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Ischemia/reperfusion
Kinds of Ischemia/reperfusion Terms modified by Ischemia/reperfusion Selected AbstractsStat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotectionHEPATOLOGY, Issue 2 2003Xiu-Da Shen Ischemia/reperfusion (I/R) injury remains an important problem in clinical organ transplantation. There is growing evidence that T lymphocytes, and activated CD4+ T cells in particular, play a key role in hepatic I/R injury. This study analyzes the role of signal transducer and activator of transcription 4 (Stat4) and Stat6 signaling in liver I/R injury. Using a partial lobar warm ischemia model, groups of wild-type (WT), T cell,deficient, Stat4-/Stat6-deficient knockout (KO) mice were assessed for the extent/severity of I/R injury. Ninety minutes of warm ischemia followed by 6 hours of reperfusion induced a fulminant liver failure in WT and Stat6 KO mice, as assessed by hepatocellular damage (serum alanine aminotransferase [sALT] levels), neutrophil accumulation (myeloperoxidase [MPO] activity) and histology (Suzuki scores). In contrast, T cell deficiency (nu/nu mice) or disruption of Stat4 signaling (Stat4 KO mice) reduced I/R insult. Unlike adoptive transfer of WT or Stat6-deficient T cells, infusion of Stat4-deficient T cells failed to restore hepatic I/R injury and prevented tumor necrosis factor , (TNF-,) production in nu/nu mice. Diminished TNF-,/Th1-type cytokine messenger RNA (mRNA)/protein elaborations patterns, along with overexpression of heme oxygenase-1 (HO-1),accompanied hepatic cytoprotection in Stat4 KO recipients. In contrast, HO-1 depression restored hepatic injury in otherwise I/R resistant Stat4 KOs. In conclusion, Stat4 signaling is required for, whereas Stat4 disruption protects against, warm hepatic I/R injury in mice. The cytoprotection rendered by Stat4 disruption remains HO-1,dependent. [source] Alcoholic fatty liver differentially induces a neutrophil-chemokine and hepatic necrosis after ischemia-reperfusion in ratHEPATOLOGY, Issue 2 2000Shinwa Yamada M.D. Primary graft nonfunction of steatotic liver allograft is one of the factors causing shortage of donor livers. Ischemia/reperfusion (I/R) injury is an important contributory factor to primary graft nonfunction. In this study, we investigated the complex chain of events from transcription factor activation to necrosis through cytokine induction and apoptosis in steatotic rat liver after warm I/R. Rats with alcoholic or nonalcoholic fatty liver were subjected to hepatic warm I/R and compared with control rats. Rats fed an ethanol diet for 6 to 8 weeks developed severe hepatic necrosis accompanied by increased neutrophil recruitment after I/R, compared with rats with nonalcoholic fatty liver or control. Hepatic apoptosis as assessed by DNA fragmentation at 4 hours after I/R, however, increased to a similar degree in each of the 2 fatty liver models compared with the control. Alcoholic fatty liver exposed to I/R showed a rapid increase in nuclear factor-,B (NF-,B) binding activity at 1 hour after I/R, which preceded an increased expression of tumor necrosis factor , (TNF-,) and cytokine-induced neutrophil chemoattractant-1 (CINC-1). In contrast, nonalcoholic fatty liver did not show such potentiation of either NF-,B activation or cytokine induction after I/R. Our results have indicated that alcoholic fatty liver may differentially induce CINC-1 production and hepatic necrosis after I/R. Furthermore, our results suggest that apoptosis per se does not always lead to necrosis in the liver following I/R. [source] Pretreatment with melatonin exerts anti-inflammatory effects against ischemia/reperfusion injury in a rat middle cerebral artery occlusion stroke modelJOURNAL OF PINEAL RESEARCH, Issue 2 2004Zhong Pei Abstract:, Inflammatory response following cerebral ischemia/reperfusion plays a key pathogenic role in ischemic cerebral damage. Nitric oxide (NO), cyclooxygenase-2 (COX-2) and myeloperoxidase (MPO) are important inflammatory mediators. Neuronal NO synthase (nNOS) is a major initial source of excessive NO during ischemia/reperfusion. Induction of COX-2 and infiltration of polymorphonuclear cells expressing MPO are critical factors in delayed inflammatory damage. Previously, we demonstrated that administration of melatonin before ischemia significantly reduced the infarct volume in a rat middle cerebral artery occlusion (MCAO) stroke model. In this study, we examined the effect of pretreatment with melatonin at 5 mg/kg on the immunoreactivity (ir) for nNOS, COX-2, MPO, and glial fibrillary acidic protein (GFAP) at 24, 48, and 72 hr after right-sided endovascular MCAO for 1 hr in adult male Sprague,Dawley rats. Melatonin did not affect the hemodynamic parameters. When compared with rats with sham MCAO, ischemia/reperfusion led to an ipsilateral increase in cells with positive ir for nNOS (similar at all times) and in ir-GFAP (similar at all times). Ischemia/reperfusion led to appearance of cells with positive ir for COX-2 (greatest at 24 hr with a tendency to increase again at 72 hr) or MPO (greatest at 24 hr). A single dose of melatonin significantly lessened the ipsilateral increase in cells with positive ir for nNOS, COX-2 or MPO, but did not influence the ipsilateral change in ir-GFAP. Our results suggest that melatonin treatment mediates neuroprotection against ischemia/reperfusion injury partly via inhibition of the consequential inflammatory response. [source] Investigation of reperfusion injury and ischemic preconditioning in microsurgeryMICROSURGERY, Issue 1 2009Wei Zhong Wang M.D. Ischemia/reperfusion (I/R) is inevitable in many vascular and musculoskeletal traumas, diseases, free tissue transfers, and during time-consuming reconstructive surgeries in the extremities. Salvage of a prolonged ischemic extremity or flap still remains a challenge for the microvascular surgeon. One of the common complications after microsurgery is I/R-induced tissue death or I/R injury. Twenty years after the discovery, ischemic preconditioning has emerged as a powerful method for attenuating I/R injury in a variety of organs or tissues. However, its therapeutic expectations still need to be fulfilled. In this article, the author reviews some important experimental evidences of I/R injury and preconditioning-induced protection in the fields relevant to microsurgery. © 2008 Wiley-Liss, Inc. Microsurgery, 2009. [source] Inhibition of Matrix