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Journal of Hepatology Oct 2019Hepatic ischemia-reperfusion injury (IRI) is a major complication of hemorrhagic shock, liver resection and transplantation. YAP, a key downstream effector of the Hippo...
BACKGROUND & AIMS
Hepatic ischemia-reperfusion injury (IRI) is a major complication of hemorrhagic shock, liver resection and transplantation. YAP, a key downstream effector of the Hippo pathway, is essential for determining cell fate and maintaining homeostasis in the liver. We aimed to elucidate its role in IRI.
METHODS
The role of YAP/Hippo signaling was systematically studied in biopsy specimens from 60 patients after orthotopic liver transplantation (OLT), and in a mouse model of liver warm IRI. Human biopsy specimens were collected after 2-10 h of cold storage and 3 h post-reperfusion, before being screened by western blot. In the mouse model, the role of YAP was probed by activating or inhibiting YAP prior to ischemia-reperfusion.
RESULTS
In human biopsies, high post-OLT YAP expression was correlated with well-preserved histology and improved hepatocellular function at postoperative day 1-7. In mice, the ischemia insult (90 min) triggered intrinsic hepatic YAP expression, which peaked at 1-6 h of reperfusion. Activation of YAP protected the liver against IR-stress, by promoting regenerative and anti-oxidative gene induction, while diminishing oxidative stress, necrosis/apoptosis and the innate inflammatory response. Inhibition of YAP aggravated hepatic IRI and suppressed repair/anti-oxidative genes. In mouse hepatocyte cultures, activating YAP prevented hypoxia-reoxygenation induced stress. Interestingly, YAP activation suppressed extracellular matrix synthesis and diminished hepatic stellate cell (HSC) activation, whereas YAP inhibition significantly delayed hepatic repair, potentiated HSC activation, and enhanced liver fibrosis at 7 days post-IRI. Notably, YAP activation failed to protect Nrf2-deficient livers against IR-mediated damage, leading to extensive fibrosis.
CONCLUSION
Our novel findings document the crucial role of YAP in IR-mediated hepatocellular damage and liver fibrogenesis, providing evidence of a potential therapeutic target for the management of sterile liver inflammation in transplant recipients.
LAY SUMMARY
In the clinical arm, graft YAP expression negatively correlated with liver function and tissue damage after human liver transplantation. YAP activation attenuated hepatocellular oxidative stress and diminished the innate immune response in mouse livers following ischemia-reperfusion injury. In the mouse model, YAP inhibited hepatic stellate cell activation, and abolished injury-mediated fibrogenesis up to 7 days after the ischemic insult.
Topics: Animals; Apoptosis; Cell Cycle Proteins; Cells, Cultured; Disease Models, Animal; Hippo Signaling Pathway; Humans; Inflammation; Liver; Liver Diseases; Liver Transplantation; Oxidative Stress; Protein Serine-Threonine Kinases; Reperfusion Injury; Shock, Hemorrhagic; Signal Transduction; Transcription Factors; Warm Ischemia
PubMed: 31201834
DOI: 10.1016/j.jhep.2019.05.029 -
Nature Aug 2022After cessation of blood flow or similar ischaemic exposures, deleterious molecular cascades commence in mammalian cells, eventually leading to their death. Yet with...
After cessation of blood flow or similar ischaemic exposures, deleterious molecular cascades commence in mammalian cells, eventually leading to their death. Yet with targeted interventions, these processes can be mitigated or reversed, even minutes or hours post mortem, as also reported in the isolated porcine brain using BrainEx technology. To date, translating single-organ interventions to intact, whole-body applications remains hampered by circulatory and multisystem physiological challenges. Here we describe OrganEx, an adaptation of the BrainEx extracorporeal pulsatile-perfusion system and cytoprotective perfusate for porcine whole-body settings. After 1 h of warm ischaemia, OrganEx application preserved tissue integrity, decreased cell death and restored selected molecular and cellular processes across multiple vital organs. Commensurately, single-nucleus transcriptomic analysis revealed organ- and cell-type-specific gene expression patterns that are reflective of specific molecular and cellular repair processes. Our analysis comprises a comprehensive resource of cell-type-specific changes during defined ischaemic intervals and perfusion interventions spanning multiple organs, and it reveals an underappreciated potential for cellular recovery after prolonged whole-body warm ischaemia in a large mammal.
