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Common marginal donor liver mainly consists of fatty donor liver, elderly donor liver, small volume donor liver and liver graft from donation after cardiac death (DCD), etc. The application of marginal donor liver may resolve the severe shortage of donor liver to certain extent. Nevertheless, marginal donor liver yields a higher risk of ischemia-reperfusion injury (IRI) and causes more severe IRI than normal donor liver, which is a main cause for the failure of transplantation. In addition, oxidative stress is a major risk factor causing IRI of marginal donor liver. Therefore, how to mitigate oxidative stress and alleviate IRI of marginal donor liver has become a hot spot in clinical practice. Reactive oxygen species (ROS)-mediated oxidative stress occurs throughout the whole process of IRI. In this article, the role of oxidative stress in IRI of marginal donor liver transplantation and the ROS-targeted prevention and treatment were reviewed, aiming to provide reference for clinical practice.
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Objective To evaluate the effect of high mobility group box 1 (HMGB1)/ cysteinyl aspartate specific proteinase (Caspase)-1/Gasdermin D (GSDMD) signaling axis-mediated hepatocyte pyroptosis on liver ischemia-reperfusion injury (IRI). Methods C57BL/6 mice were randomly divided into the sham operation group (Sham group), IRI 2 h group, IRI 6 h group, IRI 12 h group, glycyrrhizic acid (GA)+Sham group and GA+IRI 12 h group (n=8 in each group). AML12 cells were evenly divided into the Sham group, IRI 12 h group, GA+Sham group and GA+IRI 12 h group. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), interleukin (IL)-1β and IL-6 in each group were detected by enzyme-linked immune absorbent assay(ELISA). The messenger ribonucleic acid (mRNA) levels of IL-1β and IL-6 were detected by reverse transcription polymerase chain reaction(RT-PCR). The pathological score of liver ischemia and cell apoptosis were compared among all groups. The expression level of HMGB1 in the liver tissues of each group was determined by immunohistochemistry. The expression levels of HMGB1, Caspase-1 and GSDMD proteins in the mouse liver tissues and AML12 cells were measured by Western blot. Results Compared with the Sham group, the serum levels of ALT, AST, IL-1β and IL-6 and the relative expression levels of IL-1β and IL-6 mRNA in the liver tissues were all significantly up-regulated after IRI in each group (all P < 0.05), and showed significant time-dependent pattern along with the prolongation of reperfusion time. Compared with the Sham group, the pathological score of hepatic ischemia and the apoptosis rate of hepatocytes were significantly increased after IRI in each group (all P < 0.05). Immunohistochemical results showed that the expression level of HMGB1 in the liver tissues was significantly up-regulated after IRI, which showed an increasing trend along with the prolongation within the period of 2-12 h. Western blot showed that compared with the Sham group, the relative expression levels of HMGB1, Caspase-1 and GSDMD proteins in vivo and in vitro were up-regulated in the IRI 12 h group. The relative expression level of HMGB1 protein was significantly up-regulated, whereas those of Caspase-1 and GSDMD proteins were significantly down-regulated in the GA+IRI 12 h group compared with those in the IRI 12 h group (all P < 0.05). Conclusions Hepatocytes probably activate the Caspase-1/GSDMD signaling pathway by releasing HMGB1, thereby triggering hepatocyte pyroptosis and leading to liver IRI. Inhibition of extracellular release of HMGB1 by GA may mitigate liver IRI.