Metalloproteinase-9 Attenuates Acute Small-for-Size Liver Graft Injury in RatsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2010Z. Y. Ma Ischemia/reperfusion (I/R) and portal hypertension have been implicated in small-for-size liver graft dysfunction. Matrix metalloproteinases-2 and -9 (MMP-2/9) are critically proposed to involve in hepatic I/R injury and activated by hemodynamic force. We hypothesized that MMP-2/9 overexpression played a crucial role in acute graft injury following small-for-size liver transplantation (LT). Rats were randomly assigned into four groups: 75% partial hepatectomy (PH); 100% LT; 25% LT and 25% LT treated with CTT peptide (MMP-2/9 inhibitor). ELISA, real-time PCR, gelatin zymography and immunohistochemistry were used to determine the expression pattern of MMP-2/9 in liver tissue. MMP-9 expression was significantly increased 6 h after reperfusion and reached a peak 12 h in the 25% LT group, whereas MMP-2 was expressed in all groups invariably. Compared with the 25% LT group, rats from CTT-treated group exhibited markedly decreased alanine aminotransferase and total bilirubin values, downregulated proinflammatory cytokines, attenuated malondialdehyde (MDA) and myeloperoxidase (MPO) activities, and improved liver histology. Likewise, MMP-9 inhibition significantly reduced number of TUNEL-positive cells and caspase-3 activity, along with decreased protein levels of Fas and Fas-L. Specifically, rat survival was also improved in the CTT-treated group. These results support critical function of MMP-9 involved in acute small-for-size livergraft injury. [source] Elective coronary angioplasty with 60 s balloon inflation does not cause peroxidative injuryEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2002K. Cedro Abstract Background The aim of this study was to evaluate the ongoing controversial issue of whether ischemia/reperfusion during elective coronary angioplasty evokes myocardial peroxidative injury. Design We measured indicators of free radical damage to lipids (free malondialdehyde) and proteins (sulphydryl groups) in coronary sinus blood in 19 patients with stable angina who were undergoing elective angioplasty for isolated stenosis of the proximal left anterior descending coronary artery. Ischemia induced by 60 s balloon inflations was confirmed by lactate washout into coronary sinus after deflation, with immediate and 1 min samples. Peroxidative injury was assessed from washout of (a) malondialdehyde measured directly by high performance liquid chromatography and (b) reduced sulphydryl groups, inverse marker of protein oxidative stress. Results Mean lactate concentration immediately after each deflation increased by 120,150% of the initial value, confirming ischemia and showing that blood originated largely from the ischemic region. Lack of myocardial production of malondialdehyde was confirmed by (a) no arteriovenous differences in individual basal concentrations (aortic, range 0·33,12·03 nmol mL,1, mean 7·82; coronary sinus blood, range 0·52,15·82 nmol mL,1, mean 8·18), and (b) after deflations, mean concentrations were not significantly different from preocclusion value. There was no decrease in concentration of sulphydryl groups throughout angioplasty. Conclusion Elective coronary angioplasty with 60 s balloon inflations is a safe procedure that does not induce peroxidative myocardial injury as assessed by methods used in the present study. [source] Effects of melatonin and caffeic acid phenethyl ester on testicular injury induced by myocardial ischemia/reperfusion in ratsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2005Mukaddes E Abstract Experimental studies indicate that ischemia/reperfusion (I/R) causes remote organ injury although the molecular mechanism has not been clearly defined. In this report, the role of oxidative injury on testicular damage following myocardial I/R injury and the effects of antioxidant agents, melatonin and caffeic acid phenethyl ester (CAPE), on testicular injury were investigated. As far as we know, this is the first report demonstrating that myocardial I/R induces damage to the testes. Thirty-two male Wistar rats were randomly divided into four groups: sham operation (SO), I/R + vehicle, I/R + melatonin, and I/R + caffeic acid phenethyl ester. To produce cardiac damage, the left main coronary artery was occluded for 30 min, followed by 120 min reperfusion, in anesthetized rats. Serum nitric oxide (NO) and malondialdehyde (MDA) levels and morphological changes were examined. I/R was accompanied by a significant increase in serum MDA and NO levels, whereas, melatonin and CAPE administration significantly reduced these values. Melatonin was more efficient in reducing MDA levels than CAPE (P < 0.05). I/R induced myocardial damage, manifested as the histopathological evidence of intracellular vacuolization, interstitial edema, neutrophil infiltration and coagulative necrosis. I/R + vehicle group showed many histological alterations such as focal tubular atrophy, and degeneration and disorganization of the seminiferous epithelium in testes. The number of atrophic tubules and degenerating cells was significantly higher in I/R + vehicle group than that of SO group. Melatonin and CAPE significantly reduced the number of degenerating cells; additionally, melatonin reduced the number of atrophic tubules (P < 0.05). Our results indicate that myocardial I/R induces severe testicular damage and antioxidant agents, especially melatonin, have protective effects on testicular injury after myocardial I/R. Our data emphasize that oxygen-based reactants may play a central role in remote organ injury. [source] Complement and its implications in cardiac ischemia/reperfusion: strategies to inhibit complementFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2001Tiphaine Monsinjon Although reperfusion of the ischemic myocardium is an absolute necessity to salvage tissue from eventual death, it is also associated with pathologic changes that represent either an acceleration of processes initiated during ischemia or new pathophysiological changes that were initiated after reperfusion. This so-called ,reperfusion injury' is accompanied by a marked inflammatory reaction, which contributes to tissue injury. In addition to the well known role of oxygen free radicals and white blood cells, activation of the complement system probably represents one of the major contributors of the inflammatory reaction upon