METABOLIC DYSREGULATION AND MITOCHONDRIAL DYSFUNCTION DEFINE INJURY PROFILES OF DONOR KIDNEYS AFTER BRAIN DEATH AND ISCHAEMIA-REPERFUSION
M Lo FaroM. Zeeshan AkhtarH. HuangMaria KaisarR. RebolledoKarl MortenLisa C. HeatherHenri G. D. LeuveninkS FuggleBenedikt M. KesslerChristopher W. PughRutger J. Ploeg
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Cerebral ischemia results in a poor oxygen supply and cerebral infarction. Reperfusion to the ischemic area is the best therapeutic approach. Although reperfusion after ischemia has beneficial effects, it also causes ischemia/reperfusion (I/R) injury. Increases in oxidative stress, mitochondrial dysfunction, and cell death in the brain, resulting in brain infarction, have also been observed following cerebral I/R injury. Mitochondria are dynamic organelles, including mitochondrial fusion and fission. Both processes are essential for mitochondrial homeostasis and cell survival. Several studies demonstrated that an imbalance in mitochondrial dynamics after cerebral ischemia, with or without reperfusion injury, plays an important role in the regulation of cell survival and infarct area size. Mitochondrial dysmorphology/dysfunction and inflammatory processes also occur after cerebral ischemia. Knowledge surrounding the mechanisms involved in the imbalance in mitochondrial dynamics following cerebral ischemia with or without reperfusion injury would help in the prevention or treatment of the adverse effects of cerebral injury. Therefore, this review aims to summarize and discuss the roles of mitochondrial dynamics, mitochondrial function, and inflammatory processes in cerebral ischemia with or without reperfusion injury from in vitro and in vivo studies. Any contradictory findings are incorporated and discussed.
Brain ischemia
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Ischemia-reperfusion injury represents a pathological condition characterized by an initial undersupply of blood to an area or organ followed by a restoration of perfusion and concomitant reoxygenation (= reperfusion). Ischemia typically occurs in the presence of embolism or thrombosis but can also be triggered by surgery and transplantation. Anyway, the disturbance in perfusion results in a severe imbalance between metabolic supply and demand, subsequently causing tissue hypoxia [1]. Notably, these initial changes cause time-dependent molecular and structural alterations. In this context, it is also important to consider that all tissues and organs are susceptible to ischemia, but susceptibility to an ischemic insult differs between organ systems. Whereas the brain can endure ischemia only a few minutes, other tissues (e.g., muscle) are able to withstand ischemia for a long time without signs of irreversible damage.
Interestingly, restoration of blood flow and reoxygenation is commonly associated with an exacerbation of tissue injury and a profound inflammatory response (“reperfusion injury”) [1, 2]. Ischemia-reperfusion injury contributes to pathology in a wide range of conditions.
For example, myocardial ischemia followed by reperfusion typically manifests in microvascular dysfunction, death of myocytes, and myocardial stunning or dysfunction.
Ischemia-reperfusion injury (IRI) of the lung, for example, following transplantation, is characterized by nonspecific alveolar damage, edema formation, and hypoxemia. The clinical spectrum of pulmonary IRI may range from mild hypoxemia to acute respiratory distress syndrome.
In contrast to other organs, the brain is particularly susceptible to ischemia and irreversible neuronal damage already occurs after only 5 minutes of complete ischemia [3]. For brain ischemia, as occurring in the setting of stroke, reestablishing reperfusion seems to be only beneficial, if carried out within a short time period after the onset of ischemia. Reperfusion of ischemic stroke seems to be very critical, as patients may suffer from cerebral reperfusion injury manifesting in fatal cerebral edema formation and intracranial hemorrhage.
IRI of the kidney may occur in the setting of transplantation and cardiac arrest and during cardiac surgery. Here it is important to note that renal injury is usually associated with a high morbidity and mortality. The cortical-medullary region is the most susceptible region to tubular injury, inflammation, and vascular alterations.
