Reduce Ischemia-reperfusion Injury Research Articles

Remote Ischaemic Pre-Conditioning Reduces Intestinal Ischaemia Reperfusion Injury in a Newborn Rat

ObjectiveRemote ischaemic conditioning (RIC) has been shown to reduce ischaemia-reperfusion injury(IRI) in multiple organ systems. IRI is seen in multiple bowel pathologies in the newborn, including NEC. We investigated the potential of RIC as a novel therapy for various intestinal pathologies in the newborn. MethodsWe used an established intestinal IRI model in rat pups which results in similar intestinal injury to necrotising enterocolitis (NEC). Animals were randomly allocated to IRI only(n = 14), IRI + RIC(n = 13) or sham laparotomy(n = 10). The macroscopic extent of intestinal injury is reported as a percentage of total small bowel. Injury severity was measured using Chiu-Park scoring. Neutrophil infiltration/activation was assayed by myeloperoxidase activity. Immunohistochemistry was used to assess the expression of hypoxia-inducible factor alpha (HIF-1α). Data are median (interquartile range). ResultsAnimals that underwent RIC showed a decreased extent of macroscopic injury from 100%(85–100%) in the IRI only group to 58%(15–84%, p = 0.003) in the IRI + RIC group. Microscopic injury score was significantly lower in animals that underwent RIC compared to IRI alone (3.5[1.25–5] vs 5.5[4–6], p = 0.014). Intestinal myeloperoxidase activity in animals exposed to IRI was 3.4 mU/mg of tissue (2.5–3.7) and 2.1 mU/mg(1.5–2.8) in the IRI + RIC group(p = 0.047). HIF-1α expression showed a non-significant trend towards reduced expression in the IRI + RIC group. ConclusionsRIC reduces the extent and severity of bowel injury in this animal model, supporting the hypothesis that RIC has therapeutic potential for intestinal diseases in the newborn.

Effect of remote ischemic preconditioning in patients undergoing laparoscopic colorectal cancer surgery: a randomized controlled trial

Background Remote ischemic preconditioning (RIPC) is reported to reduce ischemia-reperfusion injury (IRI) in many vital organs by inhibiting a systemic inflammatory response. Inflammation also plays an essential role in the pathophysiology of prolonged post-operative ileus (PPOI) in patients undergoing colorectal cancer (CRC) surgery. However, the role of RIPC is unclear in reducing the incidence of PPOI in patients undergoing CRC surgery. Methods This was a prospective, randomized trial of RIPC vs. placebo-controlled in patients undergoing elective laparoscopic CRC surgery. Eighty patients were randomized to either a RIPC group or a control group (40 per arm), with computer-generated randomization. The aim was to determine whether RIPC improved the recovery of gut function. The primary outcomes assessed were time to gastrointestinal tolerance and incidence of PPOI. Results Median time to stool of the RIPC group was significantly lower than that of the control group [RIPC vs. control, 4.0 (3.0, 6.0) vs. 5.0 (4.0, 7.8) days, p = 0.027]. Median time to gastrointestinal tolerance and incidence of PPOI in the RIPC group were lower than the control group; however, there were no statistical differences between the two groups [RIPC vs. control: 5.0 (3.0, 7.0) vs. 6.0 (4.0, 8.8) days, p = 0.178; 15 vs. 30%, p = 0.108]. Conclusion RIPC could shorten the median time to stool in patients undergoing laparoscopic CRC surgery, but did not improve the overall recovery time of gut function or reduce the incidence of PPOI. Registration number ChiCTR2100043313 (http://www.chictr.org.cn). Key points Question: In patients undergoing laparoscopic CRC surgery, does RIPC improve time to the overall recovery of gut function and reduce the incidence of PPOI? Findings: In this randomized clinical trial that included 80 patients undergoing elective laparoscopic CRC surgery, no significant difference was found between the RIPC group and the control group concerning median time to gastrointestinal tolerance and incidence of PPOI. Meaning: RIPC did not improve the time for overall recovery of gut function or reduce the incidence of PPOI in patients undergoing laparoscopic CRC surgery.