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Objective To evaluate the effect and mechanism of nicotinamide mononucleotide (NMN) on ischemia-reperfusion injury (IRI) induced by donor liver after cardiac death in rat models. Methods Rat models of orthotopic liver transplantation were established by "magnetic ring + double cuff" method. SD rats were randomly divided into the sham operation group (Sham group), orthotopic liver transplantation group (OLT group), NMN treatment + orthotopic liver transplantation group (NMN group), NMN+sirtuin-3 (Sirt3) inhibitor (3-TYP) + orthotopic liver transplantation group (NMN+3-TYP group), respectively. Pathological changes and hepatocyte apoptosis of the rats were observed in each group. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were determined. Superoxide dismutase (SOD) and malondialdehyde (MDA) contents in liver tissues were detected. The expression levels of Sirt3, microtubule-associated protein 1 light chain 3 (LC3)Ⅱ, PTEN-induced putative kinase 1 (PINK1), Parkin and translocase of the outer mitochondrial membrane 20 (TOMM20) in liver tissues were measured. Postoperative survival of the rats in each group was analyzed. Results Compared with the Sham group, serum ALT and AST levels were higher in the OLT group. Compared with the OLT group, the levels of ALT and AST were decreased in the NMN group. Compared with the NMN group, the levels of ALT and AST were increased in the NMN +3-TYP group (all P < 0.05). The liver tissue structure of rats in the Sham group was basically normal. In the OLT group, pathological changes, such as evident congestion, vacuolar degeneration and hepatocyte necrosis, were observed in the liver tissues. Compared with the Sham group, Suzuki score and apoptosis rate were higher in the OLT group. Suzuki score and apoptosis rate in the NMN group were lower than those in the OLT group. Suzuki score and apoptosis rate in the NMN+3-TYP group were higher compared with those in the NMN group (all P < 0.05). Compared with the Sham group, the SOD content was decreased, whereas the MDA content was increased in the OLT group. Compared with the OLT group, the SOD content was increased, whereas the MDA content was decreased in the NMN group. Compared with the NMN group, the SOD content was decreased, whereas the MDA content was increased in the NMN+3-TYP group (all P < 0.05). Compared with the Sham group, the relative expression levels of Sirt3 and TOMM20 proteins were down-regulated, whereas those of PINK1, Parkin and LC3Ⅱproteins were up-regulated in the OLT group. Compared with the OLT group, the relative expression levels of Sirt3, PINK1, Parkin and LC3Ⅱproteins were up-regulated, whereas that of TOMM20 protein was down-regulated in the NMN group. Compared with the NMN group, the relative expression levels of PINK1, Parkin and LC3Ⅱproteins were down-regulated, whereas that of TOMM20 protein was up-regulated in the NMN+3-TYP group (all P < 0.05). In the Sham group, the 7 d survival rate of rats was 100%, 50% in the OLT group, 75% in the NMN group and 58% in the NMN+3-TYP group, respectively. Conclusions NMN may enhance the antioxidative capacity of the liver, induce PINK1/Parkin-mediated mitochondrial autophagy, and alleviate IRI of the liver by up-regulating Sirt3, thereby playing a protective role in the donor liver after cardiac death.
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Liver transplantation is an effective treatment of end-stage liver diseases. However, liver ischemia-reperfusion injury (IRI) and rejection significantly cause the decrease of survival rate of liver graft. Therefore, it is urgent to explore a novel method, which can not only alleviate liver IRI, but also promote immune tolerance of allograft, thereby improving the survival rate of liver graft. Extracellular vesicle (EV) is nanoparticle released from cells into the extracellular microenvironment, which may alleviate graft injury by repairing autophagy, immunosuppression and accelerating tissue regeneration. Hence, EV becomes a research hot spot in the field of liver transplantation. Nevertheless, the clinical application of EV encounters multiple challenges, such as separation, purification, identification, storage of EV and how to deliver EV to the target cells. In this article, the mechanism of EV in liver IRI, the challenges in clinical application of EV and the potential application of EV were reviewed, aiming to provide reference for the clinical application of EV in liver transplantation.