Topics: Animals; Cell Death; Cell Survival; Cytoprotection; Gene Expression Profiling; Ischemia; Organ Specificity; Perfusion; Swine; Warm Ischemia
PubMed: 35922506
DOI: 10.1038/s41586-022-05016-1 -
Acta Biochimica Polonica 2018Organ injury during ischemia is one of the clinical problems of today's transplantation. It occurs during warm ischemia time (WIT) when the blood flow is cut off and... (Review)
Review
Organ injury during ischemia is one of the clinical problems of today's transplantation. It occurs during warm ischemia time (WIT) when the blood flow is cut off and during cold ischemia when a graft is chilled in situ until the circulation is restored to the recipient organism. Fast cooling of the organ slows down metabolism and activates intracellular enzymes, which minimizes the effects of warm ischemia. Unfortunately, hypothermia also results in inhibition of ATP synthesis, cell swelling and intracellular acidity. That is why research is continually being conducted to develop new fluids for rinsing and storing organs, as well as to optimize the composition of those that are already in use, which will allow for longer and more effective graft storage and restoration of their optimal functions after transplantation. This article provides current information on rinsing and storage fluids available on the global market. It also discusses tips for the fluid modifications with hormones and micronutrients.
Topics: Humans; Organ Preservation Solutions; Organ Transplantation; Reperfusion Injury; Temperature
PubMed: 29352749
DOI: 10.18388/abp.2017_2312 -
Experimental and Clinical... Mar 2021Chronic kidney disease is the most common type of organ failure worldwide, with a prevalence of 13.4% for all stages. Organ transplant is the only curative option for... (Review)
Review
Chronic kidney disease is the most common type of organ failure worldwide, with a prevalence of 13.4% for all stages. Organ transplant is the only curative option for end-stage kidney failure. However, the shortage of organ donors remains a major obstacle in organ transplant, with donation after circulatory death being the most viable path to increasing the donor pool. The circumstances that surround this type of donation are different from donation after brain death, namely concerning warm ischemia times, which are longer and may preclude a successful transplant. This article describes the pathophysiology of warm ischemia and summarizes recent developments in technological and methodological practices that mitigate the mechanisms of warm ischemia. Anoxia, mitochondrial dysfunction, calcium overload, oxidative and nitrosative stress, immune response, and no reflow are the main mechanisms by which ischemia leads to cell death and organ dysfunction. In situ oxygenated recirculation, abdominal normothermic organ recirculation, abdominal hypothermic organ recirculation, and ex vivo machine perfusion ensure continued organ perfusion and prevent prolonged warm ischemia in organ donation. These practices, coupled with optimizations in the identification and assessment of potential donors after circulatory death, may lead to a significant increase in the number and success rates of organ transplant worldwide.
Topics: Death; Humans; Tissue Donors; Warm Ischemia
PubMed: 32799784
DOI: 10.6002/ect.2020.0081 -
Experimental and Clinical... Feb 2020
Topics: Anastomosis, Surgical; Delayed Graft Function; Graft Survival; Humans; Kidney Transplantation; Treatment Outcome; Warm Ischemia
PubMed: 32170860
DOI: 10.6002/ect.2019.0317 -
Canadian Journal of Kidney Health and... 2023Prolonged warm ischemia time (WIT) and cold ischemia time (CIT) are independently associated with post-transplant graft failure; their combined impact has not been...
BACKGROUND
Prolonged warm ischemia time (WIT) and cold ischemia time (CIT) are independently associated with post-transplant graft failure; their combined impact has not been previously studied. We explored the effect of combined WIT/CIT on all-cause graft failure following kidney transplantation.
METHODS
The Scientific Registry of Transplant Recipients was used to identify kidney transplant recipients from January 2000 to March 2015 (after which WIT was no longer separately reported), and patients were followed until September 2017. A combined WIT/CIT variable (excluding extreme values) was separately derived for live and deceased donor recipients using cubic splines; for live donor recipients, the reference group was WIT 10 to <23 minutes and CIT >0 to <0.42 hours, and for deceased donor recipients the WIT was 10 to <25 minutes and CIT 1 to <7.75 hours. The adjusted association between combined WIT/CIT and all-cause graft failure (including death) was analyzed using Cox regression. Secondary outcomes included delayed graft function (DGF).