Perioperative Management for the First Uterine Transplant in Southern Europe: A Case Report

The aim of this study was to describe perioperative management concerning the living donor uterine transplantation program at the Hospital Clinic (Barcelona, Spain), in the first successful procedure in Southern Europe. Before the date of surgery, both the donor and the recipient are evaluated in the outpatient clinic to detect any possible comorbidities that might complicate or altogether disallow the procedure. In the donor, with a robotically performed surgery, complications regarding cerebral and upper airway edema, as well as reduced access to the patient once docking occurs, are of utmost importance. An aggressive antithrombotic regimen must be in place that includes heparin administered both to the donor and the recipient and aspirin to the recipient. Different strategies to reduce ischemia-reperfusion injury have been studied, with reduced ischemia times currently being the most effective. After surgery, both donor and recipient were taken to the intensive care unit overnight, transferred to the conventional ward the following day and discharged from the hospital within the week. The recipient had her first menstrual period 47 days after the surgery. The description of challenges regarding perioperative care of women who undergo uterine transplant programs and the rationale in anesthetic management may help other teams implant this program as a solution for a disease that profoundly impairs quality of life.

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.

Exosomes Derived from Bone Marrow Mesenchymal Stem Cells Alleviate Ischemia-Reperfusion Injury and Promote Survival of Skin Flaps in Rats.

Free tissue flap transplantation is a classic and important method for the clinical repair of tissue defects. However, ischemia-reperfusion (IR) injury can affect the success rate of skin flap transplantation. We used a free abdomen flap rat model to explore the protective effects of exosomes derived from bone marrow mesenchymal stem cells (BMSCs-exosomes) against the IR injury of the skin flap. Exosomes were injected through the tail vein and the flaps were observed and obtained on day 7. We observed that BMSCs-exosomes significantly reduced the necrotic lesions of the skin flap. Furthermore, BMSCs-exosomes relieved oxidative stress and reduced the levels of inflammatory factors. Apoptosis was evaluated via the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and Western blot analysis of Bax, Bcl-2. Simultaneously, BMSCs-exosomes promoted the formation of new blood vessels in the IR flap, as confirmed by the increased expression level of VEGFA and the fluorescence co-staining of CD31 and PCNA. Additionally, BMSCs-exosomes considerably increased proliferation and migration of human umbilical vein endothelial cells and promoted angiogenesis in vitro. BMSCs-exosomes could be a promising cell-free therapeutic candidate to reduce IR injury and promote the survival of skin flaps.

Creatine phosphate preconditioning reduces ischemiareperfusion injury in isolated rat heart

Aim . To study the effect of simultaneous administration of creatine phosphate immediately before ischemia on cardiodynamic parameters and biomarkers of oxidative stress in the coronary venous blood flow during retrograde perfusion in an isolated rat heart. Materials and methods . 20 Wistar albino rats were divided into 2 groups: group 1 (control) and group 2 (experimental), 10 rats per group. Cannulation and retrograde perfusion of aorta of an isolated rat heart with Krebs–Henseleit buffered solution by Landendorff was performed. Both groups underwent ischemia-reperfusion injury, which included global ischemia for 20 minutes followed by reperfusion for 30 minutes. The group 2 (experimental) was preconditioned with creatine phosphate at a dose of 0.2 mmol/l for 5 min before ischemia. We registered cardiodynamic parameters and indicators of oxidative stress at the point of stabilization, at the 1st and 30th minutes of reperfusion. Results . With the impact of creatine phosphate at the 30th minute of reperfusion in the group 2 in comparison with group 1, there was found an increase in the maximum and minimum speed of pressure elevation in the left ventricle (1.7 and 1.9 times, respectively), and of systolic and diastolic pressure in the left ventricle (1.5 and 1.6 times, respectively). Biomarkers of oxidative stress (lipid peroxidation index, nitrites, superoxide anion radical and hydrogen peroxide) were also statistically significantly lower in the group 2 after the 1st minute of reperfusion (by 1.2 times, by 1.4 times, by 2.8 times and 1.9 times, respectively), and after the 30th minute (1.3 times, 2.1 times, 1.9 times and 2.1 times, respectively). Conclusion . The administration of creatine phosphate into the coronary flow 5 minutes before the onset of ischemia has a protective effect on myocardial contractility. Reduction of oxidative stress and damage can be considered as a protective effect of creatine phosphate.