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Objective To investigate the effect and its molecular mechanism of phosphoglycerate mutase 5 (PGAM5) mediated pyroptosis on liver ischemia-reperfusion injury (IRI). Methods C57 mouse models of liver IRI were established and randomly divided into the 6 h reperfusion (6 h group) and 12 h reperfusion (12 h group), and sham operation group (sham group) was established too, 10 rats in each group. The effect of IRI on the parameters in the liver tissues and serum samples was evaluated. The expression levels of PGAM5 and cysteinyl aspartate specific proteinase (Caspase)-1 in the liver tissues during IRI were quantitatively detected. The IRI models of liver cells were established (IRI group). The IRI models of liver cells were established after pretreatment with Caspase-1 inhibitor Z-YVAD-FMK (inhibitor group). The untreated AML12 cells were allocated into the control group. The effect of inhibiting Caspase-1 activity on pyroptosis was analyzed. AML12 cells were transfected with PGAM5 small interfering ribonucleic acid (siRNA) (siRNA group) and siRNA-negative control (siRNA-NC) (siRNA-NC group) by liposome 3000, and then IRI models of liver cells were established. The untreated AML12 cells were assigned into the control group. The effect of PGAM5 mediated pyroptosis on IRI of liver cells was assessed. Results In the 6 h and 12 h groups, partial liver cell edema, hepatic sinusoid narrowing, central vein congestion and occasional spot necrosis were observed in the mouse liver tissues, and these changes in the 12 h group were more aggravated than those in the 6 h group. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the 6 h and 12 h groups were higher than those in the sham group, and the values in the 12 h group were higher than those in the 6 h group. The levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β were increased in the 6 h and 12 h groups, and the values in the 12 h group were lower than those in the 6 h group. The relative expression levels of IL-1β messenger ribonucleic acid (mRNA) in the mouse liver tissues in the 6 h and 12 h groups were up-regulated, and the value in the 12 h group was lower than that in the 6 h group. The cell apoptosis rates in the liver tissues were significantly increased in the 6 h and 12 h groups, and the value in the 12 h group was remarkably lower than that in the 6 h group (P < 0.01-0.05). Compared with the sham group, the relative expression levels of PGAM5 mRNA and protein in the mouse liver tissues in the 6 h and 12 h groups were significantly up-regulated, and the values in the 12 h group were significantly higher than those in the 6 h group (P < 0.01-0.05). The protein expression levels of PGAM5 and Caspase-1 in the liver tissues were up-regulated in the 6 h and 12 h groups. Compared with the control group, the relative expression levels of NOD-like receptor protein 3 (NLRP3), cleaved Caspase-1 and Gasdermin D (GSDMD) proteins were up-regulated and the fluorescence intensity of GSDMD was increased in the IRI group. Compared with the IRI group, the relative expression levels of NLRP3, cleaved Caspase-1 and GSDMD proteins were significantly down-regulated and the fluorescence intensity of GSDMD was considerably decreased in the inhibitor group (P < 0.01-0.05). Compared with the control group, the cell survival rate was significantly decreased, and the relative expression levels of PGAM5, NLRP3, cleaved Caspase-1 and GSDMD proteins were significantly up-regulated in the siRNA-NC group (P < 0.01-0.05). Compared with the siRNA-NC group, the cell survival rate was remarkably increased, whereas the relative expression levels of PGAM5, NLRP3, cleaved Caspase-1 and GSDMD proteins were significantly down-regulated in the siRNA group (P < 0.01-0.05). Conclusions PGAM5 may aggravate the liver IRI in mouse models probably by mediating pyroptosis via PGAM5/Caspase-1/GSDMD signaling pathway and aggravating liver cell injury.
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Objective To explore the mechanism of human umbilical cord mesenchymal stem cell (HUC-MSC) alleviating ischemia-reperfusion injury (IRI) of liver cells through mitochondrial transfer. Methods Normal human liver cell line L02 was divided into the blank control group, oxygen-glucose deprivation (OGD) group, experimental control group, and L02 and HUC-MSC co-culture group (L02+HUC-MSC group). L02+HUC-MSC group was further divided into 10:1 co-culture subgroup (group A), 4:1 co-culture subgroup (group B), 2:1 co-culture subgroup (group C), 1:1co-culture subgroup (group D) and 1:2 co-culture subgroup (group E) according to different co-culture ratio of L02 and HUC-MSC. The apoptosis rate and relative reactive oxygen species (ROS) level of L02 cells were detected by flow cytometry. The MitoTracker positive rate of L02 cells was detected by flow cytometry. The mitochondrial transfer from HUC-MSC to L02 cells was observed by laser confocal microscope. Results The apoptosis rate and relative ROS level of L02 cells in the OGD group were significantly higher than those in the blank control group (both P < 0.05). Compared with the OGD group, the apoptosis rates of L02 cells in group B, C, D and E were significantly decreased (all P < 0.05), and the relative ROS level of L02 cells in group E was significantly declined (P < 0.05). The MitoTracker positive rate of L02 cells did not significantly differ between group A and experimental control group (P>0.05), whereas the MitoTracker positive rates of L02 cells in group B, C, D and E were significantly higher than that in the experimental control group in a concentration-dependent manner (all P < 0.05). Under the laser confocal microscope, mitochondrial transfer fromHUC-MSC to L02 cells could be observed through tunneling nanotube (TNT). Conclusions HUC-MSC may alleviate cell apoptosis and reduce ROS level of liver cells after IRI via direct mitochondrial transfer between cells.
