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Inflammatory Signalling Associated with Brain Dead Organ Donation: From Brain Injury to Brain Stem Death and Posttransplant Ischaemia Reperfusion Injury  [PDF]
Ryan P. Watts,Ogilvie Thom,John F. Fraser
Journal of Transplantation , 2013, DOI: 10.1155/2013/521369
Abstract: Brain death is associated with dramatic and serious pathophysiologic changes that adversely affect both the quantity and quality of organs available for transplant. To fully optimise the donor pool necessitates a more complete understanding of the underlying pathophysiology of organ dysfunction associated with transplantation. These injurious processes are initially triggered by catastrophic brain injury and are further enhanced during both brain death and graft transplantation. The activated inflammatory systems then contribute to graft dysfunction in the recipient. Inflammatory mediators drive this process in concert with the innate and adaptive immune systems. Activation of deleterious immunological pathways in organ grafts occurs, priming them for further inflammation after engraftment. Finally, posttransplantation ischaemia reperfusion injury leads to further generation of inflammatory mediators and consequent activation of the recipient’s immune system. Ongoing research has identified key mediators that contribute to the inflammatory milieu inherent in brain dead organ donation. This has seen the development of novel therapies that directly target the inflammatory cascade. 1. Introduction Organ transplantation is the gold standard treatment for patients with end stage solid organ failure. An ever increasing disparity between available organs and potential recipients is the cause of avoidable morbidity and mortality [1–4]. Ongoing efforts are being made to increase the quantity and quality of organs available for transplant. Although outcomes from non-heart-beating donors have become increasingly successful [5], the majority of organs are still donated from donors after brain death (BD). Significant brain injury of any aetiology will cause a systemic response [6], creating a proinflammatory environment prior to the occurrence of brain death itself. BD then also creates a variety of inflammatory, haemodynamic and endocrine effects, which induce adverse sequelae in distant organs [7–10]. Finally, ischaemia-reperfusion injury (IRI), inherent in transplantation, generates reactive oxygen species (ROS), activates complement, and independently drives cytokine release and inflammation [11, 12]. Every transplanted organ from a BD donor will face these stages of potential injury. Consequently, donor management must consider each step from donor to recipient in order to maximise recipient outcomes. The purpose of this paper is to explore the current understanding of the three main contributors to injury that an organ will travel through from donor to
Histopathologic changes during mesenteric ischaemia and reperfusion
JK Lapido, SA Seidel, LA Bradshaw, S Halter, JP Wikswo Jr, WO Richards
West African Journal of Medicine , 2003,
Abstract: The basic electrical rhythm (BER) of the intestine is known to decrease during mesenteric ischaemia. Some studies have reported the relationship between the BER and the pathologic changes that occur in the bowel during vascular injury. However, these changes have not been completely elucidated. This study describes the histopathologic pattern when the rabbit small intestine was subjected to ischaemia of varying time lengths (30 – 150 minutes) and subsequent reperfusion for six hours. Intestinal biopsies were taken at baseline, at the end of ischaemia, and at hourly intervals during reperfusion. Microscopic examination of the biopsies revealed evidence of progressive infarction of the mucosa during ischaemia. There was an acute worsening of the pathology during reperfusion, the severity being greater when reperfusion was preceded by longer periods of ischaemia. These changes were statistically significant. The observed pattern in this study shows clearly that reperfusion injury is reflected in the histopathologic response and that this is worse in severity than the response to ischaemia. Studies of longer duration should further clarify the picture during recovery in ischaemia/reperfusion injuries of the bowel.
The effect of Nitroprusside on the renal ischaemia-reperfusion injury
Kadkhodaee M,Hanson GR,Willgoss DA,Gobe GC
Acta Medica Iranica , 2002,
Abstract: Nitric oxide (NO) is implicated as an important mediator of, or intermediary in, inflammation, immunity and neurotransmission. In the kidney, No is involved in haemodynamic regulation, control of vascular tone and tubular function. Formation of oxygen-derived free radicals (OFR) have been documented in renal ischaemia- reperfusion before. In this study , we investigated the significance of No formation, by the addition of nitroprusside (0.2 mm) as an No donor, in the ischaemia- reperfused (IR) kidneys. Induction of Ir significantly reduced renal function compared to controls. In this study, nitroprusside showed beneficial effects on renal morphology although did not alter function over a short period of time.