reperfusion. The complement may be activated through three different pathways: the classical, the alternative, and the lectin pathway. During reperfusion, complement may be activated by exposure to intracellular components such as mitochondrial membranes or intermediate filaments. Two elements of the activated complement contribute directly or indirectly to damages: anaphylatoxins (C3a and C5a) and the membrane attack complex (MAC). C5a, the most potent chemotactic anaphylatoxin, may attract neutrophils to the site of inflammation, leading to superoxide production, while MAC is deposited over endothelial cells and smooth vessel cells, leading to cell injury. Experimental evidence suggests that tissue salvage may be achieved by inhibition of the complement pathway. As the complement is composed of a cascade of proteins, it provides numerous sites for pharmacological interventions during acute myocardial infarction. Although various strategies aimed at modulating the complement system have been tested, the ideal approach probably consists of maintaining the activity of C3 (a central protein of the complement cascade) and inhibiting the later events implicated in ischemia/reperfusion and also in targeting inhibition in a tissue-specific manner. [source] Nitric oxide reduces astrocytic lactate production and induces neuronal vulnerability in stroke-prone spontaneously hypertensive ratsGLIA, Issue 4 2008Kazuo Yamagata Abstract Nitric oxide (NO) leads to neuronal death in ischemia/reperfusion (I/R), including stroke. Here, we examined the NO-induced vulnerability of neurons and lactate production by astrocytes in stroke-prone spontaneously hypertensive rats (SHRSP) in vitro. Neuronal cell death induced by the NO donor sodium nitroprusside (SNP) was significantly increased in SHRSP compared with Wistar kyoto rats (WKY). Furthermore, levels of lactate production by astrocytes were significantly reduced in SHRSP compared with WKY. At the same time, expressions of the lactate dehydrogenase (LDH) and monocarboxylate transporter 1 (MCT1) genes were significantly decreased by SNP in SHRSP compared with WKY. Moreover, in astrocytes isolated from SHRSP, the gene expression of isoforms of 6-phosphofracto-2-kinase (PFK2), a master regulator of glycolysis, namely PFK2.1, PFK2.2, PFK2.3, and PFK2.4, had deteriorated significantly. Notably, the SNP-evoked gene expression of PFK2.4 was lower in astrocytes of SHRSP than those of WKY. These results indicated that the neurons and astrocytes of SHRSP differed in responsiveness to SNP from those of WKY. This difference might explain the deficiency of energy and vulnerability to SNP of the neurons of SHRSP. © 2008 Wiley-Liss, Inc. [source] Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury,HEPATOLOGY, Issue 3 2006Laura Llacuna The molecular mechanisms of hepatic ischemia/reperfusion (I/R) damage are incompletely understood. We investigated the role of ceramide in a murine model of warm hepatic I/R injury. This sphingolipid induces cell death and participates in tumor necrosis factor (TNF) signaling. Hepatic ceramide levels transiently increased after the reperfusion phase of the ischemic liver in mice, because of an early activation of acidic sphingomyelinase (ASMase) followed by acid ceramidase stimulation. In vivo administration of an ASMase inhibitor, imipramine, or ASMase knockdown by siRNA decreased ceramide generation during I/R, and attenuated serum ALT levels, hepatocellular necrosis, cytochrome c release, and caspase-3 activation. ASMase-induced ceramide generation activated JNK resulting in BimL phosphorylation and translocation to mitochondria, as the inhibition of ASMase by imipramine prevented these events. In contrast, blockade of ceramide catabolism by N-oleyolethanolamine (NOE), a ceramidase inhibitor, enhanced ceramide levels and potentiated I/R injury compared with vehicle-treated mice. Pentoxifylline treatment prevented TNF upregulation and ASMase activation. Furthermore, 9 of 11 mice treated with imipramine survived 7 days after total liver ischemia, compared with 4 of 12 vehicle-treated mice, whereas 8 of 8 NOE-treated mice died within 2 days of total liver ischemia. In conclusion, ceramide generated from ASMase plays a key role in I/R-induced liver damage, and its modulation may be of therapeutic relevance. (HEPATOLOGY 2006.) [source] Ischemic preconditioning affects interleukin release in fatty livers of rats undergoing ischemia/reperfusionHEPATOLOGY, Issue 3 2004Anna Serafín The present study evaluates the effect of ischemic preconditioning on interleukin-1 (IL-1) and interleukin-10 (IL-10) generation following hepatic ischemia/reperfusion (I/R) in normal and steatotic livers as well as the role of nitric oxide (NO) in this process. Increased IL-1, and IL-10 levels were observed in normal livers after I/R. Steatotic livers showed higher IL-1, levels than normal livers, and IL-10 at control levels. The injurious role of IL-1, and the benefits of IL-10 on hepatic I/R injury was shown with the use of IL-1 receptor antagonist (IL-1ra), anti-IL-10 polyclonal antibody against IL-10 (anti-IL-10) and exogenous IL-10. The effective dose of these treatments was different in both types of livers. Preconditioning prevented IL-1, release and increased IL-10 generation after I/R in normal and steatotic livers. IL-1, or anti-IL-10 pretreatments reversed the benefits of preconditioning. IL-1, action inhibition in a preconditioned group that was pretreated with anti-IL-10 did not modify the benefits of preconditioning. In addition, anti-IL-10 pretreatment in the preconditioned group resulted in IL-1, levels comparable to those observed after I/R. NO inhibition eliminated the benefits of preconditioning on IL-10 release, IL-1, levels, and hepatic injury. In conclusion, preconditioning, through IL-10 overproduction, inhibits IL-1, release and the ensuing hepatic I/R injury in normal and steatotic livers. IL-10 generation induced by preconditioning could be mediated by NO. (HEPATOLOGY 2004;39:688,698.) [source] Interleukin 18 causes hepatic ischemia/reperfusion injury by suppressing anti-inflammatory cytokine expression in miceHEPATOLOGY, Issue 3 2004Dan Takeuchi Hepatic ischemia/reperfusion injury is a clinically important problem. While the mechanisms of the initial event and subsequent neutrophil-dependent injury are somewhat understood, little is known about the regulation of endogenous hepatoprotective effects on this injury. Interleukin 