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Reperfusion Injury (reperfusion + injury)
Kinds of Reperfusion Injury Selected AbstractsROSIGLITAZONE, AN AGONIST OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA, PREVENTS CONTRALATERAL TESTICULAR ISCHAEMIA,REPERFUSION INJURY IN PREPUBERTAL RATSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2007Mustafa Inan SUMMARY 1Rosiglitazone plays a positive role in the reparation of ischaemia,reperfusion (I/R) injury in different tissues. Thus, we examined its biochemical and histological effects on the contralateral testes to determine whether exogenous rosiglitazone affords any protection against testicular damage. 2Forty-eight prepubertal male Wistar-Albino rats were divided into six groups. Testicular torsion was created by rotating the right testis 720° in a clockwise direction for 5 h in all groups except group I, which was the sham-control group. In group II, bilateral orchiectomy was performed following the torsion period. After detorsion both testes were removed in the fifth hour in group III and on the seventh day in group IV. In group V, one-shot rosiglitazone (4 mg/kg) was administered 40 min before detorsion and both testes were removed following the torsion period. In group VI, rosiglitazone was administered (4 mg/kg) 40 min before detorsion and for 7 days, and then both testes were harvested. The tissue levels of malondialdehyde (MDA) were measured and mean testicular biopsy score (MTBS) and mean seminiferous tubule diameter (MSTD) were examined. Immunoexpression of endothelial nitric oxide synthase (eNOS) in testes tissues was investigated by immunohistochemical studies. 3In the contralateral testis, the MTBS and MSTD values of group VI were significantly higher than those in group IV. Immunohistochemically, mild eNOS immunostaining was present in the germ cells of the contralateral testes in group IV after I/R. In group VI, intense eNOS immunoreactivity was seen in the contralateral testes. 4Rosiglitazone reduces contralateral testicular damage formed after unilateral testicular torsion and alleviates the oxidative events. [source] The Physiology of Endothelial Xanthine Oxidase: From Urate Catabolism to Reperfusion Injury to Inflammatory Signal TransductionMICROCIRCULATION, Issue 3 2002AVEDIS MENESHIAN ABSTRACT Xanthine oxidoreductase (XOR) is a ubiquitous metalloflavoprotein that appears in two interconvertible yet functionally distinct forms: xanthine dehydrogenase (XD), which is constitutively expressed in vivo; and xanthine oxidase (XO), which is generated by the posttranslational modification of XD, either through the reversible, incremental thiol oxidation of sulfhydryl residues on XD or the irreversible proteolytic cleavage of a segment of XD, which occurs at low oxygen tension and in the presence of several proinflammatory mediators. Functionally, both XD and XO catalyze the oxidation of purines to urate. However, whereas XD requires NAD+ as an electron acceptor for these redox reactions, thereby generating the stable product NADH, XO is unable to use NAD+ as an electron acceptor, requiring instead the reduction of molecular oxygen for this purine oxidation and generating the highly reactive superoxide free radical. Nearly 100 years of study has documented the physiologic role of XD in urate catabolism. However, the rapid, posttranslational conversion of XD to the oxidantgenerating form XO provides a possible physiologic mechanism for rapid, posttranslational, oxidant-mediated signaling. XO-generated reactive oxygen species (ROS) have been implicated in various clinicopathologic entities, including ischemia/reperfusion injury and multisystem organ failure. More recently, the concept of physiologic signal transduction mediated by ROS has been proposed, and the possibility of XD to XO conversion, with subsequent ROS generation, serving as the trigger of the microvascular inflammatory response in vivo has been hypothesized. This review presents the evidence and basis for this hypothesis. [source] Donor Pretreatment with Tetrahydrobiopterin Saves Pancreatic Isografts from Ischemia Reperfusion Injury in a Mouse ModelAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2010M. Maglione Depletion of the nitric oxide synthase cofactor tetrahydrobiopterin (H4B) during ischemia and reperfusion is associated with severe graft pancreatitis. Since clinically feasible approaches to prevent ischemia reperfusion injury (IRI) by H4B-substitution are missing we investigated its therapeutic potential in a murine pancreas transplantation model using different treatment regimens. Grafts were subjected to 16 h cold ischemia time (CIT) and different treatment regimens: no treatment, 160 ,M H4B to perfusion solution, H4B 50 mg/kg prior to reperfusion and H4B 50 mg/kg before recovery of organs. Nontransplanted animals served as controls. Recipient survival and endocrine graft function were assessed. Graft microcirculation was analyzed 2 h after reperfusion by intravital fluorescence microscopy. Parenchymal damage was assessed by histology and nitrotyrosine immunohistochemistry, H4B tissue levels by high pressure liquid chromatography (HPLC). Compared to nontransplanted controls prolonged CIT resulted in significant microcirculatory deterioration. Different efficacy according to route and timing of administration could be observed. Only donor pretreatment with H4B resulted in almost completely abrogated IRI-related damage showing graft microcirculation comparable to nontransplanted controls and restored intragraft H4B levels, resulting in significant reduction of parenchymal damage (p < 0.002) and improved survival and endocrine function (p = 0.0002 each). H4B donor pretreatment abrogates ischemia-induced parenchymal damage and represents a promising strategy to prevent IRI following pancreas transplantation. [source] Cytoprotective Effects of a Cyclic RGD Peptide in Steatotic Liver Cold Ischemia and Reperfusion InjuryAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2009C. Fondevila The serious need for expanding the donor population has attracted attention to the use of steatotic donor livers in orthotopic liver transplantation (OLT). However, steatotic livers are highly susceptible to hepatic ischemia,reperfusion injury (IRI). Expression of fibronectin (FN) by endothelial cells is an important feature of hepatic response to injury. We report the effect of a cyclic RGD peptide with high affinity for the ,5,1, the FN integrin receptor, in