Mice lacking the β2 adrenergic receptor have a unique genetic profile before and after focal brain ischaemia  [cached]
Robin E White,Curtis Palm,Lijun Xu,Evelyn Ling
ASN Neuro , 2012, DOI: 10.1042/an20110020
Abstract: The role of the β2AR (β2 adrenergic receptor) after stroke is unclear as pharmacological manipulations of the β2AR have produced contradictory results. We previously showed that mice deficient in the β2AR (β2KO) had smaller infarcts compared with WT (wild-type) mice (FVB) after MCAO (middle cerebral artery occlusion), a model of stroke. To elucidate mechanisms of this neuroprotection, we evaluated changes in gene expression using microarrays comparing differences before and after MCAO, and differences between genotypes. Genes associated with inflammation and cell deaths were enriched after MCAO in both genotypes, and we identified several genes not previously shown to increase following ischaemia (Ccl9, Gem and Prg4). In addition to networks that were similar between genotypes, one network with a central core of GPCR (G-protein-coupled receptor) and including biological functions such as carbohydrate metabolism, small molecule biochemistry and inflammation was identified in FVB mice but not in β2KO mice. Analysis of differences between genotypes revealed 11 genes differentially expressed by genotype both before and after ischaemia. We demonstrate greater Glo1 protein levels and lower Pmaip/Noxa mRNA levels in β2KO mice in both sham and MCAO conditions. As both genes are implicated in NF-κB (nuclear factor κB) signalling, we measured p65 activity and TNFα (tumour necrosis factor α) levels 24 h after MCAO. MCAO-induced p65 activation and post-ischaemic TNFα production were both greater in FVB compared with β2KO mice. These results suggest that loss of β2AR signalling results in a neuroprotective phenotype in part due to decreased NF-κB signalling, decreased inflammation and decreased apoptotic signalling in the brain.
Mouse Models for Myocardial Ischaemia/Reperfusion  [PDF]
Conci E,Pachinger O,Metzler B
Journal für Kardiologie , 2006,
Abstract: Die letzten Jahre wurden durch bemerkenswerte Fortschritte im Verst ndnis der Pathophysiologie der koronaren Herzkrankheit gepr gt. Die myokardiale Isch mie ist haupts chlich durch die Atherosklerose der Koronargef e bedingt. Obwohl die funktionellen Folgen von verminderter Blutversorgung am Herzmuskel hinl nglich bekannt sind, ist die koronare Herzkrankheit immer noch die h ufigste Todesursache in der westlichen Welt. Deshalb richten sich die therapeutischen Bemühungen auf die Wiederherstellung der Perfusion in den isch mischen Arealen, um die Entstehung einer Gewebsnekrose zu vermeiden und um die Funktion des Organs wiederherzustellen. Die Reperfusion von isch mischem Gewebe geht allerdings oft mit mikrovaskul rer Dysfunktion einher, die sich durch Beeintr chtigung der endothelabh ngigen Vasodilatation in Arteriolen und Ansammlung von Leukozyten in den Kapillaren manifestiert. Die Verfügbarkeit einer gro en Anzahl an Knockout-M usen erm glicht wichtige Erkenntnisse über das Zustandekommen der Myokardsch digung durch Isch mie und Reperfusion. Deshalb sind Mausmodelle von gro em Interesse für die Entwicklung neuer therapeutischer Strategien beim Menschen.
Cyclosporine action on kidneys of rats submitted to normothermic ischaemia and reperfusion
Cologna, Adauto José;Lima, Lucy Vieira da Silva;Tucci Jr., Silvio;Suaid, Haylton Jorge;Reis, Rodolfo Borges;Tirapelli, Luis Fernando;Rodrigues Jr., Ant?nio Antunes;Martins, Antonio Carlos Pereira;
Acta Cirurgica Brasileira , 2008, DOI: 10.1590/S0102-86502008000700007
Abstract: purpose: to verify if rat kidneys lesioned by ischaemia followed by reperfusion are affected by cyclosporine a (csa). methods: male wistar rats were randomly divided into three groups, control (gs) and experimental (g1 and g2). g1 was subdivided in two: g1a composed of animals submitted to 60 minutes ischaemia and g1c with the same ischaemic procedure associated to 20 mg/kg/day csa. group g2 was subdivided and treated in the same way as g1 except that ischaemia was applied only for 40 minutes. clamping the left renal artery followed by right side nephrectomy induced kidney ischaemia. serum urea and creatinine were quantified on the day of surgery (d0) and in the following day (d1). twenty four hours after reperfusion the left kidney was removed and histologically analyzed. results: group gs had normal values for urea and creatinine both on d0 and d1 and did not show structural alterations. renal function was not significantly different when g2c was compared to gs (p>0.05). tissue lesions were smaller in g2c than in the other groups. conclusions: renal function was protected by csa, which also reduced tissue lesions in the kidneys of rats submitted to 40 minutes ischaemia.