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How to improve the long-term prognosis of transplant kidney and solve the shortage of donor kidney are still two major problems that plague clinicians. Among them, ischemia-reperfusion injury (IRI), rejection, infection, and immunosuppressive therapy are important issues in the research field of renal transplantation. Therefore, strengthening the literature study in the field of renal transplantation and understanding the nature of transplant kidney related diseases and international frontier research hotspots, help to further improve the function and prolong the survival time of the transplant kidney in clinic. This article interpreted literatures on the research hotspots and new progress in the field of renal transplantation in the third quarter of 2020, combined with the meeting minutes of the 12th Lingnan Reading Club, and reviewed from the three aspects of IRI, rejection and infection.
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Ischemia-reperfusion injury (IRI) is a common pathophysiological phenomenon, secondary to multiple pathological processes, such as organ transplantation, acute kidney injury and myocardial infarction. IRI may significantly aggravate the severity of diseases and increase the fatality of patients. Aseptic inflammation is one of the critical mechanisms of IRI. Damage-associated molecular pattern (DAMP) is a pivotal substance, which mediates aseptic inflammation. After released into extracellular space, it could effectively activate the immune system, and initiate and maintain the inflammatory responses by binding with pattern recognition receptor (PRR). Neutrophil extracellular trap (NET) is a DNA-based network structure released by neutrophils during the process of inflammatory responses, which contains histones and multiple granular proteins. Recent studies have demonstrated that DAMP and NET may aggravate IRI via aseptic inflammation. In this article, relevant studies of DAMP, NET and their relationship in IRI were reviewed, which was of great significance for understanding the pathophysiological mechanism of IRI and studying the corresponding prevention and treatment strategies.
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High-quality donor organs is of significance for the success of organ transplantation. However, standard donors fail to meet the requirements of kidney transplantation due to the increasing quantity of patients with kidney failure. Marginal donor kidneys have been widely applied in clinical practice, which also poses challenges to the existing preservation methods of donor kidneys. Ischemia-reperfusion injury (IRI) is one of the critical factors affecting the early graft function after kidney transplantation. In addition, it exerts harmful effect upon the long-term survival of the graft. Current studies have demonstrated that hemoglobin-based oxygen carrier (HBOC) may reduce the IRI during kidney transplantation, effectively improve the preservation quality and prolong the preservation time of donor kidney. In this article, the research progress on HBOC in kidney transplantation was reviewed, aiming to provide reference for modifying the preservation method of donor kidney, improve the quality of donor kidney and enhance clinical prognosis of the recipients.
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Ischemia-reperfusion injury (IRI) is one of the main causes of early graft dysfunction after renal transplantation. In China, organ transplantation has entered into the era of organ donation after citizen's death. The increased risk of cardiopulmonary resuscitation, prolonged hypoperfusion time and warm ischemia time of donors may lead to IRI of the graft, and affect the short- and long-term clinical prognosis of the recipient and graft. Under IRI and other stress conditions, the mechanism of mitochondrial dynamics, mainly manifested by dynamic regulation of mitochondrial division and fusion, exert critical effect upon the biological function of mitochondria. Cell apoptosis caused by mitochondrial injury is the key event leading to acute kidney injury, which is mainly manifested by the imbalance of the regulatory mechanism of mitochondrial dynamics. In this article, the research progress on the regulatory mechanism of mitochondrial dynamics on renal IRI was reviewed, aiming to provide reference for improving the clinical outcomes of renal transplantation.
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Renal ischemia-reperfusion injury (IRI) commonly occurs in renal transplantation, which is an important pathophysiological process that causes acute renal failure and severely affects clinical prognosis of the recipients. Inflammatory response plays a critical role in the pathogenesis and pathological process of IRI. Activated NOD-like receptor protein 3(NLRP3) inflammasome can mediate the maturation and release of various pro-inflammatory cytokines, thereby regulating the inflammatory response and relevant cell functions. In this article, the mechanism underlying NLRP3 inflammasome and its related inflammatory signaling pathway in renal IRI were reviewed, aiming to provide novel ideas for clinical prevention and treatment of renal IRI.