a rat model of steatotic liver cold ischemia, followed by transplantation. RGD peptide therapy ameliorated steatotic IRI and improved the recipient survival rate. It significantly inhibited the recruitment of monocyte/macrophages and neutrophils, and depressed the expression of pro-inflammatory mediators, such as inducible nitric oxide synthase (iNOS) and interferon (IFN)-,. Moreover, it resulted in profound inhibition of metalloproteinase-9 (MMP-9) expression, a gelatinase implied in leukocyte migration in damaged livers. Finally, we show that RGD peptide therapy reduced the expression of the 17-kDa active caspase-3 and the number of apoptotic cells in steatotic OLTs. The observed protection against steatotic liver IRI by the cyclic RGD peptides with high affinity for the ,5,1 integrin suggests that this integrin is a potential therapeutic target to allow the successful utilization of marginal steatotic livers in transplantation. [source] Cardioprotective Effects of Angiotensin II Type 1 Receptor Blockade with Olmesartan on Reperfusion Injury in a Rat Myocardial Ischemia-Reperfusion ModelCARDIOVASCULAR THERAPEUTICS, Issue 1 2010Wangde Dai We determined the effects of olmesartan on infarct size and cardiac function in a rat ischemia/reperfusion model. Rats underwent 30 min of left coronary artery (CA) occlusion followed by 2 h of reperfusion. In protocol 1, the rats received (by i.v.) 1 mL of vehicle at 10 min after CA occlusion (Group 1, n = 15); olmesartan (0.3 mg/kg) at 10 min after CA occlusion (Group 2, n = 15); 1 mL of vehicle at 5 min before CA reperfusion (Group 3, n = 15); or olmesartan (0.3 mg/kg) 5 min before CA reperfusion (Group 4, n = 15). In protocol 2, the rats received (by i.v.) 1 mL of vehicle at 5 min before CA reperfusion (Group 5, n = 21); or olmesartan (3 mg/kg) at 5 min before CA reperfusion (Group 6, n = 21). Systemic hemodynamics, left ventricular (LV) function, LV ischemic risk zone, no-reflow zone, and infarct size were determined. In protocol 1, olmesartan (0.3 mg/kg) did not affect blood pressure (BP), heart rate, LV ± dp/dt or LV fractional shortening during the experimental procedure, and did not alter no-reflow or infarct size. In protocol 2, olmesartan (3 mg/kg) significantly reduced infarct size to 21.7 ± 4.1% from 34.3 ± 4.1% of risk zone in the vehicle group (P= 0.035), but did not alter the no-reflow size. Prior to CA reperfusion, olmesartan (3 mg/kg) significantly reduced mean BP by 22% and LV ±dp/dt, but did not affect heart rate. At 2 h after reperfusion, olmesartan significantly decreased heart rate by 21%, mean BP by 14%, and significantly increased LV fractional shortening from 54.1 ± 1.4% to 61.3 ± 1.6% (P= 0.0018). Olmesartan significantly reduced myocardial infarct size and improved LV contractility at a dose (3 mg/kg) with systemic vasodilating effects but not at a lower dose (0.3 mg/kg) without hemodynamic effects. [source] Cyclical ischaemic preconditioning modulates the adaptive immune response in human limb ischaemia,reperfusion injuryBRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 4 2009P. J. Sullivan Background: Reperfusion injury (RI) has significant local and systemic consequences. Ischaemic preconditioning (IPC) modulates RI and the innate immune response. This study examined whether IPC attenuates RI-mediated changes in lymphocyte populations and function following elective surgery. Methods: Twenty-five patients sustaining 1 h of tourniquet ischaemia during cruciate ligament reconstruction were randomized before surgery to three 5-min ischaemia cycles separated by 5 min of reperfusion, or to a control group. Systemic levels of interleukin (IL) 4 and interferon (IFN) ,, and surface expression of CD45ro/ra, CD62L and CD95 were measured. T cells were examined systemically and in stimulated serum co-culture to determine CD4/CD8 and Th1/Th2 shifts through intracellular cytokine production. Results: CD4 CD45ro cell numbers increased after RI without IPC, whereas CD8 cells expressing CD45ro and CD95 increased with IPC. Preconditioned serum in co-culture attenuated increases in CD4 and decreases in CD8 numbers, a process prevented by inhibition of antigen activation. Following RI, systemic IL-2 levels were significantly lower after IPC, whereas co-culture with post-RI serum increased proinflammatory intracellular cytokine production. Conclusion: IPC modulated T cell responses in limb RI through reduced activation and proinflammatory cytokine production by CD4 cells, while preventing CD4/CD8 derangement. IPC prevented lymphocyte-directed immune dysfunction. Copyright © 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] Effects of the PAF receptor antagonist UK74505 on local and remote reperfusion injuries following ischaemia of the superior mesenteric artery in the ratBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2000D G Souza The effects of the long lasting and potent PAF receptor antagonist UK74505 were assessed on the local and remote injuries following ischaemia and reperfusion (I/R) of the superior mesenteric artery (SMA) in rats. In a severe model of ischaemia (120 min) and reperfusion (120) injury, in addition to the local and remote increases in vascular permeability and neutrophil accumulation, there was significant tissue haemorrhage, blood neutropenia, systemic hypotension and elevated local and systemic TNF-, levels. Post-ischaemic treatment with the selectin blocker fucoidin (10 mg kg,1) prevented neutrophil accumulation in tissue and, in consequence, all the local and systemic injuries following severe I/R. Treatment with an optimal dose of UK74505 (1 mg kg,1) also reversed local and remote neutrophil accumulation, increases in vascular permeability and intestinal haemorrhage. UK74505 partially inhibited blood neutropenia and reperfusion-induced hypotension. Interestingly, both fucoidin and UK74505 prevented the local, but not systemic, increases of TNF-, levels following severe I/R injury, demonstrating an important role of migrating cells for the local production of TNF-,. However, the results do not support a role for PAF as an intermediate molecule in the production of systemic TNF-,. The beneficial effects of UK74505 and other PAF receptor antagonists in models of I/R injury in animals and the safety of UK74505 use in man warrant further investigations of the use of this drug as preventive measure for I/R injury in humans. British Journal of Pharmacology (2000) 131, 1800,1808; doi:10.1038/sj.bjp.0703756 [source] Pretreatment with insulin before ischaemia reduces infarct size in Langendorff-perfused rat heartsACTA PHYSIOLOGICA, Issue 2 2009B. N. Fuglesteg Abstract Aim:, To compare the possible role of Akt and mammalian target of rapamycin (mTOR) in mediating cardioprotection against ischaemia under three different conditions: (1) During ischaemic preconditioning (IPC), (2) when insulin was given as a pretreatment agent (InsPC) and (3) when insulin was given as a reperfusion cell survival agent (InsR). Methods:, Isolated perfused rat hearts were subjected to IPC (3 × 5 min) or InsPC (50 mU mL,1; 3 × 5 min), before 30 min of regional ischaemia followed by 120 min of reperfusion ± 1L-6-hydroxymethyl- chiro -inositol-2 - [(R)-2- O -methyl-3- O -octadecylcarbonate] (HIMO) (20 ,m; Akt inhibitor) or rapamycin (1 nm; mTOR inhibitor). In addition, insulin (3 mU mL,1) was given at the onset of reperfusion, ±HIMO or rapamycin. Risk zone (R) and infarct size (I) were determined with Evans blue and tetrazolium staining respectively. Western blot analysis was performed on tissue from Langendorff-perfused rat hearts and cell lysates from cultured HL1 cells. Results:, IPC, InsPC and InsR treatment resulted in a significant reduction in infarct size compared to controls (all P < 0.05). This protective effect of IPC and insulin was abolished by the inhibitors. However, the putative Akt inhibitor, although capable of abolishing cardioprotection induced by insulin, was not able to inhibit insulin-induced phosphorylation of Akt in Langendorff-perfused rat hearts and cultured HL1 cells. The target for this compound therefore remains to be determined. Conclusion:, IPC and insulin (either as InsPC or InsR) appear to activate mTOR, and this kinase seems to play an essential role in cardioprotection against ischaemia and reperfusion injury as rapamycin blocked the protection. [source] Exposure of rats to hyperoxia enhances relaxation of isolated aortic rings and reduces infarct size of isolated heartsACTA PHYSIOLOGICA, Issue 4 2002P. Tähepõld ABSTRACT Exposure of rats to hyperoxia before organ harvesting protected their isolated hearts against global ischaemia,reperfusion injury in a previous study. The present study investigates whether hyperoxia influences vasomotor function and regional ischaemia of the heart. Isolated rings of the thoracic aorta were obtained from rats immediately or 24 h after in vivo exposure to 60 min of hyperoxia (>95% O2), and the in vitro dose,response to phenylephrine (PHE), prostaglandin F2, (PGF2,) and endothelin-1 (ET-1), acetylcholine (Ach) and sodium nitroprusside (SNP) was assessed. Hyperoxia in vivo increased the relaxation of aortic rings to Ach and SNP, while it delayed contraction to PHE. The effect was more evident when the vessels were harvested immediately rather than 24 h after hyperoxic exposure. In separate experiments rat hearts were isolated immediately after hyperoxia, buffer-perfused, and subjected to 30 min of regional ischaemia and reperfused for 120 min. Infarct size was determined by triphenyl tetrazolium chloride staining. Hyperoxia significantly reduced infarct size. In normoxic controls 23.0 ± 8.3% of the area at risk was infarcted, while in hyperoxic animals infarct size was 14.8 ± 5.6% of the area at risk (P = 0.012). Exposure of rats to hyperoxia modifies the vasomotor response of isolated aortic rings, and reduces the infarct size of isolated rat heart. These novel aspects of hyperoxic treatment require further studies to explore the potential of its clinical application. [source] Effects of labedipinedilol-A, third-generation dihydropyridine-type calcium blocker, on ouabain-induced arrhythmiaDRUG DEVELOPMENT RESEARCH, Issue 1 2008Jhy-Chong Liang Abstract Labedipinedilol-A, a novel dihydropyridine-type calcium antagonist with ,/,-adrenoceptor blocking properties, has been reported to produce a cardioprotective effect against ischemia reperfusion injury in rats. We investigated the protective effects of labedipinedilol-A on ouabain-induced tonotropy and arrhythmias in isolated whole atria, and using patch-clamp techniques to study the underlying mechanism of its antiarrhythmic activity on isolated cardiac myocytes. Labedipinedilol-A (10,µM) suppressed the tonotropic effect of ouabain significantly and prolonged the onset time of extra-systole (arrhythmia) induced by ouabain in isolate atria. In the voltage-clamp study, labedipinedilol-A (1,100,µM) reduced the peak amplitude of sodium inward current (INa) and L-type calcium current (ICa-L), and shifted the current-voltage (I-V) curve upward in a concentration-dependent manner. In contrast, the addition of labedipinedilol-A increased transient outward potassium current (Ito) and inward rectifier potassium current (IK1) significantly. Labedipinedilol-A (10,µM) also effectively depressed the isoproterenol-induced increase in the Ca2+ current. These results show that labedipinedilol-A blocks ICa-L and INa, and increases Ito and IK1. These findings indicate that labedipinedilol-A produces direct cardiac action, probably due to the inhibition of cardiac Na+ and Ca2+ channels. Our results suggest that labedipinedilol-A may reduce the membrane conduction through inhibition of ionic channels which decrease ouabain-induced arrhythmia. Drug Dev Res 69:26,33, 2008 © 2008 Wiley-Liss, Inc. [source] Methylene blue attenuates lung injury after mesenteric artery clamping/unclampingEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 6 2004A. A. Weinbroum Abstract Background, This controlled, experimental study was designed to assess the effects of intratracheal and intravenous methylene blue on reperfusion lung injury following superior mesenteric artery clamping/unclamping. Materials and methods, Superior mesenteric arteries of 144 anaesthetized adult male Wistar rats (n = 12/group) were clamped for 1 h. Ten minutes before unclamping, methylene blue or its vehicle was administered intratracheally or intravenously, followed by a 3 h-respiratory assessment and postexperimental assessment of survival. Results, Intravenous 3 and 9 mg kg,1 but not higher methylene blue doses, and intratracheal 6-mg kg,1 but not lower doses, significantly (P < 0·05) reduced the 100% increase in plateau pressure, 30% reduction in PO2/FiO2, fourfold augmented bronchoalveolar lavage-retrieved volume and the increased polymorphonuclear leukocytes/bronchoalveolar cells' ratio associated with unclamping of the superior mesenteric artery. Lung tissue