RESULTS
A total of 137 125 recipients were included. For live donor recipients, patients with prolonged WIT/CIT (60 to ≤120 minutes/3.04 to ≤24 hours) had the highest adjusted hazard ratio (HR) for graft failure (HR = 1.61, 95% confidence interval [CI] = 1.14-2.29 relative to the reference group). For deceased donor recipients, a WIT/CIT of 63 to ≤120 minutes/28 to ≤48 hours was associated with an adjusted HR of 1.35 (95% CI = 1.16-1.58). Prolonged WIT/CIT was also associated with DGF for both groups although the impact was more driven by CIT.
CONCLUSIONS
Combined WIT/CIT is associated with graft loss following transplantation. Acknowledging that these are separate variables with different determinants, we emphasize the importance of capturing WIT and CIT independently. Furthermore, efforts to reduce WIT and CIT should be prioritized.
PubMed: 37333478
DOI: 10.1177/20543581231178960 -
International Journal of Molecular... Aug 2021Ischemia/reperfusion injury (IRI) remains a significant problem to be solved in uterus transplantation (UTx). Melatonin and glycine have been shown to possess direct...
Ischemia/reperfusion injury (IRI) remains a significant problem to be solved in uterus transplantation (UTx). Melatonin and glycine have been shown to possess direct cytoprotective activities, mainly due to their antioxidative and anti-inflammatory properties. The aim of this study was to investigate the protective effects of melatonin and glycine and their combination on IRI in a rat model of warm ischemia. In this study, rats were assigned to eight groups, including sham and IRI ( = 80). Melatonin and glycine alone or their combination were administered prior to 1 h of uterus ischemia followed by 1 h of reperfusion. Melatonin (50 mg/kg) was administered via gavage 2 h before IRI and glycine in an enriched diet for 5 days prior to intervention. Uterus IRI was estimated by histology, including immunohistochemistry, and biochemical tissue analyses. Histology revealed that uterus IRI was significantly attenuated by pretreatment with melatonin ( = 0.019) and glycine ( = 0.044) alone as well as their combination ( = 0.003). Uterus IRI led to increased myeloperoxidase expression, which was significantly reduced by melatonin ( = 0.004), glycine ( < 0.001) or their combination ( < 0.001). The decline in superoxide dismutase activity was significantly reduced in the melatonin ( = 0.027), glycine ( = 0.038) and combined treatment groups ( = 0.015) when compared to the IRI control group. In conclusion, melatonin, glycine and their combination significantly reduced oxidative stress-induced cell damage after IRI in a small animal warm ischemia model, and, therefore, clinical studies are required to evaluate the protective effects of these well-characterized substances in uterus IRI.
Topics: Animals; Antioxidants; Disease Models, Animal; Female; Glycine; Glycine Agents; Melatonin; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Uterus; Warm Ischemia
PubMed: 34445081
DOI: 10.3390/ijms22168373 -
Transplantation Direct Jun 2022The expansion of donation after circulatory determination of death (DCDD) programs and unmet demands for kidney transplantation indicate that there is a need to improve...
BACKGROUND
The expansion of donation after circulatory determination of death (DCDD) programs and unmet demands for kidney transplantation indicate that there is a need to improve the efficiency and utilization of these organs.
METHODS
We studied all DCDD donors retrieved for kidney transplantation in Australia between 2014 and 2019 and determined the factors associated with nonutilization using least absolute shrinkage and selection operator and random forest models. Self-organizing maps were used to group these donors into clusters with similar characteristics and features associated with nonutilization were defined.
RESULTS
Of the 762 DCDD donors, 116 (15%) were not utilized for kidney transplantation. Of the 9 clusters derived from self-organizing map, 2 had the highest proportions of nonutilized kidneys. Factors for nonutilization (adjusted odds ratio [95% confidence interval], per SD increase) were duration from withdrawal of cardiorespiratory support till death (1.38 [1.16-1.64]), admission and terminal serum creatinine (1.43 [1.13-1.85]) and (1.41 [1.16-1.73]). Donor kidney function and duration of warm ischemia were the main factors for clinical decisions taken not to use kidneys from DCDD donors.
CONCLUSIONS
Donor terminal kidney function and the duration of warm ischemia are the key factors for nonutilization of DCDD kidneys. Strategies to reduce the duration of warm ischemia and improve post-transplant recipient kidney function may reduce rates of nonutilization.
