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1
Mankad, Pankaj Shashikant. "Ischaemia-reperfusion injury and endothelial dysfunction." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392286.
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Amrani, Mohamed. "Postischemic coronary flow and reperfusion injury." Thesis, Imperial College London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307467.
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Koo, Dicken D. H. "Ischaemia/reperfusion injury in renal transplantation." Thesis, University of Oxford, 1999. http://ora.ox.ac.uk/objects/uuid:e0177fd9-1504-4c76-b9fd-6e7ae0b6b466.
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Kidney transplants from both living-related (LRD) and living unrelated (LURD) donors have superior function and survival than transplants from cadaver donors. This may be unsurprising as kidneys from living donors are procured under optimal conditions, from healthy donors with minimal ischaemia times. In contrast, cadaver kidneys are obtained from traumatised donors and may experience extended periods of cold ischaemic storage before transplantation. An immunohistochemical analysis has been performed on biopsies obtained before, and immediately after transplantation, to investigate the potential causes of early inflammatory events associated with cadaver renal transplantation that may influence subsequent graft outcome. An immunohistochemical analysis of biopsies obtained before transplantation demonstrated upregulated expression of endothelial E-selectin and proximal tubular expression of ICAM-1, VCAM-1 and HLA Class II antigens in cadaver donor kidneys. Analysis of donor parameters demonstrated that traumatic physiological events experienced in intensive care around the time of brain death were significantly associated with the induction of proinflammatory antigens. Antigen induction in cadaver donor kidneys before transplantation was significantly associated with early acute rejection. Furthermore, in cadaveric kidneys with long cold ischaemia times, glomerular neutrophil infiltration and deposition of activated platelets expressing P-selectin on intertubular capillaries were detected following reperfusion, in association with impaired short and long term graft function. Expression of inflammatory mediators were absent in all LRD renal allografts before and after reperfusion. A clinical trial was performed to determine whether ischaemia/reperfusion injury may be ameliorated by reflushing cadaver kidneys after cold storage to remove harmful products that may have accumulated in the vessel lumen. Reflushing did not prevent the inflammatory events observed after reperfusion or improve graft function. Therefore, a novel, oxygen free radical scavenger (lec-SOD) was obtained to assess its potential efficacy in preventing ischaemia/reperfusion injury. Lec-SOD bound with high affinity to macro- and microvascular endothelial cells under cold hypoxic conditions following incorporation into Marshall's preservation solution, significantly inhibiting cold hypoxia induced cell death, adhesion molecule induction and neutrophil adhesion. Furthermore, preservation of kidneys with lec- SOD for 18 hr in an experimental model of chronic renal allograft rejection, significantly attenuated neutrophil infiltration and MHC Class I induction day 1 post-transplant, with improved long term renal function. The results presented in this Thesis demonstrate that donor factors and cold ischaemia/ reperfusion injury elicit an early inflammatory response that may influence graft outcome of cadaver kidneys. Refinements in donor management and organ preservation may limit the deleterious effects of ischaemia/reperfusion injury in cadaver renal allografts, increasing graft survival to that observed in living donor transplantation.
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Nitisha, Hiranandani. "Impact of Reperfusion Injury on Heart." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1239720273.
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Aluri, Hema. "INTRA-MITOCHONDRIAL INJURY DURING ISCHEMIA-REPERFUSION." VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/474.
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Cardiac injury is increased following ischemia-reperfusion. Mitochondria are the “effector organelles” that are damaged during ischemia (ISC) when there is no blood flow. Resumption of metabolism by damaged mitochondria during reperfusion (REP) results in increased cell injury. Current therapeutic interventions to pre-condition and post-condition the heart during ISC are ineffective during certain conditions like aging and diabetes due to defects in the signaling cascades. In contrast, mitochondrial-based strategies are effective in protecting the heart during ISC-REP. Hence direct therapeutic targeting of dysfunctional mitochondria will provide the potential to bypass the upstream signaling defects and intervene directly upon the effector organelle. Novel mitochondrial-targeted therapy relies on understanding the sites in the electron transport chain (ETC) that are damaged by ISC and produce cell-injury during REP. This project identifies a novel pathological role of cytochrome c in depleting cardiolipin during ischemia after which the mitochondria are in a defective condition that leads to additional cell death during reperfusion. During ischemia oxidants from complex III oxidize cytochrome c, forming a peroxidase, which causes oxidative damage and depletion of cardiolipin. Depletion of cardiolipin disrupts normal physiology and augments cell death. Identification of the innovative pathobiology during ISC-REP recognizes a novel therapeutic target, cytochrome c peroxidase, which can be a focal point for new therapeutic interventions to decrease cardiac injury. In order to maintain homeostatis, living organisms have the methionine sulfoxide reductase system, which reduce both free and protein bound Met(O) back to methionine (Met) in the presence of thioredoxin. Oxidized Trx is inactive and unable to bind to ASK1 thereby activating ASK1 and causing cell death via p38/JNK pathways thereby contributing to the pathogenesis of myocardial ISC-REP injury. In this study we have shown that inhibition of ASK1 protects the heart during REP via the modulation of mitochondria that sustained damage during ISC. The mitochondrial-based mechanism of cardioprotection with ASK1 inhibition enhanced the functional integrity of the inner mitochondrial membrane retaining cytochrome c thereby decreasing cell death. This therapeutic intervention is a key step to achieve the ultimate goal to improve clinical outcomes in patients that suffer an acute myocardial infarction.
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Fitridge, Robert Alwyn. "Reperfusion injury in focal cerebral ischaemia /." Title page, table of contents and abstract only, 1995. http://web4.library.adelaide.edu.au/theses/09MS/09msf546.pdf.
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MIHAYLOV, PLAMEN VESELINOV. "Ischemic reperfusion injury in Liver transplantation." Doctoral thesis, Università degli studi di Pavia, 2021. http://hdl.handle.net/11571/1434014.
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About 119,592 patients are currently on the organ transplant waiting list in the US, with the number increasing by 5% every year. In 2017, 11,640 candidates were added to the liver transplant waiting list. While the increase in the number of liver transplants is encouraging, the organ shortage remains critically high. During 2015, 1673 patients died without undergoing transplant and another 1227 were removed from the waiting list due to being too sick to undergo transplant.
The major untapped pool of donor organs that could be used to alleviate this crisis in organ transplantation are steatotic livers and livers from Donors after Cardiac Death (DCD). Steatotic liver grafts are associated with an early allograft dysfunction rate of 60%-80% compared with less than 5% for nonsteatotic grafts. This is due to their poor tolerance to ischemic reperfusion injury. On the other hand, only 27% (518/1884) of the DCD livers were transplanted in 2017. The single major reason for this is the severe ischemia reperfusion injury in these livers.
The severity of ischemic reperfusion injury is an important determinant of allograft function post-transplant. However, the mechanisms that contribute to increased susceptibility of steatotic and DCD grafts to ischemic reperfusion injury remains poorly defined. In solid organ transplantation, graft damage subsequent to ischemic reperfusion injury may result in delayed graft function. In the worst case, this complication can lead to primary graft non- function resulting in an urgent need of re-transplantation.
Ischemic reperfusion injury is the consequence of temporary interruption of blood flow to the liver. Warm ischemia reperfusion injury occurs during clamping of vascular inflow during prolonged liver resections and during a donation after cardiac death organ retrieval procedure. Cold ischemia reperfusion injury results from maintenance of the liver in cold preservation and subsequent reperfusion of the graft during transplantation. Apart from its pivotal role in the pathogenesis of the liver’s post reperfusion injury, it has also been involved as an underlying mechanism responsible for the dysfunction and injury of other organs as well. Liver ischemia and reperfusion in settings of liver transplant represent an event with consequences that influence the function of many organs including the lung, kidney, intestine, pancreas, adrenals, and myocardium among others. The molecular and clinical manifestation of these remote organ injuries can ultimately lead to multiple organ dysfunction syndrome.
The objective of this thesis is to give a full and comprehensive analysis of ischemic reperfusion injury in liver transplantation.<br>About 119,592 patients are currently on the organ transplant waiting list in the US, with the number increasing by 5% every year. In 2017, 11,640 candidates were added to the liver transplant waiting list. While the increase in the number of liver transplants is encouraging, the organ shortage remains critically high. During 2015, 1673 patients died without undergoing transplant and another 1227 were removed from the waiting list due to being too sick to undergo transplant.
The major untapped pool of donor organs that could be used to alleviate this crisis in organ transplantation are steatotic livers and livers from Donors after Cardiac Death (DCD). Steatotic liver grafts are associated with an early allograft dysfunction rate of 60%-80% compared with less than 5% for nonsteatotic grafts. This is due to their poor tolerance to ischemic reperfusion injury. On the other hand, only 27% (518/1884) of the DCD livers were transplanted in 2017. The single major reason for this is the severe ischemia reperfusion injury in these livers.