polymorphonuclear leukocytes count, total xanthine oxidase activity and wet-to-dry-weight ratio were also normal in these dose-treated groups. These effective regimens were also associated with longer animal survival. Conclusions, Intratracheal methylene blue mitigates lung reperfusion injury following superior mesenteric artery clamping/unclamping at a similar magnitude as an intravenous regimen. This finding is a novel potential use of methylene blue in vivo. [source] Impaired liver regeneration and increased oval cell numbers following T cell,mediated hepatitis,HEPATOLOGY, Issue 1 2007Ian N. Hines The regeneration of liver tissue following transplantation is often complicated by inflammation and tissue damage induced by a number of factors, including ischemia and reperfusion injury and immune reactions to the donor tissue. The purpose of the current study is to characterize the effects of T cell,mediated hepatitis induced by concanavalin A (ConA) on the regenerative response in vivo. Liver regeneration following a partial (70%) hepatectomy (pHx) was associated with elevations in serum enzymes and the induction of key cell cycle proteins (cyclin D, cyclin E, and Stat3) and hepatocyte proliferation. The induction of T cell,mediated hepatitis 4 days before pHx increased serum enzymes 48 hours after pHx, reduced early cyclin D expression and Stat3 activation, and suppressed hepatocyte proliferation. This inhibition of proliferation was also associated with increased expression of p21, the activation of Smad2, the induction of transforming growth factor beta and interferon gamma expression, and reduced hepatic interleukin 6 production. Moreover, the ConA pretreatment increased the numbers of separate oval cell-like CD117+ cells and hematopoietic-like Sca-1+ cell populations 48 hours following pHx. The depletion of natural killer (NK) cells, an important component of the innate immune response, did not affect liver injury or ConA-induced impairment of hepatocyte proliferation but did increase the numbers of both CD117-positive and Sca-1,positive cell populations. Finally, splenocytes isolated from ConA-pretreated mice exerted cytotoxicity toward autologous bone marrow cells in an NK cell,dependent manner. Conclusion: T cell,mediated hepatitis alters early cytokine responses, reduces hepatocellular regeneration, and induces NK cell,sensitive oval cell and hematopoietic-like cell expansion following pHx. (HEPATOLOGY 2007;46:229,241.) [source] Biliverdin therapy protects rat livers from ischemia and reperfusion injuryHEPATOLOGY, Issue 6 2004Constantino Fondevila Heme oxygenase (HO-1) provides a cellular defense mechanism during oxidative stress and catalyzes the rate-limiting step in heme metabolism that produces biliverdin (BV). The role of BV and its potential use in preventing ischemia/reperfusion injury (IRI) had never been studied. This study was designed to explore putative cytoprotective functions of BV during hepatic IRI in rat liver models of ex vivo perfusion and orthotopic liver transplantation (OLT) after prolonged periods of cold ischemia. In an ex vivo hepatic IRI model, adjunctive BV improved portal venous blood flow, increased bile production, and decreased hepatocellular damage. These findings were correlated with amelioration of histological features of IRI, as assessed by Suzuki's criteria. Following cold ischemia and syngeneic OLT, BV therapy extended animal survival from 50% in untreated controls to 90% to 100%. This effect correlated with improved liver function and preserved hepatic architecture. Additionally, BV adjuvant after OLT decreased endothelial expression of cellular adhesion molecules (P-selectin and intracellular adhesion molecule 1), and decreased the extent of infiltration by neutrophils and inflammatory macrophages. BV also inhibited expression of inducible nitric oxide synthase and proinflammatory cytokines (interleukin 1,, tumor necrosis factor ,, and interleukin 6) in OLTs. Finally, BV therapy promoted an increased expression of antiapoptotic molecules independently of HO-1 expression, consistent with BV being an important mediator through which HO-1 prevents cell death. In conclusion, this study documents and dissects potent cytoprotective effects of BV in well-established rat models of hepatic IRI. Our results provide the rationale for a novel therapeutic approach using BV to maximize the function and thus the availability of donor organs. (HEPATOLOGY 2004;40:1333,1341.) [source] Induction of cellular resistance against Kupffer cell,derived oxidant stress: A novel concept of hepatoprotection by ischemic preconditioningHEPATOLOGY, Issue 2 2003Rolf J. Schauer Ischemic preconditioning (IP) triggers protection of the liver from prolonged subsequent ischemia. However, the underlying protective mechanisms are largely unknown. We investigated whether and how IP protects the liver against reperfusion injury caused by Kupffer cell (KC)-derived oxidants. IP before 90 minutes of warm ischemia of rat livers in vivo significantly reduced serum alanine aminotransferase (AST) levels and leukocyte adherence to sinusoids and postsinusoidal venules during reperfusion. This protective effect was mimicked by postischemic intravenous infusion of glutathione (GSH), an antioxidative strategy against KC-derived H2O2. Interestingly, no additional protection was achieved by infusion of GSH to preconditioned animals. These findings and several additional experiments strongly suggest IP mediated antioxidative effects: IP prevented oxidant cell injury in isolated perfused rat livers after selective KC activation by zymosan. Moreover, IP prevented cell injury and pertubations of the intracellular GSH/GSSG redox system caused by direct infusion of H2O2 (0.5 mmol/L). IP-mediated resistance against H2O2 could neither be blocked by the adenosine A2a antagonist DMPX nor mimicked by A2a agonist CGS21680. In contrast, H2O2 resistance was abolished by the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580, but induced when p38 MAPK was directly activated by anisomycin. In conclusion, we propose a novel concept of hepatoprotection by IP: protection of liver cells by enhancing their resistance against KC-derived H2O2. Activation of p38 MAPK and preservation of the intracellular GSH/oxidized glutathione (GSSG) redox system, but not adenosine A2a receptor stimulation, seems to be pivotal for the development of H2O2 resistance in preconditioned livers. [source] Low-dose TNF-, protects against hepatic