12 (IL-12) plays a role in the induction of this injury, but involvement of interleukin 18 (IL-18) has not been clarified. Using a murine model of partial hepatic ischemia and subsequent reperfusion, the aim of the current study was to determine whether IL-18 is up-regulated during hepatic ischemia/reperfusion and to determine the role of endogenous IL-18 in the development and regulation of inflammatory hepatic ischemia/reperfusion injury. Hepatic IL-18 expression was up-regulated from 1 to 8 hours after reperfusion. Hepatic ischemia/reperfusion induced nuclear factor-,B (NF-,B) and activator protein 1 (AP-1) activation, as defined by electrophoretic mobility shift assay, and caused significant increases in liver neutrophil recruitment, apoptosis, hepatocellular injury, and liver edema as defined by liver myeloperoxidase content, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labeling (TUNEL) staining, serum aminotransferase levels, and liver wet-to-dry weight ratios. In mice treated with neutralizing antibody to IL-18, ischemia/reperfusion-induced increases in CXC chemokine expression, activation of NF-,B and AP-1, and apoptosis were greatly reduced. Furthermore, under blockade of IL-18, anti-inflammatory cytokines such as IL-4 and IL-10 were greatly up-regulated. Signal transducer and activator of transcription 6 (STAT6) was significantly activated under blockade of IL-18. These conditions also caused significant reduction in liver neutrophil sequestration and liver injury. In conclusion, the data suggest that IL-18 is required for facilitating neutrophil-dependent hepatic ischemia/reperfusion injury through suppressing anti-inflammatory cytokine expression. (HEPATOLOGY 2004;39:699,710.) [source] Enhanced expression of B7-1, B7-2, and intercellular adhesion molecule 1 in sinusoidal endothelial cells by warm ischemia/reperfusion injury in rat liverHEPATOLOGY, Issue 4 2001Naosuke Kojima To elucidate a role of costimulatory molecule and cell adhesion molecule in hepatic ischemia/reperfusion injury, we examined an alteration in B7-1 (CD80), B7-2 (CD86), and intercellular adhesion molecule 1 (ICAM-1; CD54) expression in the rat liver after warm ischemia/reperfusion injury. To induce hepatic warm ischemia in a rat model, both portal vein and hepatic artery entering the left-lateral and median lobes were occluded by clamping for 30 minutes or 60 minutes, and then reperfused for 24 hours. B7-1, B7-2, and ICAM-1 expressions in the liver were analyzed by immunofluorescence staining and real-time reverse transcription polymerase chain reaction (RT-PCR). Although B7-1 and B7-2 expressions were at very low levels in the liver tissues from normal or sham-operated control rats, both B7-1 and B7-2 expressions were enhanced at protein and messenger RNA (mRNA) levels in the affected, left lobes after warm ischemia/reperfusion. ICAM-1 protein and mRNA were constitutively expressed in the liver of normal and sham-operated control rats, and further up-regulated after warm ischemia/reperfusion. Localization of increased B7-1, B7-2, and ICAM-1 proteins, as well as von Willebrand factor as a marker protein for endothelial cells, was confined by immunofluorescence staining to sinusoidal endothelial cells in hepatic lobules. Data from quantitative real-time RT-PCR analysis revealed that B7-1 and B7-2 mRNA levels were elevated in hepatic lobes after warm ischemia/reperfusion (5.13- and 52.9-fold increase, respectively), whereas ICAM-1 mRNA expression was rather constitutive but further enhanced by warm ischemia/reperfusion (4.24-fold increase). These results suggest that hepatic sinusoidal endothelial cells play a pivotal role as antigen-presenting cells by expressing B7-1 and B7-2 in warm hepatic ischemia/reperfusion injury, and that B7-1 and/or B7-2 might be the primary target to prevent early rejection and inflammatory reactions after hepatic ischemia/reperfusion injury associated with liver transplantation. [source] Iron chelation prevents lung injury after major hepatectomyHEPATOLOGY RESEARCH, Issue 8 2010Konstantinos Kalimeris Aim:, Oxidative stress has been implicated in lung injury following ischemia/reperfusion and resection of the liver. We tested whether alleviating oxidative stress with iron chelation could improve lung injury after extended hepatectomy. Methods:, Twelve adult female pigs subjected to liver ischemia for 150 min, 65,70% hepatectomy and reperfusion of the remnant liver for 24 h were randomized to a desferrioxamine (DF) group (n = 6) which received i.v. desferrioxamine to a total dose of 100 mg/kg during both ischemia and reperfusion, and a control (C) group (n = 6). We recorded hemodynamic and respiratory parameters, plasma interleukin-6 and malondialdehyde levels, as well as liver malondialdehyde and protein carbonyls content. Total non-heme iron was measured in lung and liver. Pulmonary tissue was evaluated histologically for its nitrotyrosine and protein carbonyls content and for superoxide dismutase (SOD) and platelet-activating factor acetylhydrolase (PAF-AcH) activities. Results:, Reperfusion of the remnant liver resulted in gradual deterioration of gas-exchange and pulmonary vascular abnormalities. Iron chelation significantly decreased the oxidative markers in plasma, liver and the lung and lowered activities of pulmonary SOD and PAF-AcH. The improved liver function was followed by improved arterial oxygenation and pulmonary vascular resistance. DF also improved alveolar collapse and inflammatory cell infiltration, while serum interleukin-6 increased. Conclusion:, In an experimental pig model that combines liver resection with prolonged ischemia, iron chelation during reperfusion of the remnant liver is associated with improvement of several parameters of oxidative stress, lung injury and arterial oxygenation. [source] Cholestasis enhances liver ischemia/reperfusion-induced coagulation activation in ratsHEPATOLOGY RESEARCH, Issue 2 2010Jaap J. Kloek Aim:, Cholestasis is associated with increased morbidity and mortality in patients undergoing major liver surgery. An additional risk is induced when vascular inflow occlusion is applied giving rise to liver ischemia/reperfusion (I/R) injury. The role of the coagulation system in this type of injury is elusive. The aim of the current study was to assess activation of coagulation following hepatic I/R injury in cholestatic rats. Methods:, Male Wistar rats were randomized into two groups and