422.2: Investigating Galectin-3 as a Novel Therapeutic Target To Block Inflammation and Reduce Ischemia Reperfusion Injury During Vascular Composite Allograft Transplantation

Introduction: Vascularized Composite Allograft (VCA) transplantation is a treatment option for complex injuries that leave patients with structural and functional deficits that cannot be adequately reconstructed. During transplantation, grafts are subjected to hypoxic/ischemic injury during procurement, storage, and reperfusion. Skin and muscle containing VCA are highly susceptible to ischemia reperfusion injury. Galectin-3 is an endogenous β-galactoside binding lectin known to play a role in driving inflammatory responses in response to hypoxic/ischemic stress. Blocking galectin-3 using known inhibitors including modified citrus pectin (MCP) has been shown in animal models to reduce inflammation and fibrosis. We hypothesized that galectin-3 significantly contributes to VCA IRI and that blocking galectin-3 can serve as a novel therapeutic approach to prevent or reduce IRI. We aimed to determine the role of galectin-3 in VCA ischemia reperfusion injury and the effect of blocking galectin-3 using MCP in syngeneic VCA models. Method: Male Brown Norway rats underwent syngeneic hind limb transplantation following 0, 6 or 24 hours of cold ischemia time. A group of rats receiving hind limbs subjected to 24 hours of static cold storage were treated with MCP (1% w/v) in the drinking water starting one week prior to transplantation. Recipient serum and donor VCA tissues were collected at end-of-study 6 days post transplantation. Sera and tissues collected from naive Brown Norway rats were included as controls. Sera levels of galectin-3 were determined by sandwich ELISA (Novus Biologics, Inc). Galectin-3 expression in the muscle was determined by Western Blotting. The degree of inflammation in the muscle tissue was determined by H&E. Results: Sera galectin-3 levels averaged 0.854±0.557ng/ml in naïve BN rats (n=7), 4.232±2.134ng/ml in recipients of grafts transplanted immediately without static cold storage (n=3), 12.86±1.292ng/ml in recipients of grafts subjected to 6 hours cold storage without MCP treatment (n=3),20.10±3.185ng/ml in recipients of grafts subjected to 24 hours cold storage without MCP treatment (n=6), and 12.77±2.098ng/ml in recipients of grafts subjected to 24 hours cold storage with MCP treatment (n=9) (Figure 1A). Galectin-3 expression in the VCA muscle increased according to the extent of cold ischemia. MCP treatment decreased muscle galectin-3 expression (Figure 1B) and inflammation in the muscle (Figure 2) post transplantation.Conclusion: Galectin-3 levels significantly increased in recipient sera and donor muscle within a week in rats transplanted with donor VCA grafts subjected to prolonged ischemia. Blocking galectin-3 using MCP can reduce the amount of galectin-3 in circulation and muscle tissue post transplantation and may decrease inflammation associated with VCA IRI. Galectin-3 may serve as a novel therapeutic target to reduce inflammation associated with ischemic injury and improve VCA outcomes. DOD CDMRP RTRP W81XWH1910163 RT180168.

P2.17: Retrograde Reperfusion of the Renal Graft in Adult Recipient To Reduce Ischemia-Reperfusion Injury

P2.17: Retrograde Reperfusion of the Renal Graft in Adult Recipient To Reduce Ischemia-Reperfusion Injury

The role of ex-situ perfusion for thoracic organs.