ischemia-reperfusion injury in mice: Implications for preconditioningHEPATOLOGY, Issue 1 2003Narci Teoh Tumor necrosis factor , (TNF-,) is implicated in the pathogenesis of hepatic ischemia reperfusion injury but can also prime hepatocytes to enter the cell cycle. Ischemic preconditioning protects against ischemia-reperfusion (IR) liver injury and is associated with activation of nuclear factor ,B (NF-,B) and cell cycle entry. We examined the pattern of TNF-, release during hepatic IR in the presence or absence of ischemic preconditioning, and we tested whether a single low-dose injection of TNF could mimic the biologic effects of ischemic preconditioning. In naïve mice, hepatic and plasma levels of TNF-, rose during hepatic ischemia, reaching high levels after 90 minutes; values remained elevated during reperfusion until 44 hours. Following the ischemic preconditioning stimulus, there was an early rise in hepatic and serum TNF-, levels, but, during a second prolonged ischemic interval peak, TNF-, values were lower than in naïve mice and declined to negligible levels by 2 hours reperfusion. An injection with 1 ,g or 5 ,g/kg body weight TNF-, 30 minutes prior to hepatic IR substantially reduced liver injury determined by liver histology and serum alanine aminotransferase (ALT) levels. As in ischemic preconditioning, TNF-, pretreatment activated NF-,B DNA binding, STAT3, cyclin D1, cyclin-dependent kinase 4 (cdk4) expression, and cell cycle entry, determined by proliferating cell nuclear antigen (PCNA) staining of hepatocyte nuclei. In conclusion, the hepatoprotective effects of "preconditioning" can be simulated by TNF-, injection, which has identical downstream effects on cell cycle entry. We propose that transient increases in TNF-, levels may substitute for, as well as, mediate the hepatoprotective effects of ischemic preconditioning against hepatic IR injury. [source] Gene delivery of Cu/Zn-superoxide dismutase improves graft function after transplantation of fatty livers in the ratHEPATOLOGY, Issue 6 2000Thorsten G. Lehmann Oxygen-derived free radicals play a central role in reperfusion injury after organ transplantation, and fatty livers are particularly susceptible. Endogenous radical scavengers such as superoxide dismutase (SOD) degrade these radicals; however, SOD is destroyed rapidly when given exogenously. Therefore, an adenoviral vector encoding the Cu/Zn-SOD gene (Ad.SOD1) was used here to test the hypothesis that organ injury would be reduced and survival increased in a rat model of transplantation of fatty livers. Donors received chow diet (untreated), high-fat diet, or ethanol-containing high-fat diet. Some of the ethanol-fed donors were infected either with the gene lacZ encoding bacterial ,-galactosidase (Ad.lacZ), or Ad.SOD1. After liver transplantation, SOD activity and protein expression in liver, survival, histopathology, release of transaminases, free radical adducts in bile, and activation of NF-,B, I,B kinase (IKK), Jun-N-terminal kinase (JNK), and TNF, were evaluated. Ad.SOD1 treatment increased survival dramatically, blunted transaminase release, and reduced necrosis and apoptosis significantly. Free radical adducts were increased two-fold in the ethanol group compared with untreated controls. Ad.SOD1 blunted this increase and reduced the activation of NF-,B. However, release of TNF, was not affected. Ad.SOD1 also blunted JNK activity after transplantation. This study shows that gene therapy with Ad.SOD1 protects marginal livers from failure after transplantation because of decreased oxygen radical production. Genetic modification of fatty livers using viral vectors represents a new approach to protect marginal grafts against primary nonfunction. [source] Ischaemic preconditioning of the graft in adult living related right lobe liver transplantation: impact on ischaemia,reperfusion injury and clinical relevanceHPB, Issue 7 2010Paola Andreani Abstract Background:, Ischaemic preconditioning (IPC) of the right liver graft in the donor has not been studied in adult-to-adult living related liver transplantation (LRLT). Objective:, To assess the IPC effect of the graft on ischaemia reperfusion injury in the recipient and compare recipient and donor outcomes with and without preconditioned grafts. Patients and methods:, Alternate patients were transplanted with right lobe grafts that were (n= 22; Group Precond) or were not (n= 22; Group Control) subjected to IPC in the living donor. Liver ischaemia,reperfusion injury, liver/kidney function, morbidity/mortality rates and outcomes were compared. Univariate and multivariate analyses were performed to identify factors predictive of the aspartate aminotransferase (AST) peak and minimum prothrombin time. Results:, Both groups had similar length of hospital stay, morbidity/mortality, primary non-function and acute rejection rates. Post-operative AST (P= 0.8) and alanine aminotransferase (ALT) peaks (P= 0.6) were similar in both groups (307 ± 189 and 437 ± 302 vs. 290 ± 146 and 496 ± 343, respectively). In univariate analysis, only pre-operative AST and warm ischemia time (WIT) were significantly associated with post-operative AST peak (in recipients). In multivariate analysis, the graft/recipient weight ratio (P= 0.003) and pre-operative bilirubin concentration (P= 0.004) were significantly predictive of minimum prothrombin time post-transplantation. Conclusions:, Graft IPC in the living related donor is not associated with any benefit for the recipient or the donor and its clinical value remains uncertain. [source] Hyperbaric oxygen therapy and liver transplantationHPB, Issue 3 2007VIJAYARAGAVAN MURALIDHARAN Abstract Liver transplantation is the treatment of choice for end stage liver disease and is often used for primary liver malignancies. The main limitation of its wider application is the availability of suitable donor organs. The use of marginal donor organs, split-liver transplantation and living-related liver transplantation techniques contribute to increase the donor pool. However, the use of these techniques is associated with a higher risk of post transplantation organ dysfunction, predominantly due to ischaemia, preservation and reperfusion injury (IPRI). A number of studies have demonstrated that hyperbaric oxygen (HBO) therapy influences IPRI and consequential acute cellular rejection. This article reviews the rationale of HBO therapy in the field of transplantation with particular emphasis on liver