Generally, IRI of a single organ causes the release of different proinflammatory mediators, which may subsequently induce inflammation in other organs, thereby potentially contributing to multiple organ dysfunction or even failure [4].
Different pathological processes contribute to tissue injury secondary to ischemia-reperfusion. During ischemia, limited oxygen availability leads to an impaired endothelial cell barrier function with a concomitant increase in vascular permeability and leakage due to decreases of intracellular cAMP levels caused by a reduced adenylate cyclase activity [1]. Furthermore, ischemia-reperfusion induces cell death due to apoptosis, necrosis, and autophagy [5]. During the ischemic period, alterations in the transcriptional control of gene expression likewise occur. Another mechanism implicated in the pathophysiology of injury during ischemia is the inhibition of oxygen-sensing prolyl hydroxylase (PHD) enzymes, because they require oxygen as a cofactor. Hypoxia-triggered inhibition of PHD enzymes induces the posttranslational activation of hypoxia and inflammatory signaling cascades, which in turn regulate the stability of the transcription factors, hypoxia-inducible factor (HIF) and nuclear factor-κB (NF-κB) [2].
Reperfusion of ischemic tissue activates a complex inflammatory response without the involvement of pathogenic triggers, a phenomenon also referred to as sterile inflammation. During the initiation of this inflammatory response, endogenous molecules act as alarmins or danger-associated molecular patterns (DAMPs) [6]. The inflammatory process is stimulated through self-antigens, which are functional components of intact cells but become stimulators of innate immunity when released from injured or dying cells [6]. In 1996, Weiser et al. discovered and described a novel mechanism for reperfusion injury that involves antibody deposition and activation of the complement system leading to an acute inflammatory response [7]. One decade later, the concept of innate autoimmunity was introduced, which is based on the discovery that circulating natural antibodies recognize self-antigens and elicit an acute inflammatory response involving the complement system [8]. Although ischemia-reperfusion is typically established in a sterile environment, activation of innate and adaptive immune responses occurs and contributes to injury, including activation of pattern-recognition receptors such as TLRs and inflammatory cell trafficking into the injured organ [9]. During this inflammatory process, the coagulation system is also activated, because the innate immune system and coagulation system are highly interconnected [10]. As ischemia-reperfusion injury is a common clinical problem and is associated with relevant complications, it is important to identify therapeutic approaches which prevent or at least mitigate ischemia-reperfusion-induced organ injury and organ dysfunction.
This special issue is devoted to the modulation of ischemia-reperfusion injury by different measures and contains eight original papers addressing this clinically relevant topic. These papers are accompanied by two review articles dealing with the effects of anesthetics on ischemia-reperfusion injury. Papers from B. U. Togrul et al., D. Dohman et al., and Y. Demirci et al. are focusing on ischemia-reperfusion injury of the liver. In two of these three papers, different therapeutic interventions on hepatic ischemia-reperfusion injury are evaluated, whereas the third paper is a retrospective study in which the authors investigated the efficacy and safety of intermittent portal triad clamping with low central venous during liver resection. In this context, it has been reported that remote ischemic preconditioning and therapeutic interventions can reduce liver damage after inducing ischemia-reperfusion injury. The studies by S. C. Karahan et al., B. Michele et al., S. C. Karahan et al., D. Dohman et al., and G. Altun et al. elucidate the effects of different anesthetic techniques and drugs on ischemia-reperfusion injury. These eight papers are entitled as follows: “The effects of remote ischemic preconditioning and N-acetylcysteine with remote ischemic preconditioning in rat hepatic ischemia-reperfusion injury model” by B. U. Togrul et al., “The effects of spinal, inhalation, and total intravenous anesthetic techniques on ischemia-reperfusion injury in arthroscopic knee surgery” by S. C. Karahan et al., “Efficacy and safety of hepatectomy performed with intermittent portal triad clamping with low central venous pressure by D. Dohman et al., “Adalimumab ameliorates abdominal aorta cross clamping induced liver injury in rats” by Y. Demirci et al., “Evidence for the use of isoflurane as a replacement for chloral hydrate anesthesia in experimental stroke: an ethical issue” by B. Michele et al., “The effect of dexmedetomidine on oxidative stress during pneumoperitoneum” by S. C. Karahan et al., “The comparison of the effects of sevoflurane inhalation anesthesia and intravenous propofol anesthesia on oxidative stress in one lung ventilation” by D. Dohman et al., and “Role of ethyl pyruvate on systemic inflammatory response and lung injury in an experimental model of ruptured abdominal aortic aneurysm” by G. Altun et al.