The severity of ischemic reperfusion injury is an important determinant of allograft function post-transplant. However, the mechanisms that contribute to increased susceptibility of steatotic and DCD grafts to ischemic reperfusion injury remains poorly defined. In solid organ transplantation, graft damage subsequent to ischemic reperfusion injury may result in delayed graft function. In the worst case, this complication can lead to primary graft non- function resulting in an urgent need of re-transplantation.
Ischemic reperfusion injury is the consequence of temporary interruption of blood flow to the liver. Warm ischemia reperfusion injury occurs during clamping of vascular inflow during prolonged liver resections and during a donation after cardiac death organ retrieval procedure. Cold ischemia reperfusion injury results from maintenance of the liver in cold preservation and subsequent reperfusion of the graft during transplantation. Apart from its pivotal role in the pathogenesis of the liver’s post reperfusion injury, it has also been involved as an underlying mechanism responsible for the dysfunction and injury of other organs as well. Liver ischemia and reperfusion in settings of liver transplant represent an event with consequences that influence the function of many organs including the lung, kidney, intestine, pancreas, adrenals, and myocardium among others. The molecular and clinical manifestation of these remote organ injuries can ultimately lead to multiple organ dysfunction syndrome.
The objective of this thesis is to give a full and comprehensive analysis of ischemic reperfusion injury in liver transplantation.
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Thummachote, Mr Yongsuk. "The pathopysiological consequence of ischaemia reperfusion injury." Thesis, University of London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498481.
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Kinross, James M. "Systems metabolism of intestinal ischaemia/reperfusion injury." Thesis, Imperial College London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.543342.
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Winbladh, Anders. "Microdialysis in Liver Ischemia and Reperfusion injury." Doctoral thesis, Linköpings universitet, Kirurgi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-68651.
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Introduction: New chemotherapy regimens and improvements in surgical technique have increased the number of patients with liver tumours eligible for curative liver resection. There is a significant risk of bleeding during liver surgery, but this risk can be reduced if the portal inflow is temporarily closed; i.e. the Pringles maneuver (PM). If the PM is used, the liver will suffer from ischemia and reperfusion injury (IRI). If the liver remnant is too small or if the patient has chronic liver disease, the IRI may inhibit the regeneration of the liver remnant. The patient may then die from postoperative liver failure. Several strategies have been tried to protect the liver from IRI. For instance can the PM be applied in short intervals or reactive oxygen species can be scavenged by antioxidants. There are no sensitive methods available for studying IRI in patients and little is known how IRI affects the metabolism in the liver. Microdialysis is a technique that allows for continuous sampling of interstitial fluid in the organ of interest Aim: To investigate the effects of ischemia and reperfusion on glucose metabolism in the liver using the microdialysis technique. Method: A porcine model of segmental ischemia and reperfusion was developed. The hepatic perfusion and glucose metabolism was followed for 6-8 hours by placing microdialysis catheters in the liver parenchyma (studies I-III). In study IV, 16 patients were randomized to have 10 minutes of ischemic preconditioning prior to the liver resection, which was performed with 15 minutes of ischemia and 5 minutes of reperfusion repetitively until the tumour(s) were resected. Results: During ischemia the glucose metabolism was anaerobic in the ischemic segment, while the perfused segment had normal glucose metabolism. Urea was added in the perfusate of the microdialysis catheters and was found to be a reliable marker of liver perfusion. The antioxidant NAcetylcystein (NAC) improved the hepatic aerobic glucose metabolism in the pig during the reperfusion, shown as reduced levels of lactate and improved glycogenesis in the hepatocytes. This can be explained by the scavenging of nitric oxide by NAC as nitric oxide otherwise would inhibit mitochondrial respiration. Also IP improved aerobic glucose metabolism resulting in lower hepatic lactate levels in patients having major liver resections. Conclusion: Microdialysis can monitor the glucose metabolism both in animal experimental models and in patients during and after hepatectomy. Both NAC and IP improves aerobic glucose metabolism, which can be of value in patients with compromised liver function postoperatively.
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Björnsson, Bergþór. "Methods to Reduce Liver Ischemia/Reperfusion Injury." Doctoral thesis, Linköpings universitet, Institutionen för klinisk och experimentell medicin, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-110318.
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Introduction: During the last two decades, liver surgery has expanded enormously, partly due to improved surgical equipment and techniques as well as new and more powerful chemotherapy agents. As the liver is a very well-vascularized organ, there is an inherent risk of bleeding during liver resection. One of the most popular methods employed to reduce this risk is to close the vascular inflow to the liver using the Pringle’s maneuver (PM). However, this procedure has been recognized to cause ischemia/reperfusion injury (IRI) to the future liver remnant (FLR). In cases of extensive resection where the FLR is small and in cases when the liver suffers from chronic diseases, such as cirrhosis, IRI can greatly increase the risk of post-operative liver failure (POLF). Ischemic preconditioning (IPC) and, more recently, remote ischemic preconditioning (R-IPC) are methods that have been employed to reduce IRI. Aim: 1) To compare the effects of IPC and R-IPC in a rat model; 2) to investigate the clinical effect of IPC during modern liver surgery; 3) to investigate the role of the nitric oxide (NO) system in IRI, IPC and R-IPC; and 4) to explore the possible protective effects of nitrite administration before IRI. Methods: A rat model of segmental ischemia followed by 4 hours of reperfusion including microdialysis (μD) was developed from earlier models. The effects of IPC and R-IPC were compared using transaminases and histology as well as continuous μD sampling for glucose, pyruvate, lactate and glycerol. The role of the NO system was examined by serum and μD measurements of NOx as well as tissue measurements of iNOS mRNA and IL-1R mRNA. In study II, patients were randomized to IPC or no IPC prior to liver resection, where intermittent PM was used to decrease bleeding. Results: IPC was more effective in protecting the liver against IRI than R-IPC, as indicated by the levels of transaminases. Lower lactate levels were detected in patients treated with IPC before major liver resections than in controls. IPC reduced iNOS mRNA transcription during reperfusion; this result may be related to the early but not sustained increases in IL-1R transcription observed in the IPC group. Nitrite administered before ischemia reduced AST and ALT levels in the level after 4 hours of reperfusion; in addition, necrosis and glycerol release from the ischemic liver were reduced as well. Conclusion: IPC is more effective than R-IPC in animal models; however, this effect is unlikely to be of clinical importance. NOx decreases in the ischemic liver and the administration of nitrite before ischemia reduces IRI in rats. This may have clinical implications in the future.
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Sheth, H. "Therapeutic modulation of liver ischaemia reperfusion injury." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1318134/.
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Liver Ischaemia Reperfusion Injury (IRI) leads to production of reactive oxygen species and cytokines, which affects hepatocellular function following liver resection and transplantation. This thesis examines 2 hypotheses: 1) The role of intravenous glycine in amelioration of liver IRI in a in vivo animal model of partial lobar liver IRI. 2) Does prophylactically administered N-acetylcysteine prevent liver IRI in patients undergoing elective liver resection. Materials and Methods 1) A rabbit model of hepatic lobar IRI was used to evaluate glycine. 3 groups (n=6) Sham group (laparotomy alone), ischaemia reperfusion (I/R) group (1 hour ischaemia and 6 hours of reperfusion), and glycine I/R group (IV glycine 5 mg/kg prior to the I/R protocol) were used. Portal blood flow, bile flow and bile was analysed by H1NMR spectroscopy. Hepatic microcirculation, intracellular tissue oxygenation, serum TNFα, IL-8, ALT, AST were measured at 1, 2, 4 and 6 hours following reperfusion. 2) A randomised double blind clinical trial was conducted to assess the effect of NAC on liver IRI following liver resections. The main outcomes were: morbidity and mortality, ICAM-1 expression in liver tissue, liver function tests. Patients were randomised to receive NAC as IV infusion (NACG) or a placebo group (PG) which received 5% dextrose only. Immunohistochemistry for ICAM-1 was carried out on perioperative liver biopsies. Results 1) Glycine normalised the bile flow, reduced phosphatidylcholine shedding, lactate surge, and stimulated bile acid, pyruvate, glucose and acetoacetate release. Glycine improved portal blood flow, hepatic microcirculation by the 2nd hour, and hepatic intracellular tissue oxygenation by the 4th hour of reperfusion. Glycine ameliorated serum TNFα at 1, 2 and 4 hours and serum Il- 8, AST and ALT up to 6 hours post reperfusion as compared to the I/R alone group. 2) Of the 43 patients, 15 received NAC, 16 were randomised to the PG, 12 were excluded due to inoperable tumours. Serum ALT was reduced in NACG (p=0.001), while serum ALP was higher in the NACG (p=0.003). ICAM-1 expression was up-regulated in 6/16 patients in the PG and in 3/15 patients in NACG. ICAM-1 was down-regulated in 1/15 patients in the NACG and none in the PG, the difference was not significant. Conclusions 1) Glycine ameliorated liver IRI, improved bile flow and composition. 2) NAC ameliorated parenchymal liver injury and enhanced liver regeneration in patients undergoing elective liver resection.