transplantation. [source] Remote pharmacological post-conditioning by intrathecal morphine: cardiac protection from spinal opioid receptor activationACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 9 2010J. LING LING Background: Intrathecal morphine pre-conditioning attenuates cardiac ischemia,reperfusion injury via activation of central opioid receptors. We hypothesized that intrathecal morphine also post-conditions the myocardium in the rat. Methods: Intrathecal morphine at 0.3 ,g/kg (LMPC), 3 ,g/kg (MMPC) or 30 ,g/kg (HMPC) was administered for 5 min before 120-min reperfusion following 30-min ischemia. Infarct size as a percentage of area at risk (IS/AAR) was determined using triphenyltetrazolium staining. MMPC was repeated following the intrathecal administration of nor BNI, NTD, CTOP, or naloxone methiodide (NM), kappa, delta, mu and non-specific opioid receptor antagonists, respectively. The role of peripheral opioid, adenosine and calcitonin gene-related peptide (CGRP) receptors was examined by the intravenous administration of NM, 8-,-sulfophenyl theophylline (8-SPT) and human CGRP fragment (CGRP8,37), respectively. Results: Morphine post-conditioning at all three doses was cardioprotective (IS/AAR of LMPC=37±4%, MMPC=35±5%, HMPC=32±4%, control=50±5%, P<0.01). The prior administration of opioid receptor antagonists intrathecally, as well as intravenous 8-SPT and CGRP8,37 receptor antagonists, abolished this effect (nor BNI+MMPC=47±7%, NTD+MMPC=49±7%, CTOP+MMPC=45±9%, NM+MMPC=47±6% 8-SPT+MPC=46±5% & CGRP8,37+MPC=53±6%, P=0.63). However, the intravenous administration of NM did not prevent the protective effect (34±4%, P<0.01). Conclusions: Intrathecal morphine administration can induce pharmacological cardiac post-conditioning as it involves opioid receptor centrally but non-opioid receptors peripherally. [source] Neutrophil,independent protective effect of r,metHuG,CSF in ischaemia,reperfusion injury in rat skeletal muscleINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 1 2000Article first published online: 15 JUN 200 [source] Remifentanil post-conditioning attenuates cardiac ischemia,reperfusion injury via , or , opioid receptor activationACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2010G. T. C. WONG Background: Ischemic pre- or post-conditioning of the heart has been shown to involve opioid receptors. Remifentanil, an ultra-short-acting selective , opioid receptor agonist in clinical use, pre-conditions the rat heart against ischemia,reperfusion injury. This study investigates whether remifentanil post-conditioning is also cardioprotective. Methods: Remifentanil post-conditioning (5-min infusion at 1, 5, 10 or 20 ,g/kg/min) or ischemic post-conditioning (three cycles of a 10 s reperfusion interspersed with a 10 s ischemia) was induced in an open-chest rat heart model of ischemia and reperfusion injury, in the presence or absence of nor-binaltorphimine, naltrindole or CTOP, specific ,, , and , opioid receptor antagonists, respectively. The same sequence of experiments was repeated in the isolated heart model using the maximal protective dose of remifentanil from the dose,response studies. Results: Both ischemic and remifentanil post-conditioning reduced the myocardial infarct size relative to the control group in both models. This cardioprotective effect for both post-conditioning regimes was prevented by the prior administration of nor-binaltorphimine and naltrindole but not CTOP. The sole administration of the antagonists had no effect on the size of myocardial infarction. Conclusions: These results indicate that remifentanil post-conditioning protects the heart from ischemia,reperfusion injury to a similar extent as of ischemic post-conditioning. This protection involves , and , but not , opioid receptor activation. This drug has great potential as a clinical post-conditioning modality as it can be given in large doses without prolonged opioid-related side effects. [source] Rapid loss of motor nerve terminals following hypoxia,reperfusion injury occurs via mechanisms distinct from classic Wallerian degenerationJOURNAL OF ANATOMY, Issue 6 2008Becki Baxter Abstract Motor nerve terminals are known to be vulnerable to a wide range of pathological stimuli. To further characterize this vulnerability, we have developed a novel model system to examine the response of mouse motor nerve terminals in ex vivo nerve/muscle preparations to 2 h hypoxia followed by 2 h reperfusion. This insult induced a rapid loss of neurofilament and synaptic vesicle protein immunoreactivity at pre-synaptic motor nerve terminals but did not appear to affect post-synaptic endplates or muscle fibres. The severity of nerve terminal loss was dependent on the age of the mouse and muscle type: in 8,12-week-old mice the predominantly fast-twitch lumbrical muscles showed an 82.5% loss, whereas the predominantly slow-twitch muscles transversus abdominis and triangularis sterni showed a 57.8% and 27.2% loss, respectively. This was contrasted with a > 97% loss in the predominantly slow-twitch muscles from 5,6-week-old mice. We have also demonstrated that nerve terminal loss occurs by a mechanism distinct from Wallerian degeneration, as the slow Wallerian degeneration (Wlds) gene did not modify the extent of nerve terminal pathology. Together, these data show that our new model of hypoxia,reperfusion injury is robust and repeatable, that it induces rapid, quantitative changes in motor nerve terminals and that it can be used to further examine the mechanisms regulating nerve terminal vulnerability in response to hypoxia,reperfusion injury. [source] Apoptosis and Cardiopulmonary BypassJOURNAL OF CARDIAC SURGERY, Issue 2 2007M.S., Miljenko Kova Apoptotic index (AI) obtained with in situ terminal deoxynucleotidyl transferase-labeled dUTP nick end labeling (TUNEL) method and Bak protein expression were compared. Patients and Methods: Twenty consecutive patients who underwent coronary artery bypass surgery, myocardial samples from the right atrium were taken in three stages: before cannulation (the first sample group), after declamping (the second sample group), and 20 minutes after reperfusion (the third sample group). The percentage of apoptotic cells was determined by TUNEL method. Expression of Bak protein was immunohistochemically analyzed. Intermittent ischemia and moderate hypothermia were used as methods of myocardial management during surgery. A statistical analysis was performed by using the Friedman ANOVA analysis