Alexander Zarbock
Ahmet Eroglu
Engin Erturk
Can Ince
Martin Westphal
Hypoxia
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67 Primary non function (PNF) and delayed graft function (DGF) are major complications after liver- and kidney transplantation with a high morbidity, increased retransplantation rate and mortality. Both, PNF and DGF are significantly correlated with preservation- and reperfusion-related injury of endothelial cells and mitigate increased acute rejection rates and lower graft survival. Induction of the pathophysiologically alarming state of brain death(BD) may play an important role in modulating tissue injury and activate an inflammatory response which renders donor organs more susceptable to subsequent ischemia/reperfusion damage. This mechanism of action, however, is yet unknown. To test our hypothesis we developed a hemodynamically (in)stable BD model in the rat using frontolateral trepanation and subdural balloon catheter inflation. Following autonomic storm, confirmed brain-dead male Wistar rats were ventilated for 1h, 6h and 24h and then sacrificed. Hemodynamic profiles were documented and function of organs was studied using standard serum parameters (AST, LDH, creat, electrolytes). Brain, liver, and kidney tissue was obtained for immunohistochemical analyses to determine effects of BD on expression patterns of immediate early genes (IEGs: c-fos, c-jun) and adhesion molecules (VCAM-1/ICAM-1). Also the expression of MHC classII and the presence of leucocyte infiltrates (CD8, TcR, CD50, CD45) was studied. Healthy anaesthesized animals served as controls. With longer periods of BD a significant increase was seen in AST, LDH and creat concentrations vs controls (values for controls, 1h and 6h BD respectively: AST: 59.5±5.9, 249.8±51.1, 282±62.3; LDH: 220±50.9, 1350.4±361, 1409.3±502; creat: 42.5±3.3, 86.4±2.4, 164±65.6). Deterioration of liver function occurred prior to that of the kidney. Morphology of brain tissue after 1h BD revealed predominantly local destruction of thalamus and reticular formation vs significant pressure-related diffuse cerebral injury after 6h. C-fos and c-jun were both found after BD induction and in increasing intensity with longer duration of BD. ICAM-1 was constitutionally present in both donor organs. Expression increased after BD induction and with duration of BD. VCAM-1 was detectable after 1h and 6h BD in the kidney. In the liver after 6h BD profound VCAM-1 staining was found. There was an increase in MHC class II positive staining cells in both liver and kidney tissue. The number of CD45 positive staining cells significantly increased with duration of BD in the liver and kidneys(values for controls, 1h and 6h BD respectively: liver: 18.6±3.5, 33.4±4.6, 52.8±6.8; kidney: 25±7.0, 47.3±4.0, 53.5±5.8). No effect was seen on CD8, TcR, and CD44 that remained in their physiological range. We feel that the BD model in the rat is a useful and reproducible model to study physiological consequences of (in)stable BD on quality of donor organs. Our results indicate that prolonged periods of BD cause progressive organ dysfunction and enhancement of inflammatory response with progressive endothelial cell activation in liver and kidney which could predispose for ischemical damage. BD should no longer be regarded as a given condition but as a dynamic process during which cytoprotective intervention to improve organ quality is possible.