PubMed: 35721459
DOI: 10.1097/TXD.0000000000001331 -
European Urology Jul 2015Partial nephrectomy (PN) is the current gold standard treatment for small localized renal tumors.; however, the impact of duration and type of intraoperative ischemia on... (Review)
Review
CONTEXT
Partial nephrectomy (PN) is the current gold standard treatment for small localized renal tumors.; however, the impact of duration and type of intraoperative ischemia on renal function (RF) after PN is a subject of significant debate.
OBJECTIVE
To review the current evidence on the relationship of intraoperative ischemia and RF after PN.
EVIDENCE ACQUISITION
A review of English-language publications on renal ischemia and RF after PN was performed from 2005 to 2014 using the Medline, Embase, and Web of Science databases. Ninety-one articles were selected with the consensus of all authors and analyzed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria.
EVIDENCE SYNTHESIS
The vast majority of reviewed studies were retrospective, nonrandomized observations. Based on the current literature, RF recovery after PN is strongly associated with preoperative RF and the amount of healthy kidney parenchyma preserved. Warm ischemia time (WIT) is modifiable and prolonged warm ischemia is significantly associated with adverse postoperative RF. Available data suggest a benefit of keeping WIT <25min, although the level of evidence to support this threshold is limited. Cold ischemia safely facilitates longer durations of ischemia. Surgical techniques that minimize or avoid global ischemia may be associated with improved RF outcomes.
CONCLUSIONS
Although RF recovery after PN is strongly associated with quality and quantity of preserved kidney, efforts should be made to limit prolonged WIT. Cold ischemia should be preferred when longer ischemia is expected, especially in presence of imperative indications for PN. Additional research with higher levels of evidence is needed to clarify the optimal use of renal ischemia during PN.
PATIENT SUMMARY
In this review of the literature, we looked at predictors of renal function after surgical resection of renal tumors. There is a strong association between the quality and quantity of renal tissue that is preserved after surgery and long-term renal function. The time of interruption of renal blood flow during surgery is an important, modifiable predictor of postoperative renal function.
Topics: Carcinoma, Renal Cell; Cold Ischemia; Humans; Kidney Neoplasms; Nephrectomy; Nephrons; Organ Sparing Treatments; Postoperative Complications; Renal Insufficiency; Warm Ischemia
PubMed: 25703575
DOI: 10.1016/j.eururo.2015.01.025 -
World Journal of Hepatology Dec 2017To study the effects of warm ischemia-reperfusion (I/R) injury on hepatic morphology at the ultrastructural level and to analyze the expression of the thioredoxin (TRX)...
AIM
To study the effects of warm ischemia-reperfusion (I/R) injury on hepatic morphology at the ultrastructural level and to analyze the expression of the thioredoxin (TRX) and glutaredoxin (GRX) systems.
METHODS
Eleven patients undergoing liver resection were subjected to portal triad clamping (PTC). Liver biopsies were collected at three time points; first prior to PTC (baseline), 20 min after PTC (post-ischemia) and 20 min after reperfusion (post-reperfusion). Electron microscopy and morphometry were used to study and quantify ultrastructural changes, respectively. Additionally, gene expression analysis of TRX and GRX isoforms was performed by quantitative PCR. For further validation of redox protein status, immunogold staining was performed for the isoforms GRX1 and TRX1.
RESULTS
Post-ischemia, a significant loss of the liver sinusoidal endothelial cell (LSEC) lining was observed (P = 0.0003) accompanied by a decrease of hepatocyte microvilli in the space of Disse. Hepatocellular morphology was well preserved apart from the appearance of crystalline mitochondrial inclusions in 7 out of 11 patients. Post-reperfusion biopsies had similar features as post-ischemia with the exception of signs of a reactivation of the LSECs. No changes in the expression of redox-regulatory genes could be observed at mRNA level of the isoforms of the TRX family but immunoelectron microscopy indicated a redistribution of TRX1 within the cell.
CONCLUSION
At the ultrastructural level, the major impact of hepatic warm I/R injury after PTC was borne by the LSECs with detachment and reactivation at ischemia and reperfusion, respectively. Hepatocytes morphology were well preserved. Crystalline inclusions in mitochondria were observed in the hepatocyte after ischemia.
PubMed: 29290907
DOI: 10.4254/wjh.v9.i34.1261