of variances, the Kendall coefficient of concordance and the Wilcoxon matched pair test. Results: In the first sample group mean value of Bak expression was 2.61 ± 2.18, compared with AI 5.38 ± 3.58, after declamping (the second sample group) the mean value of Bak expression was 4.31 ± 2.68 while AI was 7.63 ± 4.38 and after 20 minutes of reperfusion in the third sample group mean value of Bak expression was 8.89 ± 4.45, while AI was 15.6 ± 8.45. When compared by using Wilcoxon matched pair test two methods significantly correlated, p > 0.0001. Conclusion: The positive correlation between AI obtained by TUNEL method and expression of Bak protein may suggest that apoptosis is activated mainly through mitochondrial activation pathway in ischemic reperfusion injury. The results suggest that ischemic reperfusion injury increases the AI in the right atrial tissue. If so, immunohistochemical expression of Bak protein could be used as a marker of myocardial ischemia induced injury. [source] Cell-penetrating peptide TAT-mediated delivery of acidic FGF to retina and protection against ischemia,reperfusion injury in ratsJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 7 2010Yi Wang Abstract The development of non-invasive ocular drug delivery systems is of practical importance in the treatment of retinal disease. In this study, we evaluated the efficacy of transactivator of transcription protein transduction domain (TAT-PTD, TAT49,57) as a vehicle to deliver acidic FGF (aFGF) to retina in rats. TAT-conjugated aFGF-His (TAT-aFGF-His) exhibited efficient penetration into the retina following topical administration to the ocular surface. Immunochemical staining with anti-His revealed that TAT-aFGF-His proteins were readily found in the retina (mainly in the ganglion cell layer) at 30 min. and remained detectable for at least 8 hrs after administration. In contrast, His+ proteins were undetectable in the retina after topical administration of aFGF-His, indicating that aFGF-His cannot penetrate the ocular barrier. Furthermore, TAT-aFGF-His, but not aFGF-His, mediated significant protection against retinal ischemia,reperfusion (IR) injury. After IR injury, retina from TAT-aFGF-His-treated rats showed better-maintained inner retinal layer structure, reduced apoptosis of retinal ganglion cells and improved retinal function compared to those treated with aFGF-His or PBS. These results indicate that conjugation of TAT to aFGF-His can markedly improve the ability of aFGF-His to penetrate the ocular barrier without impairing its biological function. Thus, TAT49,57 provides a potential vehicle for efficient drug delivery in the treatment of retinal disease. [source] Sildenafil-mediated neovascularization and protection against myocardial ischaemia reperfusion injury in rats: role of VEGF/angiopoietin-1JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 6b 2008Srikanth Koneru Abstract Sildenafil citrate (SC), a drug for erectile dysfunction, is now emerging as a cardiopulmonary drug. Our study aimed to determine a novel role of sildenafil on cardioprotection through stimulating angiogenesis during ischaemia (I) reperfusion (R) at both capillary and arteriolar levels and to examine the role of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) in this mechanistic effect. Rats were divided into: control sham (CS), sildenafil sham (SS), control + IR (CIR) and sildenafil + IR (SIR). Rats were given 0.7 mg/kg, (i.v) of SC or saline 30 min. before occlusion of left anterior descending artery followed by reperfusion (R). Sildenafil treatment increased capillary and arteriolar density followed by increased blood flow (2-fold) compared to control. Treatment with sildenafil demonstrated increased VEGF and Ang-1 mRNA after early reperfusion. PCR data were validated by Western blot analysis. Significant reduction in infarct size, cardiomyocyte and endothelial apoptosis were observed in SC-treated rats. Increased phosphorylation of Akt, eNOS and expression of anti-apoptotic protein Bcl-2, and thioredoxin, hemeoxygenase-1 were observed in SC-treated rats. Echocardiography demonstrated increased fractional shortening and ejection fraction following 45 days of reperfusion in the treatment group. Stress testing with dobutamine infusion and echocardiogram revealed increased contractile reserve in the treatment group. Our study demonstrated for the first time a strong additional therapeutic potential of sildenafil by up-regulating VEGF and Ang-1 system, probably by stimulating a cascade of events leading to neovascularization and conferring myocardial protection in in vivo I/R rat model. [source] Potentiation of angiogenic response by ischemic and hypoxic reconditioning of the heartJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1 2002Nilanjana Maulik Abstract This review is intended to discuss the newly discovered role of preconditioning which should make it an attractive therapeutic stimulus for repairing the injured myocardium. We recently found that apart from rendering the myocardium tolerant to ischemic reperfusion injury, preconditioning also potentiates angiogenesis. Our study demonstrated for the first time that both ischemic and hypoxic preconditioning triggered myocardial angiogenesis at the capillary and arteriolar levels which nicely corroborated with the improved myocardial contractile function.Hypoxic preconditioning resulted in the stimulation of VEGF, the most potent angiogenic factor known to date. In concert, endothelial cell specific tyrosine kinase receptors, Tie 1, Tie 2 and Flt-1 and Flk-1 were also significantly enhanced in the preconditioned myocardium. The redox-regulated transcription factor NFkB was found to play an essential role in the preconditioning regulation of angiogenesis [source] Short-term dietary restriction and fasting precondition against ischemia reperfusion injury in miceAGING CELL, Issue 1 2010James R. Mitchell Summary Dietary restriction (DR) extends lifespan and increases resistance to multiple forms of stress, including ischemia reperfusion injury to the brain and heart in rodents. While maximal effects on lifespan require long-term restriction, the kinetics of onset of benefits against acute stress is not known. Here, we show that 2,4 weeks of 30% DR improved survival and kidney function following renal ischemia reperfusion injury in mice. Brief periods of water-only fasting were similarly effective at protecting against ischemic damage. Significant protection occurred