Ex-situ machine perfusion for both heart (HTx) and lung transplantation (LuTx) reduces ischemia-reperfusion injury (IRI), allows for greater flexibility in geographical donor management, continuous monitoring, organ assessment for extended evaluation, and potential reconditioning of marginal organs. In this review, we will delineate the impact of machine perfusion, characterize novel opportunities, and outline potential challenges lying ahead to improve further implementation. Due to the success of several randomized controlled trials (RCT), comparing cold storage to machine perfusion in HTx and LuTx, implementation and innovation continues. Indeed, it represents a promising interface for organ-specific therapies targeting IRI, allo-immune responses, and graft reconditioning. These mostly experimental efforts range from genetic approaches and nanotechnology to cellular therapies, involving mesenchymal stem cell application. Despite tremendous potential, prior to clinical transition, more data is needed. Collectively, machine perfusion constitutes the vanguard in thoracic organ transplantation research with extensive potential for expanding the donor pool, enhancing transplant outcomes as well as developing novel therapy approaches.

Etomidate Alleviates Ischemia-Anoxia Reperfusion Injury in Intestinal Epithelial Cells by Inhibiting the Activation of traf6-Regulated NF-KB Signaling

Objective: The present study aimed to investigate the role of etomidate in intestinal cell ischemia and hypoxia-reperfusion injury and potential mechanisms. Method: In this study, we establish the intestinal epithelial cells ischemia-reperfusion model in vitro. CCK8 was used to detect cell viability and flow cytometry assay was used to detect apoptosis levels of treated OGD/R model cells. ELISA measured the expression level of oxidative stress factors and inflammatory factors. Furthermore, western blot assay was used to detect the expression the apoptosis-related factors and TNFR-associated factors in treated OGD/R model cells. Result: Etomidate does not affect the activity of intestinal epithelial cells, and can protect intestinal epithelial cells to reduce ischemiareperfusion injury, and the expression of inflammatory factors and oxidative stress in cells with mild intestinal epithelial ischemia-reperfusion injury. Etomidate alleviates apoptosis of intestinal epithelial ischemia-reperfusion injury cells. Etomidate inhibits the activation of traf6-mediated NF-κB signal during ischemia-anoxia reperfusion of intestinal epithelial cells. Conclusion: Taken together, our study demonstrated that etomidate attenuates inflammatory response and apoptosis in intestinal epithelial cells during ischemic hypoxia-reperfusion injury and inhibits activation of NF-κB signaling regulated by TRAF6.

Is Modified Del Nido Cardioplegia as Effective as Del Nido Cardioplegia in Patients With Isolated Coronary Artery Bypass Surgery?

Is modified del Nido cardioplegia superior to del Nido cardioplegia in coronary artery bypass patients? All patients underwent cardiopulmonary bypass and retrospectively were analyzed. A total of 70 patients were included in the study. Thirty-four patients who were given cold (+ 4-8C ') modified del Nido cardioplegia antegrade were evaluated. Other patients received classical del Nido cardioplegia. Hot shot warm blood cardioplegia was given to all patients before the cross-clamp was removed. The results of both groups were compared. There was no significant difference between cardiac arrest times in both groups. A statistically significant difference was found in the modified del Nido cardioplegia group in the working of the heart. Less fibrillation was observed in the modified del Nido cardioplegia group. No difference found between the groups, regarding myocardial preservation. No decrease in hemoglobin was observed in the modified del Nido group on the postoperative first day. We know that return to spontaneous sinus rhythm and fibrillation reduces ischemia-reperfusion injury. At the same time, we can see that epicardial edema was less in the modified del Nido group. We think that less anemia is an advantage of modified del Nido cardioplegia.

Attenuation of ischemia–reperfusion injury by intracoronary chelating agent administration