subjected to bile duct ligation (BDL) or sham laparotomy. After 7 days, both groups underwent 30 min partial liver ischemia. Animals were sacrificed before ischemia or after 6 h, 24 h, and 48 h reperfusion. Results:, Plasma AST and ALT levels were higher after I/R in cholestatic rats (P < 0.05). Hepatic necrosis, liver wet/dry ratio and neutrophil influx were increased in the BDL group up to 48 h reperfusion (P < 0.05). Liver synthetic function was decreased in the BDL group as reflected by prolonged prothrombin time after 6 h and 24 h reperfusion (P < 0.05). I/R in cholestatic rats resulted in a 12-fold vs. 7-fold (P < 0.01) increase in markers for thrombin generation and a 6-fold vs. 2-fold (P < 0.01) increase in fibrin degradation products (BDL vs. control, respectively). In addition, the cholestatic rats exhibited significantly decreased levels of antithrombin (AT) III and increased levels of the fibrinolytic inhibitor plasminogen activator inhibitor (PAI-1) during reperfusion. Conclusions:, Cholestasis significantly enhances I/R-induced hepatic damage and inflammation that concurs with an increased activation of coagulation and fibrinolysis. [source] Current studies on therapeutic approaches for ischemia/reperfusion injury in steatotic liversHEPATOLOGY RESEARCH, Issue 9 2008Chengfu Xu Steatotic livers are particularly vulnerable to ischemia/reperfusion (I/R) injury, resulting in poor outcomes following liver surgery and transplantation. Therapeutic approaches for I/R injury in steatotic livers are currently under intensive investigation. This review summarizes and discusses the approaches developed during the last few years to prevent hepatic I/R injury in steatotic livers. Among the proposed approaches, ischemic preconditioning and intermittent clamping are the two most promising approaches that have been applied in some clinical centers for liver surgery and transplantation, but most of others have not reached clinical application yet. [source] Roles of nuclear factor-,B in postischemic liverHEPATOLOGY RESEARCH, Issue 5 2008Thomas Shin Hepatic ischemia/reperfusion (I/R) results in a chain of events that culminate in liver dysfunction and injury. I/R injury is characterized by early oxidant stress followed by an intense acute inflammatory response that involves the transcription factor nuclear factor (NF)-,B. In addition to being a primary regulator of pro-inflammatory gene expression, NF-,B may play other roles in the hepatic response to I/R, such as mediating the expression of anti-apoptotic genes, preventing the accumulation of damaging reactive oxygen species, facilitating liver regeneration, and mediating the protective effects of ischemic preconditioning. In the present study, we review the diverse functions of NF-,B during hepatic I/R injury. [source] Subtoxic N -methyl- D -aspartate delayed neuronal death in ischemic brain injury through TrkB receptor- and calmodulin-mediated PI-3K/Akt pathway activationHIPPOCAMPUS, Issue 7 2007Jing Xu Abstract Previous studies have shown that subtoxic NMDA moderated the neuronal survival in vitro and vivo. We performed this experiment to clarify the precise mechanism underlie subtoxic NMDA delayed neuronal death in ischemic brain injury. We found that pretreatment of NMDA (100 mg/kg) increased the number of the surviving CA1 pyramidal cells of hippocampus at 5 days of reperfusion. This dose of NMDA could also enhance Akt activation after ischemia/reperfusion (I/R). Here, we examined the possible mechanism that NMDA induced Akt activation. On the one hand, we found NMDA receptor-mediated Akt activation was associated with increased expression of BDNF (brain-derived neurotrophic factor) and activation of its high-affinity receptor TrkB after I/R in the hippocampus CA1 region, which could be held down by TrkB receptor antagonist K252a. On the other hand, we found that NMDA enhanced the binding of Ca2+ -dependent calmodulin (CaM) to p85 (the regulation subunit of PI-3K), which led to the activation of Akt. W-13, an active CaM inhibitor, prevented the combination of CaM and p85 and subsequent Akt activation. Furthermore, NMDA receptor-mediated Akt activation was reversed by combined treatment with LY294002, the specific blockade of PI-3K. Taken together, our results suggested that subtoxic NMDA exerts the neuroprotective effect via activation of prosurvival PI-3K/Akt pathway against ischemic brain injury, and BDNF-TrkB signaling and Ca2+ -dependent CaM cascade might contribute to NMDA induced activation of PI-3K/Akt pathway. © 2007 Wiley-Liss, Inc. [source] Renal damage in rats induced by myocardial ischemia/reperfusion: Role of nitric oxideINTERNATIONAL JOURNAL OF UROLOGY, Issue 10 2006HAKAN PARLAKPINAR Background: It has been demonstrated that myocardial ischemia/reperfusion (MI/R) causes renal damage. However, the mechanism underlying this damage in kidneys during revascularization of myocardium is unclear. Direct renal ischemia/reperfusion has been implicated in the induction of inducible nitric oxide synthase (iNOS) that leads to increase production of nitric oxide (NO). Recently, excessive production of NO has been found to be involved in causing renal injury by formatting peroxinitrite (ONOO,). The aim of this study was to investigate whether NO has a role in this damage, using aminoguanidine (AMG), a known iNOS inhibitor and an antioxidant, in rats undergoing MI/R. Methods: Male Wistar rats were used for the experiments (n = 7 each group). In the MI/R group, the left coronary artery was occluded for 30 min and then reperfused for 120 min; the same procedure was used for the AMG group, with the additional step of AMG (200 mg/kg) administered 10 min prior to ischemia. A control group underwent sham operation. At the end of the reperfusion period, all rats were killed and their kidneys removed for biochemical determination and histopathological analysis. Results: Myocardial ischemia/reperfusion in the rat kidney was accompanied by a significant increase in malondialdehyde and NO production, and a decrease in glutathione content. Administration of AMG reduced malondialdehyde and NO production and prevented depletion of glutathione content. These beneficial changes in the biochemical parameters were also associated with parallel changes in histopathological appearance. Conclusion: These findings suggest that MI/R plays a causal role in kidney injury and AMG exerts renal-protective effects, probably by inhibiting NO production