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Renal transplantation is the optimal approach to improve the quality of life and restore normal life for patients with end-stage renal diseases.With the development of medical techniques and immunosuppressants, the shortterm survival of renal graft has been significantly prolonged, whereas the long-term survival remains to be urgently solved.Renal ischemia-reperfusion injury (IRI), acute rejection, chronic renal allograft dysfunction, renal fibrosis and other factors are still the major problems affecting the survival of renal graft.Relevant researches have always been hot spots in the field of renal transplantation.Meantime, 2020 is an extraordinary year.The novel coronavirus pneumonia (COVID-19) pandemic severely affects the development of all walks of life.Researches related to renal transplantation have also sprung up.In this article, the frontier hotspots of clinical and basic studies related to renal transplantation and the COVID-19 related researches in the field of renal transplantation in China were reviewed, aiming to provide novel therapeutic ideas and strategies.
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Objective To investigate the relationship between the interleukin (IL)-35 and the recovery of renal graft function. Methods Clinical data of 45 recipients receiving renal transplantation from donation after cardiac death (DCD) were retrospectively analyzed. According to the presence of delayed graft function (DGF) after renal transplantation, all recipients were divided into the immediate graft function (IGF) group (n=32) and DGF group (n=13). The serum creatinine (Scr) level and estimated glomerular filtration rate (eGFR) in the recipients were statistically compared between two groups at 1, 2, 3, 7, 14, 28 d and 3, 6 and 12 months after renal transplantation. The IL-35 levels in the serum and urine samples of the recipients were statistically compared between two groups at 1, 2, 3, 7, 14, 28 d following renal transplantation. Results In the DGF group, the renal function was restored slowly. Compared with the IGF group, the Scr level was significantly higher, whereas the eGFR was considerably lower in the DGF group at postoperative 7 d (both P<0.05). At 1 year after surgery, there was no significant difference in the Scr level between two groups. Compared with the IGF group, the eGFR in the DGF group was significantly lower at postoperative 1 year (P<0.05). At 1, 2, 3, 7, 14 d after operation, the serum levels of IL-35 in the DGF group were evidently lower than those in the IGF group (all P<0.05). Compared with the IGF group, the serum level of IL-35 in the DGF group was significantly increased at postoperative 28 d (P<0.05). At postoperative 1, 2, 3, 7 d, the IL-35 levels in the urine samples in the DGF group were significantly lower than those in the IGF group (all P<0.05). At postoperative 14 and 28 d, the IL-35 levels in the urine samples did not significantly differ between two groups (both P>0.05). Conclusions The low levels of IL-35 in the serum and urine of recipients after renal transplantation are associated with the incidence of DGF to certain extent, prompting that excessively weak systemic and local anti-inflammatory responses early after renal transplantation and uncontrolled excessive inflammatory response are probably the pivotal causes of DGF.
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Objective To investigate the effect of nuclear factor erythroid-2-related factor 2(Nrf2) on the anti-hypoxia and anti-apoptotic ability of mesenchymal stem cells(MSCs). Methods Human embryonic kidney cells(293FT) were transfected with recombinant plasmid which overexpressed Nrf2 and helper plasmid. High-titer lentivirus which overexpressed Nrf2 were obtained. MSCs were transfected with lentivirus with Nrf2 overexpression and empty lentiviral vector to establish Nrf2-MSCs which stably overexpressed Nrf2 (Nrf2 overexpression group) and green fluorescent protein (GFP)-MSCs(control group). The expression of green fluorescent in 2 groups was observed by fluorescence microscope. The expression level of Nrf2 protein in 2 groups was measured by Western Blot. The anti-hypoxia ability of 2 groups was observed by light microscope. The anti-apoptotic ability of 2 groups was measured by flow cytometry. Results Nrf2-MSCs which stably overexpressed Nrf2 were successfully established. Western Blot analysis revealed that the expression level of Nrf2 protein in the Nrf2 overexpression group was significantly higher than that in the control group(P<0.01). After 15 h hypoxia treatment, the cell activity in the Nrf2 overexpression group was significantly higher than that in the control group. Flow cytometry showed that the apoptosis rate in the Nrf2 overexpression group was (30.9±1.4)%, significantly lower than (61.3±1.3)% in the control group(P<0.05). Conclusions Nrf2-MSCs which can stably overexpress Nrf2 possess certain anti-hypoxia and anti-apoptotic ability in hypoxia environment.