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Mokhtarudin, Mohd Jamil Mohamed. "Mathematical modelling of cerebral ischaemia-reperfusion injury." Thesis, University of Oxford, 2016. http://ora.ox.ac.uk/objects/uuid:3f5dd7cf-e403-4cf0-b725-4ac235c1b37e.
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Restoring cerebral blood flow using reperfusion treatment is a common method in treating ischaemic stroke. Reperfusion treatment should be given within 4.5 hours from stroke onset. However, reperfusion beyond this time window poses the risk of reperfusion injuries such as intracranial haemorrhage and cerebral tissue swelling. The focus of this thesis is to study the effect of cerebral tissue swelling after reperfusion as it can occur in a few hours after the treatment. Cerebral tissue swelling may cause brain structure movement and cerebral microvessel compression; the latter may then lead to secondary ischaemia occurrence. In this thesis, two mathematical models are presented. The first model investigates the effect of ischaemia-reperfusion in the formation of cerebral tissue swelling. This model provides the understanding of suitable reperfusion conditions to reduce the effect of tissue swelling and also becomes the basis for the subsequent model. Meanwhile, the second model studies the role of a water-transporting protein, aquaporin-4 in ischaemia-reperfusion and its potential as part of treatments for cerebral tissue swelling. In addition, the ionic concentration may change during ischaemia which may be a factor contributing to cerebral tissue swelling. Thus, the effect of ionic concentration on the swelling formation is also investigated. Finally, validations of these models are achieved by developing patient-specific geometries from available ischaemic stroke patient MRI data and utilising finite element analysis. Comparison between the simulation results and the MRI data is done by quantifying the brain ventricles movement during cerebral tissue swelling.
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Mao, Xiaowen, and 毛晓雯. "Peroxynitrite/Ho-1 interaction in propofol post-conditioning protection against myocardial ischemia reperfusion injury." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193463.
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Coronary artery disease limits myocardial blood flow and results in myocardial infarction. Reperfusion therapies restore coronary flow, but may also cause myocardial ischemia reperfusion injury (MIRI). Multiple critical factors contribute to MIRI and among them, oxidative stress plays an important role. This burst of oxidative stress during reperfusion is caused by a variety of sources which collectively are called reactive oxygen species (ROS). Peroxynitrite is more cytotoxic than other ROSs, which at high concentration serves as a detrimental molecule with a variety of target. Peroxynitrite is largely produced during the early reperfusion due to the dramatically increased concentrations of superoxide (O2●-) and nitric oxide (NO). Current cardioprotective therapies against MIRI include exogenous antioxidant treatment and conditioning treatment that induced endogenous antioxidant signaling which upregulates heme oxygenase1 (HO-1), which confers its antioxidant effect in cells and tissues by degrading the latent oxidant heme and generating downstream antioxidant molecules. More importantly, peroxynitrite is closely related to HO-1 in pathogenesis of MIRI and pharmacological or genetic methods that induce over-expression of HO-1 in turn decrease the peroxynitrite generation. In this thesis we report the results of three studies designed to explore the interaction of peroxynitrite and HO-1 in cardioprotection against MIRI.
In the first study we demonstrated that HO-1 plays an essential role in chronic antioxidant treatment against MIRI in 4-week diabetic rats. Chronic antioxidant treatment with two kinds of antioxidants that target different sources of ROSs was administrated in an in vivo study with streptozotocin (STZ)-induced type 1 diabetic rats. Antioxidant treatments synergistically attenuate MIRI and cardiac dysfunction in type 1 diabetic rats by enhancing HO-1 expression, and inhibition of HO-1 expression cancelled antioxidant cardioprotection. This finding was supported by in vitro experiments in a cardiomyocyte hypoxia-reoxygenation model.
The second study explored the peroxynitrite/HO-1 interaction in propofol post-conditioning (PPC) in acute MIRI with both ex vivo and in vivo animal models. We showed that PPC conferred similar cardioprotection as an established intervention˗ischemic post-conditioning (I-PostC). PPC cardioprotection was achieved through down-regulating peroxynitrite formation and activation of HO-1 and its related signaling molecules. This finding indicates that anaesthetic post-conditioning treatment (such as PPC) can achieve similar cardioprotection as ischemic post-conditioning and can avoid potential mechanical injury that may be caused by I-PostC. Inhibition of peroxynitrite reduction and subsequent enhanced HO-1 expression may be the fundamental mechanism of PPC cardioprotection.
Lastly, we further explored PPC cardioprotection against MIRI in diabetic rats. We found that the diabetic heart lost its sensitivity to PPC and the diminished effect of PPC in inducing HO-1 over-expression may be a key mechanism. Exogenous supplementation of adiponectin, an adipocyte-derived plasma protein with anti-diabetic and anti-inflammatory properties, restored diabetic heart sensitivity to PPC that is associated with restoration of HO-1 expression. This finding may provide a potential therapy rescuing diabetic patient challenged by myocardial infarction.
The studies described in this thesis have enhanced our knowledge concerning the role of peroxynitrite in the pathogenesis of MIRI and the critical role of HO-1 in different cardioprotective therapies, in particular anaesthetic postconditioning cardioprotection.<br>published_or_final_version<br>Anaesthesiology<br>Doctoral<br>Doctor of Philosophy
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Woodfine, Lynne. "An investigation of therapeutic intervention in reperfusion injury." Thesis, University of Newcastle Upon Tyne, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361560.
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Bullard, Anthony John. "The role of erythropoietin in ischaemia/reperfusion injury." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1445332/.
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Background - Ischaemia/reperfusion accounts for a large proportion of fatalities in the developed world. Even if death is avoided, the patient suffers a deterioration in their quality of life. Erytriropoietin (EPO) has been examined in clinical studies investigating its effect in anaemic chronic heart failure patients with any positive effect attributed to the correction of anaemia. Given the recent discovery of the EPO receptor on the myocyte surface, this thesis examined whether EPO could have a direct effect on the myocardium and limit ischaeinia/reperfUsion injury and the mechanism by which any protection occurs. Methods and results - Using an isolated perfused rat model of ischaemia/reperfusion, we demonstrated that EPO could mimic preconditioning in a P1-3-Kinase (PI3K)- dependent manner. Adrninistration of EPO at reperfusion limited infarct size by activation eNOS and could be abolished by inhibitors of NOS, PI3K and ERK 1/2. This thesis also showed that EPO could delay mitochondrial permeability transition pore opening (mPTP) in an oxidative stress myocyte model of mPTP opening, an effect that was suppressed by inhibitors of NOS and PBK. A 3 week treatment of EPO reduced injury in a NOS-dependent manner that was independent of haematocrit. Finally this thesis demonstrated that administration of EPO as late as 30 minutes after commencement of reperfusion could still reduce infarct size. Conclusion - This thesis demonstrated that EPO can be used in a variety of settings to elicit a protective effect against ischaemia/reperfusion injury. This variety of effective time points promises an important future role for EPO in the treatment of ischaemic heart disease.
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Duarte, Sérgio Miguel Coelho. "Matrix-leukocyte interactions in liver ischemia-reperfusion injury." Doctoral thesis, Instituto de Ciências Biomédicas Abel Salazar, 2011. http://hdl.handle.net/10216/63694.
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Moore, Rustin MacArthur. "Large colon ischemia-reperfusion injury in the horse /." The Ohio State University, 1994. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487853913101881.
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Salloum, Fadi N. "Novel Strategies in Cardioprotection against Ischemia/Reperfusion Injury." VCU Scholars Compass, 2005. http://scholarscompass.vcu.edu/etd/1227.