DETECTION OF NITRIC OXIDE REDUCTION DURING ISCHAEMIA-REPERFUSION BY EPR SPECTROSCOPY  [PDF]
KADKHODAEE M,ZHANG B,HANSON G.R,WILLGOSS D.A
Cell Journal , 2001,
Abstract: Introduction: Acute renal failure is a common consequence of sepisis due to concurrent renal ischaemia. The role of nitric oxide (NO) in endotoxaemia and in ischaemic injury in the kidney is not well defined. Material and Methods: In this study we have used an animal model of sepsis induced by injection of bacterial lipopolysaccharide (LPS) in the rat and measured renal nitric oxide by X-band electron paramagnetic resonance (EPR) spectroscopy using the spin trap Fe2+-N-methyl-D-glucamine dithiocarbamate [Fe(MGD)2] given by intravenous injection 6 minutes before sacrifice. Results: The characteristic EPR spectrum of [Fe(NO)(MGD)2] was observed in kidneys of rats treated with LPS for 5h. Rat kidneys subjected to 20 min ischaemia and 5 min reperfusion had lower concentrations of [Fe(NO)(MGD)2] (1.0 ± 0.6 (M) compared to the contralateral nonischaemic kidneys (1.5 ± 0.9 (M, P<0.05). Conclusion: This study shows reduced levels of NO after renal ischaemia in vivo.
Effect of pomiferin administration on kidney ischaemia-reperfusion injury in rats
Lenka Barto íková, Ji í Ne as, Tomá Barto ík, Martin Pavlík, Petr Fráňa
Interdisciplinary Toxicology , 2010, DOI: 10.2478/v10102-010-0015-1
Abstract: The aim of the study was to analyse protective effects of different doses of pomiferin in therapy of reperfusion injury. Rats were randomly divided into five groups (n=10). One group was intact. Three medicated groups and one placebo group were subjected to ischaemia and reperfusion of the left kidney. Pomiferin was administrated by single gastric gavage in 2 ml of 0.5% Avicel solution in doses of 5, 10 and 20 mg/kg. The placebo group was given only Avicel solution. On day 15, all the animals were exsanguinated and the reperfused kidneys were recovered. Selected biochemical markers were assessed in blood: antioxidative enzymes, total antioxidative capacity, malondialdehyde, creatinine, urea and uric acid. Creatinine, urea and total proteins were analysed in urine and 24-hour diuresis was recorded. The kidney tissue samples were used for histopathological examination. The results confirmed the expected protective effects of pomiferin. Pomiferin supported defensive reactions of the body against free radicals (increased levels of superoxide dismutase, total antioxidative capacity), decreased lipid peroxidation (decreased malondialdehyde) and contributed to the recovery of kidney functions (creatinine and urea in blood). The best biochemical and histopathological results were achieved after pomiferin administration in the dose of 5 mg/kg.
