LD) were included. With a median perfusion duration of 100min, HOPE-Split had a significant decrease of SCS compared to Static-Split (473 min vs 538 min; p=0.02) with similar total preservation time (p=0.13). This translated into lower rates of mild to severe IRI (grade≥2; p=0.03) and significantly reduced neutrophilic infiltrate than Static-Split (p=0.04; Fig.1). The PRS was also reduced in HOPE-Split (0% vs 35%, p=0.02) with less transaminase release. Despite prolonged SCS (473 vs 117min, p&amp;lt;0.001), HOPE-Split was comparable to LD regarding grade≥2 IRI (64 vs 40%; p=0.17) and PRS (0 vs 6.7% p=0.34), with however higher transaminase release (571 vs 244 UI/L/100g; p=0.004). Overall, 3-months surgical complications, graft and recipient survival did not differ among groups. Conclusions HOPE allowed improved preservation of ex-situ split grafts compared to static cold storage, resulting in similar early IRI profiles then LD grafts. Preservation with HOPE may offer a promising strategy to improve outcomes and expand selection criteria in split LT for pediatric recipients.

Decanoic acid mitigates ischemia reperfusion injury by modulating neuroprotective, inflammatory and oxidative pathways in middle cerebral artery occlusion model of stroke in rats

Objective: Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) is an ionotropic transmembrane receptor for glutamate. AMPA receptor blockers have been reported to prevent neurological damage and enhance the post stroke recovery in rats. Decanoic acid, a medium-chain fatty acid, has been reported to exhibit non-competitive AMPA receptor antagonism. This study evaluated the effect of decanoic acid administered before and after ischemia reperfusion injury on neurological damage and post stroke recovery in rats. Methods: Middle cerebral artery occlusion (MCAo) was performed by using the intraluminal method to induce focal cerebral ischemia. Decanoic acid (120 mg/kg) was administered orally for 1 day (5-10 min post reperfusion) in one group and for 2 days (24 h pre and 5-10 min post reperfusion) in the other group. Effect on neurological damage and post stroke recovery was assessed by neurobehavioral parameters, MRI and TTC staining along with inflammatory, oxidative, apoptotic, and neuroprotective biomarkers. Results: Decanoic acid significantly reduced the MCAo induced neurological damage and infarct size. Decanoic acid treatment increased the motor coordination and grip strength. Furthermore, levels of inflammatory (TNFα, IL-1β and IL-6), oxidative stress (MDA), apoptotic (TUNEL positive cells) and neurological injury (GFAP) biomarkers were reduced after decanoic acid treatment. Anti-inflammatory cytokine (IL-10) and neuroprotective markers (NT-3, BDNF and TrkB) were found to be significantly increased with decanoic acid treatment. Conclusion: This study showed protective effects of decanoic acid against ischemia reperfusion injury in rats. Anti-inflammatory, antioxidant, neuroprotective, and anti-apoptotic properties may be responsible for the beneficial effects of decanoic acid observed in the study.

Impact of Hypothermic Oxygenated Machine Perfusion on Hepatocellular Carcinoma Recurrence after Liver Transplantation.

Machine perfusion may be able to mitigate ischemia-reperfusion injury (IRI), which increases hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). This study aimed to investigate the impact of dual-hypothermic oxygenated machine perfusion (D-HOPE) on HCC recurrence in LT. A single-center retrospective study was conducted from 2016 to 2020. Pre- and postoperative data of HCC patients undergoing LT were analyzed. Recipients of a D-HOPE-treated graft were compared to those of livers preserved using static cold storage (SCS). The primary endpoint was recurrence-free survival (RFS). Of 326 patients, 246 received an SCS-preserved liver and 80 received a D-HOPE-treated graft (donation after brain death (DBD), n = 66; donation after circulatory death (DCD), n = 14). Donors of D-HOPE-treated grafts were older and had higher BMI. All DCD donors were treated by normothermic regional perfusion and D-HOPE. The groups were comparable in terms of HCC features and estimated 5-year RFS according to the Metroticket 2.0 model. D-HOPE did not reduce HCC recurrence (D-HOPE 10%; SCS 8.9%; p = 0.95), which was confirmed using Bayesian model averaging and inverse probability of treatment weighting-adjusted RFS analysis. Postoperative outcomes were comparable between groups, except for lower AST and ALT peak in the D-HOPE group. In this single-center study, D-HOPE did not reduce HCC recurrence but allowed utilizing livers from extended criteria donors with comparable outcomes, improving access to LT for patients suffering from HCC.

Extracellular Vesicles as Drug Delivery Systems in Organ Transplantation: The Next Frontier.

Extracellular vesicles are lipid bilayer-delimited nanoparticles excreted into the extracellular space by all cells. They carry a cargo rich in proteins, lipids and DNA, as well as a full complement of RNA species, which they deliver to recipient cells to induce downstream signalling, and they play a key role in many physiological and pathological processes. There is evidence that native and hybrid EVs may be used as effective drug delivery systems, with their intrinsic ability to protect and deliver a functional cargo by utilising endogenous cellular mechanisms making them attractive as therapeutics. Organ transplantation is the gold standard for treatment for suitable patients with end-stage organ failure. However, significant challenges still remain in organ transplantation; prevention of graft rejection requires heavy immunosuppression and the lack of donor organs results in a failure to meet demand, as manifested by growing waiting lists. Pre-clinical studies have demonstrated the ability of EVs to prevent rejection in transplantation and mitigate ischemia reperfusion injury in several disease models. The findings of this work have made clinical translation of EVs possible, with several clinical trials actively recruiting patients. However, there is much to be uncovered, and it is essential to understand the mechanisms behind the therapeutic benefits of EVs. Machine perfusion of isolated organs provides an unparalleled platform for the investigation of EV biology and the testing of the pharmacokinetic and pharmacodynamic properties of EVs. This review classifies EVs and their biogenesis routes, and discusses the isolation and characterisation methods adopted by the international EV research community, before delving into what is known about EVs as drug delivery systems and why organ transplantation represents an ideal platform for their development as drug delivery systems.