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Cell damage represents a major pathomechanism in many diseases of high clinical interest, such as myocardial infarction (MI), where it plays an important role in ischemia-reperfusion (I/R) injury. Considerable progress has been made towards identifying physiological and pharmacological agents that play a key role in myocardial preconditioning against I/R injury and also elucidating the molecular changes leading to such protection.Second messengers in cellular signaling pathways, such as cGMP have been well implicated as key players in ischemic and pharmacological preconditioning (PC) of the heart. Phosphodiesterase type 5 (PDE-5) is an enzyme that specifically hydrolyzes cGMP thereby decreasing its tissue concentration. Sildenafil is a potent selective inhibitor of PDE-5 and therefore allows the accumulation of cGMP in several tissues shown to express PDE-5, including pulmonary and coronary arteries. We initially hypothesized that vasodilation induced by sildenafil may release several endogenous mediators including adenosine, bradykinin or nitric oxide (NO), that may trigger a signaling cascade leading to protection against I/R injury. Our results show that sildenafil, at a clinically relevant dose, induced powerful acute and delayed cardioprotection against I/R injury in an in vivo rabbit model via opening of mitoKATP channels. The acute cardioprotective effect of sildenafil was dependent on activation of protein kinase C in rabbits. Moreover, we observed that sildenafil induced delayed PC by NO produced through activation of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in the mouse heart. The expression of iNOS/eNOS was regulated by ERK phosphorylation and the delayed protection against I/R was blocked by PD98059, a selective ERK inhibitor. Furthermore, sildenafil-induced delayed protection was abolished in the intact heart as well as adult myocytes derived from adenosine A1 receptor knock-out mice suggesting an essential role of A1 receptor in protection. Taken together, these studies suggest that sildenafil is a powerful tool to reduce I/R injury in the animal models. Future clinical studies with relatively safe and effective PDE-5 inhibitors may have an enourmous impact on the use of these compounds in reducing I/R injury in the heart and other organs.
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Nitta, Takashi. "Myoglobin gene expression attenuates hepatic ischemia reperfusion injury." Kyoto University, 2003. http://hdl.handle.net/2433/148743.
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White, Melanie Yvonne. "Proteomics of ischemia/reperfusion injury in rabbit myocardium." Thesis, The University of Sydney, 2006. https://hdl.handle.net/2123/27890.
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Myocardial stunning is best defined as the persistent, yet reversible, contractile dysfunction
that occurs with brief myocardial ischemia / reperfusion (I/R) injury. In contrast, prolonged
ischemia results in myocardial infarction that leads to cell death of necrosis of the tissue. The
causes of stunning are not fully elucidated, however two major hypotheses currently exist;
firstly changes to calcium handling resulting from lowered cellular pH by means of anaerobic
respiration, and altered Nair/H)r antiporter kinetics, and secondly, the generation oxygen free
radical (OFR) that may occur in a dramatic ‘surge’ at the onset of reperfusion. Treatment of
ischemic myocardium with calcium channel blockers and / or OFR scavengers has been
successfully shown to prevent stunning in various animal models. Whilst much is known
about the physiological and biochemical changes that occur in stunned myocardium, very
little is known about events at the molecular level. Since stunning occurs after only brief (15
minutes low-flow in the rabbit model) ischemia and subsequent reperfusion, we hypothesized
that these molecular events are not predominated by large changes in protein expression and
abundance, yet rather by subtle and / or transient changes to protein post-translational
modifications (PTM). Such changes at the protein level are best analysed using the
technologies encompassed under the term ‘proteomics’.
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Duarte, Sérgio Miguel Coelho. "Matrix-leukocyte interactions in liver ischemia-reperfusion injury." Tese, Instituto de Ciências Biomédicas Abel Salazar, 2011. http://hdl.handle.net/10216/63694.
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Xu, Xingshun. "Novel Protective Agents against Cerebral Ischemia/Reperfusion Injury." Digital Commons @ East Tennessee State University, 2007. https://dc.etsu.edu/etd/2054.
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Stroke is the third leading cause of death and disability in the United States. At present, intravenous administration of tissue plasminogen activator (t-PA) is the only thrombolytic therapy approved by the FDA for the treatment of acute ischemic stroke. There are no other effective treatments available so far. The discovery of new drugs and new treatments for stroke to reduce mortality and disability is an urgent medical research priority. In this study, the protective effects and mechanisms of two novel agents Gly14 humanin (HNG) and necrostatin-1 (Nec-1) were examined. HNG, a highly potent neuropeptide against amyloid toxicity, exhibited anti-apoptotic properties on cerebral ischemia injury. HNG reduced infarct volume after ischemia/reperfusion injury with pre-treatment or post-treatment (i.c.v. and i.p.) in a middle cerebral artery occlusion model in mice and decreased neurological deficits induced by ischemia. The protection of HNG was mediated by inhibiting ERK activation and activating PI3K/Akt pathway. Inhibition of the PI3K/Akt pathway blocked the protective effects of HNG. Nec-1 is a specific inhibitor of necroptosis, a newly identified cell death, and was reported to reduce infarct volume even when it was administered at 6 h post-ischemia in a mouse stroke model. Interestingly, this small molecule protected against glutamate-induced oxidative toxicity in a hippocampal HT-22 cell line. It inhibited the translocation of apoptosis-inducing factor from the mitochondria to the nucleus, increased the cellular glutathione level, and decreased free radical formation after glutamate treatment. More importantly, Nec-1 inhibited BNIP3-mediated caspase-independent cell death. Cerebral ischemia/reperfusion injury involves the activation of different pathways that lead to neuronal cell death. Given this multifactorial pathnogenesis, it is possible that a cocktail of neuroprotective agents would be superior to monotherapy. In this study, a cocktail of HNG and Nec-1 was examined in vitro and in vivo. HNG and Nec-1 exerted synergistic neuroprotection on oxygen-glucose deprivation-induced cell death and cerebral ischemia/reperfusion injury. This study provided a new therapeutic strategy for the treatment of stroke by the combination of anti-apoptosis and anti-necroptosis therapy.
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Bejaoui, Mohamed. "Polyethylene glycol conditioning: An effective strategy to protect against liver ischemia reperfusion injury." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/385612.
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Ischemia is defined by the arrest of blood flow in the organ cutting thus oxygen and metabolite supply indispensable for its survival and function. Restoration of blood flow in hypoxic tissue, called reperfusion, can paradoxically result in more destructive than beneficial effects. Ischemia reperfusion injury (IRI) is an inevitable problem in many clinical situation of liver surgery such as organ transplantation, trauma and liver resection. Therapeutic strategies against IRI have been developed during the last 60 years and great advance into the mechanisms responsible of injuries have been achieved. However, efficient therapy against IRI is still lacking and few clinical studies in phase III have proven their effectiveness. This could be due in part to the complexity of the mechanisms responsible of IRI and to the specific drugs activity and their potential adverse effects.
Polyethylene glycols (PEGs) are water soluble nontoxic polymers that have been employed in many biomedical applications such as gastrointestinal disorders and drugs pegylation. Besides its usefulness as oncotic agents in preservation solutions, it has been shown that PEGs molecules protect against cold injury and ischemic damage.
In contrast to the current pharmacological strategies used against IRI, PEG presents the advantages of being a multi-target strategy. In fact, IRI is a multifactorial disease including oxidative stress, inflammation, endoplasmic reticulum stress, mitochondrial damage, and cytoskeleton alterations which lead to cell death and organ dysfunction. PEG has been associated with the majority of these events as it has been shown that PEG reduces reactive oxygen species, prevents cell death, maintains mitochondrial integrity, and reduces inflammation and endoplasmic reticulum stress. From this perspective, it is reasonable to expect that PEG administration may be an effective therapeutic strategy against liver IRI.
The aim of this thesis was to investigate the beneficial effects of PEG 35 in different models of IRI that mimic clinical situation of liver surgery. In the first study, we investigated the impact of the administration of intravenous PEG 35 before liver warm IRI. In the second one, we investigated whether intravenously administrated PEG 35 could protect against cold IRI in steatotic rat livers. Finally, we developed a new washout solution containing PEG 35 to prevent reperfusion injury after prolonged cold preservation.
The results of the present thesis demonstrated that:
- Intravenous administration of PEG 35 at 10 mg/kg protects the liver in an experimental model of warm IRI in rats. The protective mechanisms are associated with the activation of the pro survival pathways Akt and AMPK and the inhibition of apoptosis. PEG 35 also protects the hepatocyte morphology by increasing F/G-actin ratio and activating p-p38.
- Intravenous administration of PEG 35 at 10 mg/kg protects steatotic livers in an experimental model of cold IRI in obese rats. The protective effects of PEG 35 are mediated by the preservation of mitochondrial status, the stabilisation of the cytoskeleton and the regulation of the cytoprotective AMPK and Akt signalling pathways.