Ischemia–reperfusion (IR) injury accelerates myocardial injury sustained during the myocardial ischemic period and thus abrogates the benefit of reperfusion therapy in patients with acute myocardial infarction. We investigated the efficacy of intracoronary ethylenediaminetetraacetic acid (EDTA) administration as an adjunctive treatment to coronary intervention to reduce IR injury in a swine model. We occluded the left anterior descending artery for 1 h. From the time of reperfusion, we infused 50 mL of EDTA-based chelating agent via the coronary artery in the EDTA group and normal saline in the control group. IR injury was identified by myocardial edema on echocardiography. Tetrazolium chloride assay revealed that the infarct size was significantly lower in the EDTA group than in the control group, and the salvage percentage was higher. Electron microscopy demonstrated that the mitochondrial loss in the cardiomyocytes of the infarcted area was significantly lower in the EDTA group than in the control group. Echocardiography after 4 weeks showed that the remodeling of the left ventricle was significantly less in the EDTA group than in the control group: end-diastolic dimension 38.8 ± 3.3 mm vs. 43.9 ± 3.7 mm (n = 10, p = 0.0089). Left ventricular ejection fraction was higher in the EDTA group (45.3 ± 10.3 vs. 34.4 ± 11.8, n = 10, respectively, p = 0.031). In a swine model, intracoronary administration of an EDTA chelating agent reduced infarct size, mitochondrial damage, and post-infarct remodeling. This result warrants further clinical study evaluating the efficacy of the EDTA chelating agent in patients with ST-segment elevation myocardial infarction.

Rivastigmine Regulates the HIF-1α/VEGF Signaling Pathway to Induce Angiogenesis and Improves the Survival of Random Flaps in Rats.

Random skin flaps are frequently used to repair skin damage. However, the ischemic and hypoxic necrosis limits their wider application. Rivastigmine, a carbamate cholinesterase inhibitor (ChEI), has also been shown to reduce ischemia–reperfusion injury (IRI) and inflammation. This study was performed to examine the effect of rivastigmine on flap survival. Sixty male Sprague–Dawley rats with a modified McFarland flap were randomly divided into three groups: control group, 1 ml of solvent (10% DMSO + 90% corn oil); low-dose rivastigmine group (Riv-L), 1.0 mg/kg; and high-dose rivastigmine group (Riv-H), 2.0 mg/kg. All rats were treated once a day. On day 7, the skin flap survival area was measured. After staining with hematoxylin and eosin (H&E), the pathological changes and microvessel density (MVD) were examined. The expression of inflammatory factors IL-1β and IL-18, CD34, hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) was examined by immunohistochemical staining. The malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were examined to determine the degree of oxidative stress. Lead oxide/gelatin angiography showed neovascularization and laser Doppler blood flowmetry showed the blood filling volume. Rivastigmine significantly increased the flap survival area and improved neovascularization. CD34, VEGF, and HIF-1α expression were increased, These changes were more pronounced in the Riv-H group. Treatment with rivastigmine reduced the level of MDA, improved SOD activity, and reduced expression of IL-1β and IL-18. Our results indicate that Rivastigmine can increase angiogenesis and significantly improve flap survival.

Aspirin Reduces Ischemia-Reperfusion Injury Induced Endothelial Cell Damage of Arterial Grafts in a Rodent Model.

Long-term graft patency determines the prognosis of revascularization after coronary artery bypass grafting (CABG). Ischemia-reperfusion (I/R) injury of the graft suffered during harvesting and after implantation might influence graft patency. Aspirin, a nonsteroidal anti-inflammatory drug improves the long-term patency of vein grafts. Whether aspirin has the same effect on arterial grafts is questionable. We aimed to characterize the beneficial effects of aspirin on arterial bypass grafts in a rodent revascularization model. We gave Lewis rats oral pretreatment of either aspirin (n = 8) or saline (n = 8) for 5 days, then aortic arches were explanted and stored in cold preservation solution. The third group (n = 8) was a non-ischemia-reperfusion control. Afterwards the aortic arches were implanted into the abdominal aorta of recipient rats followed by 2 h of reperfusion. Endothelium-dependent vasorelaxation was examined with organ bath experiments. Immunohistochemical staining were carried out. Endothelium-dependent maximal vasorelaxation improved, nitro-oxidative stress and cell apoptosis decreased, and significant endothelial protection was shown in the aspirin preconditioned group, compared to the transplanted control group. Significantly improved endothelial function and reduced I/R injury induced structural damage were observed in free arterial grafts after oral administration of aspirin. Aspirin preconditioning before elective CABG might be beneficial on free arterial graft patency.