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Objective To observe the effect of HIF-1a/iNOS signaling pathway on myocardial ischemia-reperfusion injury in rat heart transplantation and the protective mechanism of N-acetylcysteine (NAC) on donor heart after cardiac transplantation in rats.Methods Eighty healthy male Lewis rats were randomly divided into 3 groups,the control group (0.3 ml saline was infused via inferior vena cava 30 min before donor harvest or implantation),NAC donor pretreatment group [NAC (30 mg/kg.w) was injected into the vena cava of donor rat 30 min defore donor harvest],and the NAC receptor pretreatment group (NAC 300 mg/kg.w was injected into the vena cava of the recipient rats 30 min before transplantation.The 30 min was injected into the vena cava of the recipient rats).A transplant model was established and the graft was obtained after 24 h transplantation.The expression of iNOS,HIF-1a and mRNA in cardiac muscle tissue was detected by immunohistochemistry and Real time-PCR.Results HIF-1a protein expression in graft myocardial tissue was significantly lower in NAC donor pretreatment and recipient pretreatment group compared with control group (P ＜0.05),the differences were statistically significant (2.72±0.17 vs.2.24±0.23 vs.3.14.±0.16,F=56.26,P =0.000).The iNOS protein expression in NAC donor pretreatment group,and NAC recipient pretreatment group were lower than that in the control group (1.52±0.18 vs.1.61±0.19 vs.3.30±0.18,F=232.345,P =0.000),the differences were statistically significant (P ＜ 0.05).24 h after transplantation,the differences in graft myocardial tissue HIF-1a and iNOS mRNA among the three groups were statistically significant (F=7.467,16.490,P=0.003,0.000).The expression of iNOS mRNA in the NAC receptor pretreatment group was significantly lower than that in the control group (P＜0.05).Conclusion HIF-1a/iNOS signaling pathway can regulate ischemia reperfusion injury in rat heart transplantation,and the protective effect of NAC on donor heart maybe mediated via this pathway.
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Objective To investigate the protective roles of Epigallocatechin gallate (EGCG) on liver ischemia reperfusion injury (IRI) in rats.Methods 30 healthy male SD rats were selected and equally and randomly divided into 3 groups.Sham group,IRI group and IRI-EGCG group were established to construct 70％ liver IRI rat model.Drinking water with 0.4 mg/ml EGCG was administered for 2 weeks before the experiment in IRI-EGCG group.HE staining was performed to evaluate the injury.Transaminases in serum were investigated to assess liver injury.p-p85 and p-AKT was detected by Western-blot assay.qPCR was carried out to study the mRNA expression of TNF-α,IL-6 and IL-1β in liver tissue.The secretion of TNF-α,IL-6 and IL-1 β in serum was examined with ELISA assay.Results EGCG pretreatment reduced ASTand ALT in serum [AST:(550.0 ±66.5) IU/L vs.(220.0 ±63.5) IU/L;ALT:(376.0 ± 25.7) IU/L vs.(158.0 ± 33.1) IU/L,all P ＜ 0.05] and mitigated liver tissue damage.p-p85 and p-AKT increased due to liver IRI,and IRI-EGCG group showed higher expression of p85 and AKT.The proinflammatory cytokines of TNF-α,IL-6 and IL-1 β exhibited a relatively lower mRNA expression in IRI-EGCG group comparing with IRI group.IRI-EGCG group also revealed a decreased secretion of TNF-α,IL-6 and IL-1β in serum [TNF-α:(398.0±33.4) ng/Lvs.(211.0±23.6) ng/L;IL-6:(341.0±27.3) ng/L vs.(187.0±19.6) ng/L;IL-1β:(486.0±43.7) ng/L vs.(352.0±31.5) ng/L;allP＜0.05].Conclusion EGCG pretreatment can enhance IRI-induced activation of PI3K/AKT signaling and reduce the release of proinflammatory cytokines to exert liver protective effects.