- Liver graft washout with a PEG 35-containing rinse solution increases the protection against IRI in a model of isolated perfused rat liver. .Protection was due to the inhibition of metalloproteinases, the activation of cytoprotective AMPK and eNOS signalling pathways and the preservation of cytoskeleton integrity.<br>La lesión por isquemia reperfusión (I/R) es un proceso complejo que tiene lugar cuando un órgano se ve privado del aporte sanguíneo (isquemia) y se manifiesta de forma predominante después del posterior restablecimiento del flujo sanguíneo (reperfusión). Existen numerosas situaciones en la práctica clínica en las que el hígado se ve sometido a una situación de I/R, entre ellas, la resección hepática y el trasplante hepático.
Los polietilenglicoles (PEGs) son polímeros solubles en agua, no tóxicos y con diferentes pesos moleculares. Algunos de ellos, con un peso molecular de 20 kDa (PEG 20) y de 35 kDa (PEG 35) forman parte de la composición de soluciones de preservación de órganos (SCOT e IGL-1). Además, en varios modelos experimentales de in vivo e in vitro se ha reportado que varios PEGs ejercen efectos beneficiosos.
Atendiendo a lo anteriormente expuesto, la utilización de PEGs puede constituir una excelente herramienta para prevenir el daño hepático por I/R. El objetivo de esta tesis es investigar los efectos beneficiosos del PEG 35 en diferentes modelos de lesión por I/R, que imitan una cirugía hepática.
Nuestros resultados demuestran que:
- EL PEG 35 administrado por vía intravenosa protege eficientemente el hígado de ratas contra la I/R caliente. Los mecanismos de protección están asociados con la activación de la supervivencia vía Akt y AMPK y la inhibición de la apoptosis. El PEG 35 también protege la morfología de los hepatocitos mediante el aumento de la F/G-actina y la activación de p-p38.
- La administración intravenosa de PEG 35 protege los hígados esteatósicos en un modelo de I/R fría en ratas obesas. Los efectos protectores de PEG 35 están mediados por la preservación del estado mitocondrial, la estabilización del citoesqueleto y la regulación de las vías de señalización citoprotectoras AMPK y AKT.
- La adición de PEG 35 a una nueva solucione de lavado aumenta la protección contra la lesión por I/R en un modelo de hígado de rata aislado y perfundido a través de la inhibición de las metaloproteinasas, la activación de vías de señalización citoprotectoras AMPK y eNOS y la preservación de la integridad del citoesqueleto.
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Georgiev, Panco. "Normothermic ischemia reperfusion injury in the cholestatic mouse liver /." Zürich, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000256332.
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Cohen, Ari J. "Pharmacological modification to prevent reperfusion injury following liver transplantation." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq23260.pdf.
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Brown, David Avery. "Myocardial ATP-sensitive potassium channels and ischemia/reperfusion injury." Diss., Connect to online resource, 2005. http://wwwlib.umi.com/cr/colorado/fullcit?p3190363.
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Du, Xiaojian. "Regulation of EphA2 expression in renal ischemia-reperfusion injury." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111599.
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Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury in both native kidneys and renal allografts. Previous studies in our lab have shown that a subset of Eph family receptor tyrosine kinases, including EphA2, is strongly and persistently upregulated in renal tubular cells in both in vitro and in vivo models of the renal IRI. Src kinases are necessary and sufficient for upregulation of EphA2. We have proposed that IRI-induced EphA2 upregulation may serve as a necessary step in renal tubular remodelling.<br>In this study, we have further defined the mechanism of Src kinase-induced EphA2 upregulation by identifying the -145/+137 EphA2 promoter region as the minimal region required for basal and Src kinase-induced activation of the promoter. Moreover, we have identified within this region, at position -45, a canonical cAMP response element (CRE) (Nowakowski et al.), which is essential for EphA2 promoter activation. However, we also found that the prototypical CRE-binding transcription factor, CREB, was not necessary for activation of the EphA2 promoter, suggesting that CREB-related or -unrelated transcription factors are responsible for EphA2 upregulation.
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Hau, Han Lim Kelvin. "The mitochondria and myocardial protection against ischaemia-reperfusion injury." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500392.
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宋蘭 and Lan Fion Sung. "Regulation of chemokine expression during renal ischemia/reperfusion injury." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B31244804.
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Schulman, Daniel. "The influence of age on myocardial ischaemia/reperfusion injury." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272252.
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Patel, Hetal Brijesh. "Therapeutic inhibition of complement in renal ischaemia reperfusion injury." Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.438220.
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Llwyd, Osian. "The involvement of CaMKII in myocardial ischaemia-reperfusion injury." Thesis, Cardiff University, 2012. http://orca.cf.ac.uk/43619/.
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CaMKII acts as a second messenger to Ca2+ signals within the cardiac myocyte. Cellular stresses such as ischaemia and subsequent reperfusion perturb the normal physiological oscillations of Ca2+ to cause an escalating concentration which damages the cell. CaMKII has been implicated as an injury signal during such cellular conditions. However, there are discrepancies as to whether CaMKII is a possible mechanism of ischaemic preconditioning as its inhibition can abrogate or improve the protective effect of preconditioning. This thesis investigated the effects of CaMKII inhibition in models of ischaemia-reperfusion (I-R) injury. It was hypothesised that CaMKII promotes irreversible injury caused by acute myocardial infarction (AMI), but would also have a beneficial role in mediating cardioprotection by ischaemic preconditioning. This work has demonstrated that: i) in an ex vivo rat heart model of regional I-R injury, CaMKII promoted irreversible injury but is not a feasible target for reperfusion therapy as only a pre-ischaemic intervention reduced myocardial infarction; ii) CaMKII activation was not a pre-requisite for protection with ischaemic preconditioning, although an additive protective effect of CaMKII inhibition and ischaemic preconditioning was possible; iii) models of simulated I-R or oxidative stress in the H9c2 cells did not involve CaMKII activity; iv) isolated cardiac myocytes paced at 1Hz and subjected to simulated I-R do not engage a significant amount of CaMKII activity. These studies substantiate the involvement of CaMKII during ischaemic injury and establish that it does not play a substantial role in ischaemic preconditioning. It highlights the characteristics of the kinase within in vitro models of I-R injury. Understanding CaMKII role in I-R may underpin the development of future therapeutic strategies for the management of AMI.
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Stefanutti, G. "Novel experimental therapies for intestinal ischaemia and reperfusion injury." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1334603/.
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Intestinal ischaemia and reperfusion (I/R) contributes to the pathogenesis of numerous clinical conditions in all age groups. Many of these diseases, including neonatal necrotizing enterocolitis (NEC), result in significant morbidity and mortality through multiple organ dysfunction, and available treatment is currently limited to supporting vital functions. My aims were: to investigate novel therapeutic strategies such as moderate hypothermia and peroxynitrite decomposition catalyst FeTMPyP [5,10,15,20- tetrakis(N-methyl-4'-pyridyl)porphyrinato iron (III)] in experimental models of adult and infant intestinal I/R; and to characterise the inflammatory process in human NEC, evaluating its relationship with clinical outcome. In an adult rat model, total-body moderate hypothermia applied throughout ischaemia and reperfusion counteracts oxidative stress in both the intestine and distant organs. This suggests that hypothermia could be beneficial as a preventative measure when intestinal ischaemia can be foreseen. However, in clinical practice therapy can usually be commenced only after ischaemia has occurred. In two sets of experiments, I showed that rescue hypothermia applied after mesenteric ischaemia improves outcome in both adult and neonatal rats, and this benefit is maintained after rewarming. Hypothermic protection could result from prevention of multiple organ dysfunction through several different pathways, including modulation of hepatic phosphoenergetics, pulmonary inflammatory infiltrate, cardiac energy metabolism, and systemic oxidative stress. Administration of peroxynitrite decomposition catalyst FeTMPyP as a rescue therapy at reperfusion also exerts a protective effect in neonatal rats, possibly via inhibition of adhesion molecule expression, leukocyte recruitment, and lipid peroxidation in the intestine, leading to prevention of systemic oxidative stress. In a study conducted on human specimens from neonates with NEC, tissue injury seems to be mediated via increased expression of endothelial adhesion molecules ICAM-1 and P-Selectin, leading to macrophage and neutrophil infiltration. Endothelial E-Selectin is expressed exclusively in NEC patients, and appears to be a marker of rapidly evolving disease and distant organ failure.
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Sharma, V. "Novel signalling pathways in myocardial conditioning against reperfusion injury." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1407936/.