Length of pressure-controlled reperfusion is critical for reducing ischaemia-reperfusion injury in an isolated rabbit lung model
Stefan Guth, Diethard Prüfer, Thorsten Kramm, Eckhard Mayer
Journal of Cardiothoracic Surgery , 2007, DOI: 10.1186/1749-8090-2-54
Abstract: Heart-lung blocks of 25 New Zealand white rabbits were used. After measurement of baseline values (haemodynamics and gas exchange) the lungs were exposed to 120 minutes of hypoxic warm ischaemia followed by repeated measurements during reperfusion. Group A was immediately reperfused using a flow of 100 ml/min whereas groups B, C and D were initially reperfused with a maximum pressure of 5 mmHg for 5, 15 or 30 minutes, respectively. The control group had no period of ischaemia or PCR.Uncontrolled reperfusion (group A) caused a significant pulmonary injury with increased pulmonary artery pressures (PAP) and pulmonary vascular resistance and a decrease in oxygen partial pressure (PO2), tidal volume and in lung compliance. All groups with PCR had a significantly higher PO2 for 5 to 90 min after start of reperfusion. At 120 min there was also a significant difference between group B (264 ± 91 mmHg) compared to groups C and D (436 ± 87 mmHg; 562 ± 20 mmHg, p < 0.01). All PCR groups showed a significant decrease of PAP compared to group A.Uncontrolled reperfusion results in a severe lung injury with rapid oedema formation. PCR preserves pulmonary haemodynamics and gas exchange after ischaemia and might allows for recovery of the impaired endothelial function. 30 minutes of PCR provide superior results compared to 5 or 15 minutes of PCR.Since the middle 1980s lung transplantation (LTX) has become an accepted treatment option for patients with end-stage pulmonary disease, but ischaemia reperfusion (IR) injury of the pulmonary graft is still a serious early problem after LTX [1].Ten to 20% of transplanted lung allografts develop a severe graft dysfunction (IR-injury) that yields to a high early mortality and ongoing morbidity [2-6]. The clinical features are pulmonary oedema with diffuse infiltrates in the chest radiographs, decreased lung compliance (CL), progressive hypoxaemia, and an increased pulmonary vascular resistance (PVR) [7,8]. Histological examinations show alveol
Endothelin-B Receptors and Left Ventricular Dysfunction after Regional versus Global Ischaemia-Reperfusion in Rat Hearts  [PDF]
Sofia-Iris Bibli,Eleni V. Toli,Agapi D. Vilaeti,Varnavas C. Varnavas,Giannis G. Baltogiannis,Apostolos Papalois,Zenon S. Kyriakides,Theofilos M. Kolettis
Cardiology Research and Practice , 2012, DOI: 10.1155/2012/986813
Abstract: Background. Endothelin-1 (ET-1) is implicated in left ventricular dysfunction after ischaemia-reperfusion. ETA and ETB receptors mediate diverse actions, but it is unknown whether these actions depend on ischaemia type and duration. We investigated the role of ETB receptors after four ischaemia-reperfusion protocols in isolated rat hearts. Methods. Left ventricular haemodynamic variables were measured in the Langendorff-perfused model after 40- and 20-minute regional or global ischaemia, followed by 30-minute reperfusion. Wild-type ( ) and ETB-deficient ( ) rats were compared. Infarct size was measured using fluorescent microspheres after regional ischaemia-reperfusion. Results. Left ventricular dysfunction was more prominent in ETB-deficient rats, particularly after regional ischaemia. Infarct size was smaller ( ) in wild-type ( %) than ETB-deficient ( %) rats after 40 minutes of regional ischaemia-reperfusion. Although the recovery of left ventricular function was poorer after 40-minute ischaemia-reperfusion, end-diastolic pressure in ETB-deficient rats was higher after 20 than after 40 minutes of regional ischaemia-reperfusion. Conclusion. ETB receptors exert cytoprotective effects in the rat heart, mainly after regional ischaemia-reperfusion. Longer periods of ischaemia suppress the recovery of left ventricular function after reperfusion, but the role of ETB receptors may be more important during the early phases. 1. Introduction Myocardial infarction is the most common clinical manifestation of cardiovascular disease, which remains a leading cause of death worldwide [1]. Prompt restoration of coronary blood flow in the acute phase decreases acute and long-term morbidity and mortality. However, the major limitation of this strategy is reperfusion injury, defined as a second peak of myocardial necrosis, initiated after the onset of reperfusion [2]. Endothelin-1 (ET-1) is a 21-amino-acid peptide, first identified by Yanagisawa and coworkers in 1988 [3]; in addition to its potent vasoconstrictor properties, ET-1 acts also on ventricular myocytes [4]. The effects of ET-1 are mediated via two G-protein-coupled receptors, namely, endothelin-A (ETA) and endothelin-B (ETB), which are abundantly present in the myocardium [5]. ET-1 exerts most of its effects via ETA receptors, whereas the role of ETB receptors in various disease states is incompletely understood [4]. Previous reports have demonstrated elevated circulating ET-1 levels [6–8], as well as increased ET-1 expression in the infarct zone [9], in response to prolonged myocardial ischaemia. ET-1
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