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Adenosinergic
Myocardial ischaemia
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Purpose of review The donor-associated risk factor of brain death is closely associated with ischemia and reperfusion injury. This article outlines the interference between brain death–induced graft alterations and conditions after reperfusion injury during the pretransplantation and early posttransplantation periods. Recent findings Unrelated living donor kidney transplants have a better long-term outcome than cadaver donor grafts despite a poorer human lymphocyte antigen match. Prolonged cold ischemia in cadaver donors has been identified as one important risk factor influencing graft outcome. In addition to its nonspecific injury effects, it enhances graft immunogenicity and host alloresponsiveness. Occurring early in the transplant process, it initiates a cascade of molecular and cellular events, including the release of proinflammatory mediators and attraction of various cell types infiltrating the tissues. As a consequence, acute and chronic changes develop that influence the structure and function of the organ, which may contribute to reduced graft survival. Originally considered an event surrounding organ procurement, preservation, and revascularization, it has recently been associated with donor conditions such as brain death. Experimental data have shown that brain death is an independent risk factor that induces similar pathophysiologic features as ischemia and reperfusion. Indeed, brain death–induced proinflammatory changes in donor organs show a pattern comparable to that seen after prolonged cold organ ischemia. Thus, brain death and ischemia and reperfusion injury can no be longer categorized as nonimmune, antigen-independent events. Summary Brain death and ischemia and reperfusion have a synergistic negative impact on long-term allograft outcome by enhancing graft immunogenicity and host alloresponsiveness. In the authors' opinion, graft-preserving strategies should start shortly after brain death diagnosis to improve organ quality before the transplant procedure.
Proinflammatory cytokine
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Metabolic dysfunction impacts stroke incidence and outcome. However, the intricate association between altered metabolic program due to aging, and focal ischemia in brain, circulation, and peripheral organs is not completely elucidated. Here we identified locally and systemically altered metabolites in brain, liver, and plasma as a result of normal aging, ischemic-stroke, and extended time of reperfusion injury. Comprehensive quantitative metabolic profiling was carried out using nuclear magnetic resonance spectroscopy. Aging, but healthy rats showed significant metabolic alterations in the brain, but only a few metabolic changes in the liver and plasma as compared to younger rats. But, ischemic stroke altered metabolites significantly in liver and plasma of older rats during early acute phase. Major metabolic changes were also seen in the brains of younger rats following ischemic stroke during early acute phase of injury. We further report that metabolic changes occur sequentially in a tissue specific manner during extended reperfusion time of late repair phase. First metabolic alterations occurred in brain due to local injury. Next, changes in circulating metabolites in plasma occurred during acute-repair phase transition time. Lastly, the delayed systemic effect was seen in the peripheral organ, liver that exhibited significant and persistent changes in selected metabolites during later reperfusion time. The metabolic pathways involved in energy/glucose, and amino acid metabolism, inflammation, and oxidative stress were mainly altered as a result of aging and ischemia/reperfusion. Biomarker analysis revealed citrate, lysine, and tyrosine as potential age-independent blood metabolic biomarkers of ischemia/reperfusion. Overall, our study elucidates the complex network of metabolic events as a function of normal aging and acute stroke. We further provide evidence for a clear transition from local to systemic metabolic dysfunction due to ischemic injury in a time dependent manner, which may altogether greatly impact the post-stroke outcome.
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Brain ischemia
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The mechanisms of reperfusion damage following focal cerebral ischemia are not known in detail. Recent results, however, strongly suggest that reactive oxygen species (ROS), generated during the reperfusion period, may trigger the reperfusion injury. Mitochondrial calcium overload and a permeability transition (PT) of the inner mitochondrial membrane have been shown to play an important role in production of ROS by the mitochondria. The immunosuppressant cyclosporin A (CsA), which inhibits mitochondrial PT, protects against delayed neuronal necrosis of the hippocampal CA1 sector following transient forebrain/global ischemia. In focal ischemia ("stroke"), expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) may lead to production of ROS by polymorphonuclear (PMN) leukocytes, which suggests the involvement of inflammatory and immunological reactions in reperfusion damage. The spin trap alpha-phenyl-N-tert-butyl nitrone (PBN) reduces infarct size and prevents a secondary mitochondrial dysfunction due to reperfusion, probably scavenging free radicals at the blood-endothelial cell interface.
Pathophysiology
Mitochondrial ROS
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