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Ischaemic preconditioning (IPC) and insulin protect the heart against lethal ischaemia-reperfusion (IR) by activating cardioprotective kinases such as PI3K-AKT. This thesis explores the effect of endothelial dysfunction, as seen in diabetes - a major risk factor for ischaemic heart disease, on IPC using the ESMIRO mice. These mice have dysfunctional vascular insulin receptors as well as endothelial dysfunction similar to that present in diabetes. Further, the effect of vascular insulin resistance on the ability of insulin to condition the heart against IR injury is investigated. The thesis also investigates the post-translational modification of a proapoptotic protein, BNIP3, as a possible mechanism of IPC. BNIP3 appears to a play a central role in mediating cell death in response to IR. The Langendorff technique of perfusing isolated mouse hearts was used. No change was noted in the total amount of BNIP3 in C57BL/6J mouse hearts in response to IR or IPC, though IR increased the measured amount of the carboxy-terminal end of BNIP3, a crucial effector of BNIP3 mediated cell death. IPC prevents this increase in the carboxy terminal end of BNIP3. BNIP3 phosphorylation occured in response to both IPC and IR. Thus, IPC may lead to a post-translational modification in BNIP3 preventing IR mediated increase in the carboxy-terminal of BNIP3. This is independent of BNIP3 phosphorylation. The IPC protocols used failed to significantly protect the ESMIRO mice and their wildtype littermates (WT) against IR injury or activate AKT. Furthermore insulin treatment did not significantly protect the ESMIRO mice and the WT against IR injury though, unexpectedly, AKT activation was seen in both with insulin. Finally, ESMIRO mice are more resistant than their WT littermates to an increase in ischaemic period before reperfusion. Hence, insulin transport across the endothelium appears to be independent of the insulin receptors. Ischemic tolerance noted in ESMIRO mice has also been reported in diabetes, implying that a possible mechanism underlying this ischemic tolerance may be vascular dysfunction which is common to both the ESMIRO mice and the diabetic phenotype.
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van, As Arjan Bastiaan. "Improvement of liver transplantation by reducing preservation-reperfusion injury." Doctoral thesis, University of Cape Town, 1999. http://hdl.handle.net/11427/26770.
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The liver differs from other solid organs in that it has a dual blood supply, receiving arterial blood via the hepatic artery and venous blood via the portal vein. The reperfusion injury which occurs after ischemia, has been studied to only a limited extent in the liver. In particular, the relative contribution of the portal venous blood and the hepatic arterial blood to the reperfusion injury has not been documented previously. During liver transplantation, implantation of the new liver is achieved by anastomosing the suprahepatic vena cava, the infrahepatic vena cava and the portal vein. At this stage, the liver is reperfused with portal venous blood only. Thereafter the hepatic arterial anastomosis is undertaken. The delay in providing the liver allograft with arterial blood will depend upon the difficulty in the dissection of the hepatic artery. The impact of the delay in rearterialization of the liver allograft has not been studied previously. Currently, the University of Wisconsin Solution is the gold standard for liver preservation. Celsior is a new cardioplegic solution, which has also been suggested for use for liver preservation. However, its role as a liver preservation solution has been studied to a limited extent. The aim of this study was: 1. To document the reperfusion injury after liver transplantation. 2. To document the relative contribution of the portal venous blood and the hepatic arterial blood to the reperfusion injury. 3. To investigate the impact of early rearterialization on the reperfusion injury after liver transplantation. 4. To investigate the effect of the new preservation solution, Celsior, on the reperfusion injury after liver transplantation. Large White X-Landrace pigs were subjected to orthotopic liver transplantation. The donor liver was stored in Eurocollins solution for 3 hours. The animals were randomly allocated to either rearterialization 60 minutes after portal reperfusion, rearterialization 20 minutes after portal reperfusion, simultaneously portal and arterial reperfusion, and rearterialization 20 minutes before portal venous reperfusion. In another experiment, the donor livers were stored in either Eurocollins solution, University of Wisconsin Solution, or Celsior. Blood samples were taken at various intervals and subjected to the following biochemical investigations. Malondialdehyde and vitamin A were used as markers of reperfusion injury. Hyaluronic acid levels were used as markers of endothelial cell function. Serum AST was used as a marker of hepatocellular injury. In summary, these studies showed that there was a significant reperfusion injury after portal venous reperfusion with no additional injury after rearterialization. Early rearterialization also resulted in a lesser reperfusion injury. There was also less hepatocellular injury with early rearterialization. Histological evidence of injury was also less in the livers which were rearterialized early. In addition, the livers preserved in Celsior had evidence of a lesser reperfusion injury. Thus in conclusion, in liver transplantation early rearterialization might result in better early graft function.
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Wang, Guona. "The role of lipocalin-2 in stroke reperfusion injury." Kent State University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=kent1448895817.
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Chuang, Chia-Chen. "Characterization of Reperfusion Injury-Induced ROS in Striated Muscles." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1500479949278294.
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Hunter, James Philip. "The role of hydrogen sulphide in ischaemia reperfusion injury." Thesis, University of Leicester, 2015. http://hdl.handle.net/2381/35951.
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Warm ischaemic injury occurs when an organ or region of the body is starved of oxygenated blood under normothermic conditions. Two important clinical examples of warm ischaemia are donation after circulatory death (DCD) kidney transplantation and abdominal aortic aneurysm (AAA) repair. The tissue injury that results from warm ischaemia can lead to organ dysfunction, which has important clinical consequences. In kidney transplantation warm ischaemic injury can lead to delayed graft function, increased rates of primary non-function and poorer long-term outcomes. In open AAA repair occlusion of the abdominal aorta leads to remote injury to organs such as the kidneys. Renal failure following AAA repair can cause significant morbidity including the need for renal replacement therapy. Hydrogen sulphide (H2S) is an endogenously produced gas that been shown to be protective against ischaemia-reperfusion injury. The aims of this thesis were twofold. First, the effect of H2S on ischaemia-reperfusion injury in a porcine model of direct renal ischaemia was assessed. Second, the effect of H2S on inflammation and remote renal injury was assessed using a rodent model of aortic occlusion. This research demonstrated that hydrogen sulphide, delivered as an exogenous agent, preserved renal function and reduced inflammation in a large animal model of renal warm ischaemia. Furthermore, in a rodent model of remote renal injury hydrogen sulphide also reduced systemic and renal inflammation but had no effect on renal function. In addition, there were no significant side effects from the administration of hydrogen sulphide.
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Dare, Anna Jane. "Targeting mitochondria during ischaemia-reperfusion injury in organ transplantation." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708069.
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Reyes, Leila. "Involvement of inflammatory oxidants in cardiac ischaemia/reperfusion injury." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/19667.
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Oxidative stress is a major feature of cardiac ischaemia/reperfusion (I/R) injury, with strong evidence implicating infiltrating leukocytes, in particular neutrophils, as a major source of oxidants in the infarcted myocardium. Activated leukocytes release the peroxidase enzyme, myeloperoxidase (MPO), which can produce the oxidants hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). Chapter 3 examines the differential cellular effect of (patho)-physiological levels of HOCl and HOCN in cardiomyocytes. Both HOCl and HOSCN induced cellular damage characteristic of cardiac I/R injury and highlighted two very different cellular responses in cardiomyocytes. Chapter 4 explored the therapeutic effect of selenium supplements, specifically, the dietary supplement selenomethionine (SeMet) as a form of antioxidant therapy in the in vitro cardiomyocyte model exposed to HOCl and HOSCN or hypoxia/re-oxygenation (H/R). SeMet prevented a range of cellular damage mediated by HOCl, with the protection mainly attributed to the direct scavenging ability of SeMet. In contrast, SeMet was not able to protect against the HOSCN or H/R injury induced damage. Studies were extended in Chapter 5 to examine SeMet’s ability to modulate the cellular damage observed in an experimental in vivo model of cardiac I/R injury. SeMet (2 mg kg-1) for 8 weeks resulted in the elevation of tissue selenium levels and reduced apoptosis mediated by acute I/R injury, but not the accompanying cardiac dysfunction, adverse remodelling or impaired cardiac function during late stage I/R injury. Overall, this Thesis contributed to knowledge regarding the role of HOCl and HOSCN in cardiac I/R injury, with the results suggesting that both oxidants may contribute to oxidative stress and the associated downstream cellular damage. Furthermore, this work shows that SeMet could be beneficial as secondary treatment for cardiac I/R injury and be used in conjunction with current treatment methods.
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Venardos, Kylie M. "Myocardial Antioxidant Enzyme Systems, Ischemia-Reperfusion Injury, and Selenium." Thesis, Griffith University, 2005. http://hdl.handle.net/10072/365301.