Could Ambroxol reduce cytokines in hepatic ischemia-reperfusion injury in rats?

The aim of the study is to examine the effect of Ambroxol on TNF-α and IL-1β released after liver ischemia-reperfusion injury. Many drugs are being tried to reduce ischemia-reperfusion injury, which is life threating problem after many liver surgeries. In this study, it was investigated whether Ambroxol reduces the release of pro-inflammatory cytokines released after liver ischemia-reperfusion injury. Twenty-four Wistar albino rats were divided into 3 groups as Control (CTR; n=8), hepatic ischemia reperfusion (H-IR; n=8) and hepatic ischemia reperfusion+Ambroxol (H-IR+AMB; n=8). In H-IR+AMB group, Ambroxol (30 mg/kg) was administered orally 30 minutes before ischemia period. In H-IR and H-IR+AMB groups underwent 45 minutes of hepatic ischemia followed by a 60-minute reperfusion period. After reperfusion period, tissue and blood samples were collected from euthanised animals. ALT, AST, ALP, LDH, TNF-α, IL-1β concentrations and liver tissues were evaluated. Serum ALT, ALP, AST, LDH, TNF-α and IL-1β values were lower in the H-IR+AMB group compared to the H-IR group. In the histopathological examination, hepatocyte degeneration and congestion in the H-IR group were higher than in the H-IR+AMB group. It was determined that Ambroxol treatment suppressed the production of pro-inflammatory cytokines TNF-α and IL-1β in rats undergoing hepatic ischemia reperfusion (Tab. 1, Fig. 2, Ref. 28).

Hemoglobin-Based Oxygen Carriers: Potential Applications in Solid Organ Preservation.

Ameliorating graft injury induced by ischemia and hypoxia, expanding the donor pool, and improving graft quality and recipient prognosis are still goals pursued by the transplant community. The preservation of organs during this process from donor to recipient is critical to the prognosis of both the graft and the recipient. At present, static cold storage, which is most widely used in clinical practice, not only reduces cell metabolism and oxygen demand through low temperature but also prevents cell edema and resists apoptosis through the application of traditional preservation solutions, but these do not improve hypoxia and increase oxygenation of the donor organ. In recent years, improving the ischemia and hypoxia of grafts during preservation and repairing the quality of marginal donor organs have been of great concern. Hemoglobin-based oxygen carriers (HBOCs) are “made of” natural hemoglobins that were originally developed as blood substitutes but have been extended to a variety of hypoxic clinical situations due to their ability to release oxygen. Compared with traditional preservation protocols, the addition of HBOCs to traditional preservation protocols provides more oxygen to organs to meet their energy metabolic needs, prolong preservation time, reduce ischemia–reperfusion injury to grafts, improve graft quality, and even increase the number of transplantable donors. The focus of the present study was to review the potential applications of HBOCs in solid organ preservation and provide new approaches to understanding the mechanism of the promising strategies for organ preservation.

Characterization of Novel P-Selectin Targeted Complement Inhibitors in Murine Models of Hindlimb Injury and Transplantation.

The complement system has long been recognized as a potential druggable target for a variety of inflammatory conditions. Very few complement inhibitors have been approved for clinical use, but a great number are in clinical development, nearly all of which systemically inhibit complement. There are benefits of targeting complement inhibition to sites of activation/disease in terms of efficacy and safety, and here we describe P-selectin targeted complement inhibitors, with and without a dual function of directly blocking P-selectin-mediated cell-adhesion. The constructs are characterized in vitro and in murine models of hindlimb ischemia/reperfusion injury and hindlimb transplantation. Both constructs specifically targeted to reperfused hindlimb and provided protection in the hindlimb ischemia/reperfusion injury model. The P-selectin blocking construct was the more efficacious, which correlated with less myeloid cell infiltration, but with similarly reduced levels of complement deposition. The blocking construct also improved tissue perfusion and, unlike the nonblocking construct, inhibited coagulation, raising the possibility of differential application of each construct, such as in thrombotic vs. hemorrhagic conditions. Similar outcomes were obtained with the blocking construct following vascularized composite graft transplantation, and treatment also significantly increased graft survival. This is outcome may be particularly pertinent in the context of vascularized composite allograft transplantation, since reduced ischemia reperfusion injury is linked to a less rigorous alloimmune response that may translate to the requirement of a less aggressive immunosuppressive regime for this normally nonlife-threatening procedure. In summary, we describe a new generation of targeted complement inhibitor with multi-functionality that includes targeting to vascular injury, P-selectin blockade, complement inhibition and anti-thrombotic activity. The constructs described also bound to both mouse and human P-selectin which may facilitate potential translation.