and antioxidant activities. [source] The Effects of Pentoxifylline on the Myocardial Inflammation and Ischemia-Reperfusion Injury During Cardiopulmonary BypassJOURNAL OF CARDIAC SURGERY, Issue 1 2006Hasim Ustunsoy M.D. The aim of this study is to investigate whether the addition of Ptx into the cardioplegic solutions avoids myocardial inflammatory reactions and ischemia/reperfusion (I/R) injury during extracorpereal circulation. Methods: Between December 1999 and February 2002, we operated 75 patients with the diagnoses of atrial septal defect (ASD), ventricular septal defect (VSD), valve disease, and coronary disease. The average age of patients was 42.4 and male,female ratio was 1: 1.5. The patients were divided into two groups, which were the study group (n = 40) and the control group (n = 35). We used cold blood cardioplegia mixed with St. Thomas' Hospital II cardioplegic solution for both of the groups. Ptx was added into the cardioplegic solution (500 mg/L) in the study group. Interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrotisis factor-, (TNF-,) levels in coronary sinus blood samples during cross-clamp time (X-clamp) and after releasing of it and tissue TNF-, in the right atrial appendix biopsy material that was taken after X-clamp were studied to compare the both groups. Results: After releasing X-clamp, results of blood TNF-,, IL-6, and IL-8 of both groups were statistically significant (p < 0.005). At the pathological examination, we also observed that the amount of tissue TNF-, in the control group (66 ± 17.1) was much higher than the study group (16.6 ± 5.9, p <0.005). Conclusions: These results show that Ptx may be added into cardioplegic solution to avoid the myocardial inflammation and I/R injury during open heart surgery. [source] Side Effects of Cardiopulmonary Bypass:JOURNAL OF CARDIAC SURGERY, Issue 6 2004What Is the Reality? This is due, in part, to lack of suitable control group against which bypass and cardioplegic arrest can be compared. The recent success of beating heart coronary artery bypass grafting has, however, for the first time, provided an opportunity to compare the same operation, in similar patient groups, with, or without CPB and cardioplegic arrest. CPB is associated with an acute phase reaction of protease cascades, leucocyte, and platelet activation that result in tissue injury. This is largely manifest as subclinical organ dysfunction that produces a clinical effect in those patients that generate an excessive inflammatory response or in those with limited functional reserve. The contribution of myocardial ischemia/reperfusion, secondary to aortic cross-clamping, and cardioplegic arrest, to the systemic inflammatory response and wider organ dysfunction is unknown, and requires further evaluation in clinical trials. [source] ARC protects rat cardiomyocytes against oxidative stress through inhibition of caspase-2 mediated mitochondrial pathwayJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2006Yi-Qiang Zhang Abstract Apoptosis repressor with a CARD domain (ARC) has been demonstrated to protect heart cells against ischemia/reperfusion (I/R) injury. In this study, we investigated the mechanism by which ARC protects heart cells against oxidative stress. We monitored the extent of apoptosis and activity of multiple components of the intrinsic apoptotic pathway in rat cardiac myoblast cell line H9c2 with either reduced or increased expression of ARC during oxidative stress. Overexpression of ARC-inhibited oxidative stress-induced caspase-2/3 activation, cytochrome c release, and translocation of Bax to mitochondria. Furthermore, phosphorylation of ARC at threonine 149 was found to be critical to its function. ARC containing a T149A mutation failed to translocate to mitochondria, did not inhibit caspase-2 activation, and had a dominant negative effect against the protective effect of endogenous ARC during oxidative stress. In addition, wild-type ARC but not the T149A mutant inhibited cell death induced by overexpression of caspase-2. Using a yeast two-hybrid (YTH) screening approach and co-immunoprecipitation (Co-IP), we found that protein phosphatase 2C (PP2C) interacted with ARC and that PP2C mediated-dephosphorylation of ARC inhibited its anti-apoptotic activity. Eliminating either the N-terminal CARD domain or the C-terminal P/E domain also abolished the anti-apoptotic function of ARC, suggesting that full-length ARC is required for its apoptotic inhibition. These results indicate that ARC plays an important role in protection of H9c2 cells against oxidative stress-induced apoptosis by phosphorylation-dependent suppression of the mitochondria-mediated intrinsic pathway, partially initiated through the activation of caspase-2. J. Cell. Biochem. 99: 575,588, 2006. © 2006 Wiley-Liss, Inc. [source] Mechanisms of cardioprotection by lysophospholipidsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2004Joel S. Karliner Abstract The lysophospholipids sphingosine 1-phosphate (S1P) and lysophosphosphatidic acid (LPA) reduce mortality in hypoxic cardiac myocytes. S1P is also cardioprotective in both mouse and rat models of cardiac ischemia/reperfusion (I/R) injury. Although these results are consistent with prior work in other cell types, it is not known what signaling events are critical to cardioprotection, particularly with respect to ceramide and the preservation of mitochondrial function, which is essential for cardiac cell survival. Neither receptor regulation nor signaling has been studied during I/R in the heart with or without the application of S1P or LPA. The role of sphingosine kinase in I/R and in ischemic preconditioning (IPC) has not been defined, nor has the fate or function of S1P generated by this enzyme, particularly during preconditioning or I/R, been elucidated. Whether S1P infused systemically in animal models of myocardial infarction in which survival is an end-point will be hemodynamically tolerated has not been determined. If not, the substitution of agents such as the monosialoganglioside GM-1, which activates sphingosine kinase, or the development of alternative ligands for S1P receptors will be necessary. © 2004 Wiley-Liss, Inc. [source] Reactive oxygen species in rats with chronic post-ischemia painACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 5 2009K. H. KWAK Background: An emerging theme in the study of the pathophysiology of persistent pain is the role of reactive oxygen