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Coronary heart disease remains the greatest killer of Australian's, and given our ageing population, along with increasing risk factors, it is predicted to become an even more significant problem worldwide over the next 20 years. Reperfusion, without doubt is the most effective treatment for ischemic myocardium. However, this produces deleterious effects upon cells, and depending on the severity, may ultimately lead to cell death. While the pathogenesis of ischemia-reperfusion is not completely understood, there is considerable evidence implicating reactive oxygen species (ROS) as an initial cause of the injury. ROS formed during oxidative stress can initiate lipid peroxidation, oxidize proteins to inactive states and cause DNA strand breaks, all potentially damaging to normal cellular function. ROS have been shown to be generated following routine clinical procedures such as coronary bypass surgery and thrombolysis, due to the unavoidable episode of ischemiareperfusion. Furthermore, they have been associated with poor cardiac recovery post-ischemia, with recent studies supporting a role for them in infarction, necrosis, apoptosis, arrhythmogenesis and endothelial dysfunction following ischemia-reperfusion. In normal physiological condition, ROS production is usually homeostatically controlled by endogenous free radical scavengers such as SOD, catalase, and the glutathione peroxidase
and thioredoxin reductase systems. Targeting the generation of ROS with various antioxidants has been shown to reduce injury following oxidative stress, and improve recovery from ischemia-reperfusion injury.
This thesis investigates the role of myocardial antioxidant enzymes in ischemiareperfusion injury, particularly the glutathione peroxidase (GPX) and the thioredoxin reductase (TxnRed) systems. GPX and TxnRed are selenocysteine dependent enzymes, and their activity is known to be dependent upon an adequate supply of dietary selenium and selenocysteine. In mammalian cells, the generation of selenocysteine occurs during amino acid biosynthesis and the degree of selenium (Se) incorporation into the cysteine residue is concentration dependent. Previous studies have found that up-regulation of these systems is cardioprotective and down-regulation is detrimental following ischemia-reperfusion. This thesis attempts to extend these observations by increasing not only our understanding of the roles of myocardial antioxidant enzymes in ischemia-reperfusion injury, but also the effect of dietary selenium on these systems. Furthermore, it investigates the effects of ischemia, reperfusion, and ageing on myocardial antioxidant enzymes.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>School of Health Sciences<br>Full Text
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Jahangiri, Anisa. "n-3 PUFAs and reperfusion injury in isolated cardiomyocytes." Title page, table of contents and abstract only, 2002. http://web4.library.adelaide.edu.au/theses/09PH/09phj251.pdf.
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"September 2002" Bibliography: leaves 207-230. Ch. 1. Literature review -- Ch. 2. General methods -- Ch. 3. Dietary n-3 PUFAs and reperfusion injury in isolated cardiomyocytes -- Ch. 4. The effect of dietary n-3 PUFAs on cardiomyocyte membrane fluidity, intracellular ROS and Ca 2+ levels during oxidative stress -- Ch. 5. The effect of dietary fish oil supplementation on antioxidant enzyme gene expression in rat myocardium -- Ch. 6. The effect of dietary lipids on ischaemia-reperfusion injury in rat myocardium -- Ch. 7. General discussion -- Ch. 8. Appendices. The broad aims of this thesis were to develop a cellular model for studying reperfusion injury, in order to investigate the reported protective effects of n-3 PUFAs, and to examine the underlying mechanisms associated with such protection.
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Becker, Bryan A. "The effects of ischemia-reperfusion injury on cytosolic and mitochondrial levels of glutathione in the rat kidney." Virtual Press, 2001. http://liblink.bsu.edu/uhtbin/catkey/1204198.
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This study was done to investigate the effect of ischemia-reperfusion injury on cytosolic and mitochondrial glutathione levels in the rat kidney. Glutathione is the main cellular defense against free radicals that are thought to cause ischemia-reperfusion injury. Right kidneys from anesthetized female Lewis rats (9-12 months old) were exposed to 60 minutes of ischemia followed by 0, 30, or 120 minutes of reperfusion. The kidneys were perfused with isotonic saline, harvested, homogenized, and separated into cytosolic and mitochondrial fractions by differential centrifugation. Reduced (GSH) and oxidized (GSSG) glutathione levels were measured spectrophotometrically. There were significant decreases in both the GSH levels and the % GSH/Total Glutathione in the cytosol and mitochondria of kidneys exposed to ischemia-reperfusion injury when compared to control kidneys. The glutathione levels in either the cytosol or mitochondria did not recover even after 120 minutes of reperfusion. This study demonstrates that 60 minutes of ischemia followed by 0, 30, or 120 minutes of reperfusion decreases both cytosolic and mitochondrial levels of glutathione in the rat kidney.<br>Department of Physiology and Health Science
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Nemours, Stéphane. "Identification of time- and sex-dependent pathways involved in renal ischemia-reperfusion injury in a porcine model. Link to renal cancer." Doctoral thesis, Universitat Autònoma de Barcelona, 2020. http://hdl.handle.net/10803/670696.
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Les malalties renals es deriven de defectes congènits, lesions renals agudes (AKI) o malalties renals cròniques (CKD), entre altres causes. La lesió renal d’isquèmia /reperfusió (IRI), que es troba en moltes situacions clíniques, és una de les causes principals de l’AKI que causen lesions i mort de cèl·lules epitelials del túbul proximal (PTEC). La gravetat de l’AKI i la capacitat de regenerar-se després de la lesió són determinants importants de la morbiditat i mortalitat dels pacients en un entorn hospitalari. Els homes són més propensos a la malaltia renal aguda i crònica i a avançar fins a la malaltia renal en fase final (ESRD) que les dones i actualment s’accepta que els andrògens, i no l’absència d’estrògens, són responsables d’això. S’accepta que la regeneració per PTEC supervivent és el mecanisme predominant de reparació/regeneració després de lesions tubulars isquèmiques al ronyó adult de mamífer. Les PTEC són també el lloc on s’origina el carcinoma de cèl·lules renals de cèl·lules clares (ccRCC) en humans. El ccRCC també presenta diferències de sexe, amb els homes que tenen gairebé el doble de la incidència de les dones a nivell mundial. Això va conduir a la hipòtesi que la regeneració després de lesions renals i el desenvolupament de ccRCC podrien compartir repertoris d’expressió gènica similars. Els andrògens són molt rellevants en el desenvolupament dels ronyons, cosa que suggereix que la regeneració i el càncer en les cèl·lules del túbul proximal poden recapitular, en part, els programes dependents dels andrògens en el desenvolupament del ronyó. En aquest projecte, hem volgut trobar dianes que participin en la regeneració renal i en processos de càncer renal. A més, ens va interessar estudiar la regulació de l’hormona sexual en aquestes vies. Es van realitzar anàlisis detallades de dades transcriptòmiques d’un model porcí d’AKI. Es van determinar gens que expressaven un dimorfisme sexual a tota la IRI i es van validar dianes en mostres humanes. A més, es van determinar els conjunts de gens implicats en la IRI i es van caracteritzar de manera sexual i de temps. Vam trobar que els grups genètics relacionats amb els processos de regeneració eren més actius en les dones que en els homes. A més, la resposta immune a la lesió va ser més gran en homes que en dones. Després, van vincular els processos de regeneració amb ccRCC mitjançant la superposició entre les anàlisis del transcriptomes AKI i ccRCC. A més, hem trobat diferències importants entre els transcriptomes de ronyó de ratolí i de porc després de la lesió renal. Es va establir un model in vitro d’IRI renal i es va permetre validar parcialment les troballes in vivo. Entre d’altres, vam observar que durant la IRI renal, STAT3 està regulat per la fosforilació de diferents residus. Aquest estudi constitueix una caracterització extensiva de les diferències de sexe existents durant la IRI renal. Ofereix una plantilla per caracteritzar més les diferències de sexe en malalties renals a nivell molecular.