within 1 day, persisted for several days beyond the fasting period and extended to another organ, the liver. Protection by both short-term DR and fasting correlated with improved insulin sensitivity, increased expression of markers of antioxidant defense and reduced expression of markers of inflammation and insulin/insulin-like growth factor-1 signaling. Unbiased transcriptional profiling of kidneys from mice subject to short-term DR or fasting revealed a significant enrichment of signature genes of long-term DR. These data demonstrate that brief periods of reduced food intake, including short-term daily restriction and fasting, can increase resistance to ischemia reperfusion injury in rodents and suggest a rapid onset of benefits of DR in mammals. [source] Congenital DNA repair deficiency results in protection against renal ischemia reperfusion injury in miceAGING CELL, Issue 2 2009Denis Susa Summary Cockayne syndrome and other segmental progerias with inborn defects in DNA repair mechanisms are thought to be due in part to hypersensitivity to endogenous oxidative DNA damage. The accelerated aging-like symptoms of this disorder include dysmyelination within the central nervous system, progressive sensineuronal hearing loss and retinal degeneration. We tested the effects of congenital nucleotide excision DNA repair deficiency on acute oxidative stress sensitivity in vivo. Surprisingly, we found mouse models of Cockayne syndrome less susceptible than wild type animals to surgically induced renal ischemia reperfusion injury, a multifactorial injury mediated in part by oxidative damage. Renal failure-related mortality was significantly reduced in Csb,/, mice, kidney function was improved and proliferation was significantly higher in the regenerative phase following ischemic injury. Protection from ischemic damage correlated with improved baseline glucose tolerance and insulin sensitivity and a reduced inflammatory response following injury. Protection was further associated with genetic ablation of a different Cockayne syndrome-associated gene, Csa. Our data provide the first functional in vivo evidence that congenital DNA repair deficiency can induce protection from acute stress in at least one organ. This suggests that while specific types of unrepaired endogenous DNA damage may lead to detrimental effects in certain tissues, they may at the same time elicit beneficial adaptive changes in others and thus contribute to the tissue specificity of disease symptoms. [source] Methimazole protects lungs during hepatic ischemia,reperfusion injury in rats: An effect not induced by hypothyroidismJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 5 2007Tanju Tütüncü Abstract Background:, Hepatic ischemia,reperfusion injury may lead to remote organ failure with mortal respiratory dysfunction. The aim of the present study was to analyze the possible protective effects of methimazole on lungs after hepatic ischemia,reperfusion injury. Methods:, Forty male Wistar albino rats were randomized into five groups: a control group, in which bilateral pulmonary lobectomy was done; a hepatic ischemia,reperfusion group, in which bilateral pulmonary lobectomy was done after hepatic ischemia,reperfusion; a thyroidectomy,ischemia,reperfusion group (total thyroidectomy followed by, 7 days later, bilateral pulmonary lobectomy after hepatic ischemia,reperfusion); a methimazole,ischemia,reperfusion group (following methimazole administration for 7 days, bilateral pulmonary lobectomy was done after hepatic ischemia,reperfusion); and a methimazole +l -thyroxine,ischemia,reperfusion group (following methimazole and l -thyroxine administration for 7 days, bilateral pulmonary lobectomy was performed after hepatic ischemia,reperfusion). Pulmonary tissue specimens were evaluated histopathologically and for myeloperoxidase and malondialdehyde levels. Results:, All of the ischemia,reperfusion intervention groups had higher pulmonary injury scoring indices than the control group (P < 0.001). Pulmonary injury index of the ischemia,reperfusion group was higher than that of both the methimazole-supplemented hypothyroid and euthyroid groups (P = 0028; P = 0,038, respectively) and was similar to that of the thyroidectomized group. Pulmonary tissue myeloperoxidase and malondialdehyde levels in the ischemia,reperfusion group were similar with that in the thyroidectomized rats but were significantly higher than that in the control, and both the methimazole-supplemented hypothyroid and euthyroid groups. Conclusion:, Methimazole exerts a protective role on lungs during hepatic ischemia,reperfusion injury, which can be attributed to its anti-inflammatory and anti-oxidant effects rather than hypothyroidism alone. [source] Intrinsic and extrinsic erythropoietin enhances neuroprotection against ischemia and reperfusion injury in vitroJOURNAL OF NEUROCHEMISTRY, Issue 4 2006Ruiqin Liu Abstract This study was designed to investigate the neuroprotective effect of intrinsic and extrinsic erythropoietin (EPO) against hypoxia/ischemia, and determine the optimal time-window with respect to the EPO-induced neuroprotection. Experiments were conducted using primary mixed neuronal/astrocytic cultures and neuron-rich cultures. Hypoxia (2%) induces hypoxia-inducible factor-1, (HIF-1,) activity followed by strong EPO expression in mixed cultures and weak expression in neuron-rich cultures as documented by both western blot and RT,PCR. Immunoreactive EPO was strongly detected in astrocytes, whereas EPOR was only detected in neurons. Neurons were significantly damaged in neuron-rich cultures but were distinctly rescued in mixed cultures. Application of recombinant human EPO (rhEPO) (0.1 U/mL) within 6 h before or after hypoxia significantly increased neuronal survival compared with no rhEPO treatment. Application of rhEPO after onset of reoxygenation achieved the maximal neuronal protection against ischemia/reperfusion injury (6 h hypoxia followed 24 h reoxygenation). Our results indicate that HIF-1, induces EPO gene released by astrocytes and acts as an essential mediator of neuroprotection, prove the protective role of intrinsic astrocytic-neuronal signaling pathway in hypoxic/ischemic injury and demonstrate an optimal therapeutic time-window of extrinsic rhEPO in ischemia/reperfusion injury in vitro. The results point to the potential beneficial effects of HIF-1, and EPO for the possible treatment of stroke. [source] | |||||||||||||||||||||||||||||||||||||