species (ROS). In the present study, we examined the hypothesis that the exogenous supply of antioxidant drugs during peri-reperfusion would attenuate pain induced by ischemia/reperfusion (IR) injury. We investigated the analgesic effects of three antioxidants administered during peri-reperfusion using an animal model of complex regional pain syndrome-type I consisting of chronic post-ischemia pain (CPIP) of the hind paw. Methods: Application of a tight-fitting tourniquet for a period of 3 h produced CPIP in male Sprague,Dawley rats. Low-dose allopurinol (4 mg/kg), high-dose allopurinol (40 mg/kg), superoxide dismutase (SOD, 4000 U/kg), N -nitro- l -arginine methyl ester (l -NAME, 10 mg/kg), or SOD (4000 U/kg)+l -NAME (10 mg/kg) was administered intraperitoneally just after tourniquet application and at 1 and 2 days after reperfusion for 3 days. The effects of antioxidants in rats were investigated using mechanical and cold stimuli. Each group consisted of seven rats. Results: Allopurinol caused significant alleviation in mechanical and cold allodynia for a period of 4 weeks in rats with CPIP. Both SOD and l -NAME, which were used to investigate the roles of superoxide (O2 ,,) and nitric oxide (NO) in pain, also attenuated neuropathic-like pain symptoms in rats for 4 weeks. Conclusions: Our findings suggest that O2 ,, and NO mediate IR injury-induced chronic pain, and that ROS scavengers administered during the peri-reperfusion period have long-term analgesic effects. [source] Role of interleukin-18 in the development of acute pulmonary injury induced by intestinal ischemia/reperfusion and its possible mechanismJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 2 2007Yong-jie Yang Abstract Background and Aims:, Lung injury is an important target for the systemic inflammatory response associated with intestinal ischemia/reperfusion (I/R). In the present study, the role of interleukin (IL)-18 in the development of acute pulmonary injury induced by intestinal I/R and its possible mechanism in relation to the increased activity of inducible nitric oxide synthase and tumor necrosis factor (TNF)-, were investigated. Methods:, Mice were randomly divided into three groups: normal control group without operation; sham group with sham operation; and I/R group in which mice underwent superior mesenteric artery occlusion for 30 min followed by reperfusion for 3 h. Each group received pretreatment with exogenous IL-18, anti-IL-18 neutralizing antibody or L-NIL, the selective inhibitor of inducible nitric oxide synthase, 30 min before ischemia. The expression of TNF-, was detected by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Lung injury was evaluated by means of Evans blue dye (EBD) concentration, myeloperoxidase (MPO) activity and morphological analysis. Results:, The experimental results showed that both in the sham-operated and I/R groups of animals, pretreatment with exogenous IL-18 clearly enhanced pulmonary MPO activity, microvascular leakage and the expression of TNF-, mRNA and protein. In contrast, IL-18 did not increase the TNF-, level and degree of lung injury, although it clearly enhanced the pulmonary MPO activity in normal animals. Meanwhile, IL-18 antibody given prior to ischemia led to a reduction in the sequestration of neutrophils, extravasation of EBD and downregulation of the serum level of TNF-, in the I/R group of animals. In addition, selective inhibition of inducible nitric oxide synthase (iNOS) that inhibited plasma extravasation and pulmonary injury without affecting the MPO activity could be demonstrated in all treated animals. Conclusions:, These data suggested a role of IL-18 in the activation and sequestration of neutrophils in lungs. Our results were consistent with the hypothesis that increased sequestration of neutrophils and microvascular leakage might, respectively, relate to the increased IL-18 level and the elevation of TNF-,/iNOS activity, and these two aspects might synergically contribute to intestinal I/R-induced pulmonary dysfunction. [source] Overexpression of human copper/zinc-superoxide dismutase in transgenic animals attenuates the reduction of apurinic/apyrimidinic endonuclease expression in neurons after in vitro ischemia and after transient global cerebral ischemiaJOURNAL OF NEUROCHEMISTRY, Issue 2 2005Purnima Narasimhan Abstract Oxidative stress after ischemia/reperfusion has been shown to induce DNA damage and subsequent DNA repair activity. Apurinic/apyrimidinic endonuclease (APE) is a multifunctional protein in the DNA base excision repair pathway which repairs apurinic/apyrimidinic sites in DNA. We investigated the involvement of oxidative stress and expression of APE in neurons after oxygen,glucose deprivation and after global cerebral ischemia. Our results suggest that overexpression of human copper/zinc-superoxide dismutase reduced oxidative stress with a subsequent decrease in APE expression. Production of oxygen free radicals and inhibition of the base excision repair pathway may play pivotal roles in the cell death pathway after ischemia. [source] Studies on the effects of lactate transport inhibition, pyruvate, glucose and glutamine on amino acid, lactate and glucose release from the ischemic rat cerebral cortexJOURNAL OF NEUROCHEMISTRY, Issue 1 2001J. W. Phillis A rat four vessel occlusion model was utilized to examine the effects of ischemia/reperfusion on cortical window superfusate levels of amino acids, glucose, and lactate. Superfusate aspartate, glutamate, phosphoethanolamine, taurine, and GABA were significantly elevated by cerebral ischemia, then declined during reperfusion. Other amino acids were affected to a lesser degree. Superfusate lactate rose slightly during the initial ischemic period, declined during continued cerebral ischemia and then was greatly elevated during reperfusion. Superfusate glucose levels declined to near zero levels during ischemia and then rebounded beyond basal levels during the reperfusion period. Inhibition of neuronal lactate uptake with ,-cyano-4-hydroxycinnamate dramatically elevated superfusate lactate levels, enhanced the ischemia/reperfusion evoked release of aspartate but reduced glutamine levels. Topical application of an alternative metabolic fuel, glutamine, had a dose dependent effect. Glutamine (1 mm) elevated basal superfusate glucose levels, diminished the decline in glucose during ischemia, and accelerated its recovery during reperfusion. Lactate levels