<br>Las enfermedades renales se derivan de defectos congénitos, lesiones renales agudas (AKI) o enfermedad renal crónica (CKD), entre otras causas. La lesión renal de isquemia / reperfusión (IRI), que se encuentra en muchas situaciones clínicas, es una de las causas principales de AKI que causan lesiones y muerte de células epiteliales del túbulo proximal (PTEC). La gravedad de AKI y la capacidad de regenerarse después de la lesión son determinantes importantes de la morbilidad y mortalidad de los pacientes en un entorno hospitalario. Los hombres son más propensos a la enfermedad renal aguda y crónica y avanzar hasta la enfermedad renal en fase final (ESRD) que las mujeres y actualmente se acepta que los andrógenos, y no la ausencia de estrógenos, son responsables de esto. Se acepta que la regeneración por PTEC superviviente es el mecanismo predominante de reparación/regeneración después de lesiones tubulares isquémicas en el riñón adulto de mamífero. Las PTEC son también el lugar donde se origina el carcinoma de células renales de células claras (ccRCC) en humanos. El ccRCC también presenta diferencias de sexo, con los hombres que tienen casi el doble de la incidencia de las mujeres a nivel mundial. Esto condujo a la hipótesis de que la regeneración después de lesiones renales y el desarrollo de ccRCC podrían compartir repertorios de expresión génica similares. Los andrógenos son muy relevantes en el desarrollo de los riñones, lo que sugiere que la regeneración y el cáncer en las células del túbulo proximal pueden recapitular, en parte, los programas dependientes de los andrógenos en el desarrollo del riñón. En este proyecto, hemos querido encontrar dianas que participen en la regeneración renal y en procesos de cáncer renal. Además, nos interesó estudiar la regulación de la hormona sexual en estas vías. Se realizaron análisis detallados de datos transcriptómicas de un modelo porcino de AKI. Se determinaron genes que expresaban un dimorfismo sexual en toda la IRI y se validaron dianas en muestras humanas. Además, se determinaron los conjuntos de genes implicados en la IRI y se caracterizaron de forma sexual y de tiempo. Encontramos que los grupos genéticos relacionados con los procesos de regeneración eran más activos en las mujeres que en los hombres. Además, la respuesta inmune a la lesión fue mayor en hombres que en mujeres. Después, hemos vinculado los procesos de regeneración con ccRCC mediante la superposición entre los análisis del transcriptomas AKI y ccRCC. Además, encontramos diferencias importantes entre los transcriptomas de riñón de ratón y de cerdo tras la lesión renal. Se estableció un modelo in vitro de IRI renal y se permitió validar parcialmente los hallazgos in vivo. Entre otros, observamos que durante la IRI renal, STAT3 está regulado por la fosforilación de diferentes residuos. Este estudio constituye una caracterización extensiva de las diferencias de sexo existentes durante la IRI renal. Ofrece una plantilla para caracterizar más las diferencias de sexo en enfermedades renales a nivel molecular.<br>Kidney diseases arise from congenital defects, acute kidney injury (AKI) or chronic kidney disease (CKD), among other causes. Renal ischemia/reperfusion injury (IRI), which is faced in many clinical situations, is a major cause of AKI leading to injury and death of proximal tubule epithelial cells (PTEC). The severity of AKI and the capacity to regenerate after injury are important determinants of patient morbidity and mortality in the hospital setting. Men are more prone to acute and chronic kidney disease and to progress to end-stage renal disease (ESRD) than women and it is currently accepted that androgens, and not the absence of estrogens, are responsible for that. It is accepted that regeneration by surviving PTEC is the predominant mechanism of repair/regeneration after ischemic tubular injury in the adult mammalian kidney. PTEC are also the site where the clear cell renal cell carcinoma (ccRCC) originates in humans. ccRCC also exhibits sex differences, with males having almost twice the incidence of females globally. This led to the hypothesis that regeneration after kidney injury and ccRCC development might share similar gene expression repertoires. Androgens are very relevant in kidney development, which suggests that regeneration and cancer in proximal tubule cells might recapitulate, in part, androgen-dependent programs in kidney developmental. In this project, we aimed to find targets that participate in renal regeneration and in renal cancer processes. Moreover, we were interested to study the sex hormone regulation of these pathways. Thorough analyses of transcriptomic data from a porcine model of AKI was performed. We determined genes that expressed a sexual dimorphism throughout IRI and we validated theses targets in human samples. Furthermore, we determined the gene sets involved in IRI and characterize them in a time and sex manner. We found that gene sets related to regeneration processes were more active in females than in males. Also, the immune response at injury was higher in males than in females. Afterwards, we linked regeneration processes with ccRCC by the overlap between AKI and ccRCC transcriptome analyses. Besides, we found major differences between the mouse and the pig kidney transcriptomes upon renal injury. An in vitro model of renal IRI was established and allowed to partially validate the in vivo findings. Among others, we observed that during renal IRI, STAT3 is regulated by phosphorylation of different residues. This study constitutes an extensive characterization of the sex differences that exist during renal IRI. It offers a template for further characterization of sex differences in kidney diseases at the molecular level.
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Oredsson, Sven. "Reperfusion injury in skeletal muscle with special reference to oxygen-derived free radicals as mediators /." Lund : Dept. of Surgery, Helsingborg Hospital, 1994. http://catalog.hathitrust.org/api/volumes/oclc/39056318.html.
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Mörtberg, Erik. "Assessment of the Cerebral Ischemic/Reperfusion Injury after Cardiac Arrest." Doctoral thesis, Uppsala universitet, Anestesiologi och intensivvård, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-132681.
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The cerebral damage after cardiac arrest is thought to arise both from the ischemia during the cardiac arrest but also during reperfusion. It is the degree of cerebral damage which determines the outcome in patients. This thesis focuses on the cerebral damage after cardiac arrest. In two animal studies, positron emission tomography (PET) was used to measure cerebral blood flow, oxygen metabolism and oxygen extraction in the brain. After restoration of spontaneous circulation (ROSC) from five or ten minutes of cardiac arrest there was an immediate hyperperfusion, followed by a hypoperfusion which was most evident in the cortex. The oxygen metabolism decreased after ROSC with the lowest values in the cortex. The oxygen extraction was high at 60 minutes after ROSC, indicating an ischemic situation. After ten minutes of cardiac arrest, there was a hyperperfusion in the cerebellum. In 31 patients resuscitated after cardiac arrest and treated with hypothermia for 24 hours, blood samples were collected from admission until 108 hours after ROSC. The samples were analyzed for different biomarkers in order to test the predictive value of the biomarkers. The patients were assessed regarding their neurological outcome at discharge from the intensive care unit and after six months. Brain derived neurotrophic factor (BDNF) and glial fibrillary acidic protein (GFAP) was not associated with outcome. Neuron specific enolase (NSE) concentrations were higher among those with a poor outcome with a sensitivity of 57% and a specificity of 93% when sampled 96 hours after ROSC. S-100B was very accurate in predicting outcome; after 24 hours after ROSC it predicted a poor outcome with a sensitivity of 87% and a specificity of 100%. Tau protein predicted a poor outcome after 96 hours after ROSC with a sensitivity of 71% and a specificity of 93%.
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Morsey, Hesham. "Ischaemia reperfusion injury in patients with peripheral arterial occlusive disease." Thesis, Imperial College London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.516556.
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Harrison, Ewen M. "Pharmacological strategies to reduce ischemia/reperfusion injury in kidney transplantation." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/24683.
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I investigated the influence of the phosphatidylinositol 3-kinase (PI3K)Akt pathway on HSF1 activation status. Despite effecting significant up-regulation of the PI3k/Akt pathway with insulin and insulin-like growth factor-1 (IGF-1), I did not demonstrate any change in the HSF1 trimerisation state, DNA-binding ability or nuclear localisation in renal adenocarcinoma cells (ACHN). Following treatment with insulin, a 5-fold increase in heme oxygenase-1 (HO-1) mRNA and a 4-fold increase in protein expression were observed in ACHN cells; insulin-induced HO-1 expression was also demonstrated in mouse primary tubular epithelial cells. The induction of HO-1 in ACHNs was blocked by actinomycin D and cycloheximide and was abolished by the PI3K inhibitor, LY294002, but not by the inactive analogue, LY303511. Over-expressing a dominant-negative form of Akt abrogated the HO-1 inducing effects of insulin, whereas cells transfected with a constitutively active Akt construct demonstrated an increase in HO-1 promoter activity and protein expression. The transcription factor NF-E2-related factor-2 (Nrf2) was found to translocate to the nucleus following insulin treatment in a PI3K-dependent manner. Pre-treatment with Nrf2 small-interfering RNA (siRNA) abolished insulin-induced HO-1 induction. Thus, insulin induces HO-1 mRNA and protein expression in renal cells in a PI3K/Akt and Nrf2 dependent manner. Heat shock protein 90-binding agents (HBAs) are known to up-regulate Hsps and confer cellular protection. I examined the ability of HBAs to protect the kidney in a model relevant to transplantation. Hsp70 gene expression was increased 30-40 times in ACHN cells treated with HBAs and trimerisation and DNA-binding of HSF1 was demonstrated. A 3 fold and 2 fold increase in Hsp70 and Hsp27 protein expression, respectively, was found in ACHNs treated with HBAs. HBAs protected ACHN cells from an H<sub>2</sub>O<sub>2</sub>-mediated oxidative stress and HSF1 siRNA abrogated HBA-mediated Hsp induction and protection. <i>In vivo</i>, Hsp70 was up-regulated in the kidney, liver, lungs and heart of HBA-treated mice. This was associated with a functional and morphological renal protection from IRI. Therefore, HBAs may be useful in reducing transplant-associated kidney injury.
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Sudarshan, Catherine. "Inhaled nitric oxide and reperfusion injury in experimental lung transplanation." Thesis, University of Newcastle upon Tyne, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.438028.
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