Current status of glucocorticoid usage in solid organ transplantation.

Glucocorticoids (GCs) have been the mainstay of immunosuppressive therapy in solid organ transplantation (SOT) for decades, due to their potent effects on innate immunity and tissue protective effects. However, some SOT centers are reluctant to administer GCs long-term because of the various related side effects. This review summarizes the advantages and disadvantages of GCs in SOT. PubMed and Scopus databases were searched from 2011 to April 2021 using search syntaxes covering “transplantation” and “glucocorticoids”. GCs are used in transplant recipients, transplant donors, and organ perfusate solution to improve transplant outcomes. In SOT recipients, GCs are administered as induction and maintenance immunosuppressive therapy. GCs are also the cornerstone to treat acute antibody- and T-cell-mediated rejections. Addition of GCs to organ perfusate solution and pretreatment of transplant donors with GCs are recommended by some guidelines and protocols, to reduce ischemia-reperfusion injury peri-transplant. GCs with low bioavailability and high potency for GC receptors, such as budesonide, nanoparticle-mediated targeted delivery of GCs to specific organs, and combination use of dexamethasone with inducers of immune-regulatory cells, are new methods of GC application in SOT patients to reduce side effects or induce immune-tolerance instead of immunosuppression. Various side effects involving different non-targeted organs/tissues, such as bone, cardiovascular, neuromuscular, skin and gastrointestinal tract, have been noted for GCs. There are also potential drug-drug interactions for GCs in SOT patients.

Hypothermic oxygenated perfusion ameliorates ischemia-reperfusion injury of fatty liver in mice via Brg1/Nrf2/HO-1 axis.

After cold storage (CS) and subsequent transplantation, fatty liver is more inclined to develop liver dysfunction and serious postoperative complications in contrast to healthy liver. Hypothermic oxygenated perfusion (HOPE) is a safe and efficacious system, which can repair fatty liver and reduce ischemia-reperfusion injury. The aim of this research is to investigate the function of Brg1/Nrf2/HO-1 signaling pathway in the protective effect of HOPE on ischemia-reperfusion injury of fatty liver. The mouse fatty liver model was successfully established and verified by hematoxylin-eosin (HE) staining and oil red O staining. The animals were divided into Control group, CS group and HOPE group. The levels of liver enzyme and lactate in the perfusate were used to measure liver function and cellular metabolism. HE staining and TUNEL staining were utilized to assess the tissue structure and apoptosis, respectively. The levels of superoxide dismutase, malondialdehyde and reactive oxygen species in liver tissue were measured to quantitatively analyze the degree of oxidative stress, and the expressions of protein Brg1, Nrf2 and HO-1 were detected by means of the western blot. Double-labeling immunofluorescence was to explore the colocalization of Brg1 and Nrf2. The injury of the liver in the CS group was more serious than that in the control group. However, HOPE could significantly reduce the injury, which was manifested by the improvement of liver function and cellular metabolism, and the lower degrees of apoptosis, necrosis and oxidative stress. Furthermore, the expressions of Brg1, Nrf2 and HO-1 in the HOPE group were significantly increased than those in the CS group. One-hour HOPE treatment before reperfusion can obviously improve the injury of fatty liver in mice. The underlying mechanism may be that the interaction of Brg1 and Nrf2 can selectively activate the transcription of HO-1.

Retrograde reperfusion of renal graft to reduce ischemia-reperfusion injury

Retrograde reperfusion of renal graft to reduce ischemia-reperfusion injury