were elevated during ischemia and reperfusion. These effects were not evident at 5 mm glutamine. At both concentrations, glutamine significantly elevated the superfusate levels of glutamate. Topical application of sodium pyruvate (20 mm) significantly attenuated the decline in superfusate glucose during ischemia and enhanced the levels of both glucose and lactate during reperfusion. However, it had little effect on the ischemia-evoked accumulation of amino acids. Topical application of glucose (450 mg/dL) significantly elevated basal superfusate levels of lactate, which continued to be elevated during both ischemia and reperfusion. The ischemia-evoked accumulations of aspartate, glutamate, taurine and GABA were all significantly depressed by glucose, while phosphoethanolamine levels were elevated. These results support the role of lactate in neuronal metabolism during ischemia/reperfusion. Both glucose and glutamine were also used as energy substrates. In contrast, sodium pyruvate does not appear to be as effectively utilized by the ischemic/reperfused rat brain since it did not reduce ischemia-evoked amino acid efflux. [source] Hypothyroid state does not protect but delays neuronal death in the hippocampal CA1 region following transient cerebral ischemia: Focus on oxidative stress and gliosisJOURNAL OF NEUROSCIENCE RESEARCH, Issue 12 2010Choong Hyun Lee Abstract We investigated protective effects of hypothyroidism on delayed neuronal death, gliosis, lipid peroxidation and Cu,Zn-superoxide dismutase (SOD1) in the gerbil hippocampal CA1 region (CA1) after 5 min of transient cerebral ischemia. The hypothyroidism was induced by 0.025% methimazole treatment. Free triiodothyronine and thyroxine levels were markedly decreased in the hypothyroid group. Four days after ischemia/reperfusion, only a few NeuN-immunoreactive (+) neurons were detected in the CA1 of euthyroid-ischemia (eu-ischemia) group; however, at this time point, the number of NeuN+ neurons was significantly higher in the hypothyroid-ischemia (hypo-ischemia) group than in the eu-ischemia group. At 5 days postischemia, NeuN+ neurons were significantly decreased in the hypo-ischemia group: The number of NeuN+ neurons in this group was similar to that in the eu-ischemia group. Activations of GFAP+ astrocytes and Iba-1+ microglia in the CA1 were higher in the eu-ischemia group 3 and 4 days after ischemia/reperfusion. At 5 days postischemia, the activations of both the glial cells in the CA1 were similar between the two groups. 4-Hydroxy-2-nonenal (HNE), a marker for lipid peroxidation, immunoreactivity in the eu-ischemia group was higher than in the hypo-ischemia group; at 5 days postischemia, the immunoreactivity was similar between the two groups. In contrast, SOD1 level was lower in the CA1 of the eu-ischemia group. These results suggest that hypothyroid state does not protect against delayed neuronal death but only delays the neuronal death in the hippocampal CA1 region after transient cerebral ischemia by reducing lipid peroxidation and increasing SOD1. © 2010 Wiley-Liss, Inc. [source] Neuroprotective mechanisms of curcumin against cerebral ischemia-induced neuronal apoptosis and behavioral deficitsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2005Qun Wang Abstract Increased oxidative stress has been regarded as an important underlying cause for neuronal damage induced by cerebral ischemia/reperfusion (I/R) injury. In recent years, there has been increasing interest in investigating polyphenols from botanical source for possible neuroprotective effects against neurodegenerative diseases. In this study, we investigated the mechanisms underlying the neuroprotective effects of curcumin, a potent polyphenol antioxidant enriched in tumeric. Global cerebral ischemia was induced in Mongolian gerbils by transient occlusion of the common carotid arteries. Histochemical analysis indicated extensive neuronal death together with increased reactive astrocytes and microglial cells in the hippocampal CA1 area at 4 days after I/R. These ischemic changes were preceded by a rapid increase in lipid peroxidation and followed by decrease in mitochondrial membrane potential, increased cytochrome c release, and subsequently caspase-3 activation and apoptosis. Administration of curcumin by i.p. injections (30 mg/kg body wt) or by supplementation to the AIN76 diet (2.0 g/kg diet) for 2 months significantly attenuated ischemia-induced neuronal death as well as glial activation. Curcumin administration also decreased lipid peroxidation, mitochondrial dysfunction, and the apoptotic indices. The biochemical changes resulting from curcumin also correlated well with its ability to ameliorate the changes in locomotor activity induced by I/R. Bioavailability study indicated a rapid increase in curcumin in plasma and brain within 1 hr after treatment. Together, these findings attribute the neuroprotective effect of curcumin against I/R-induced neuronal damage to its antioxidant capacity in reducing oxidative stress and the signaling cascade leading to apoptotic cell death. © 2005 Wiley-Liss, Inc. [source] Therapeutic potential of melatonin in traumatic central nervous system injuryJOURNAL OF PINEAL RESEARCH, Issue 2 2009Supriti Samantaray Abstract:, A vast literature extolling the benefits of melatonin has accumulated during the past four decades. Melatonin was previously considered of importance to seasonal reproduction and circadian rhythmicity. Currently, it appears to be a versatile anti-oxidative and anti-nitrosative agent, a molecule with immunomodulatory actions and profound oncostatic activity, and also to play a role as a potent neuroprotectant. Nowadays, melatonin is sold as a dietary supplement with differential availability as an over-the-counter aid in different countries. There is a widespread agreement that melatonin is nontoxic and safe considering its frequent, long-term usage by humans at both physiological and pharmacological doses with no reported side effects. Endeavors toward a designated drug status for melatonin may be enormously rewarding in clinics for treatment of several forms of neurotrauma where effective pharmacological intervention has not yet been attained. This mini review consolidates the data regarding the efficacy of melatonin as an unique neuroprotective agent in traumatic central nervous system (CNS) injuries. Well-documented actions of melatonin in combating traumatic CNS damage are compiled from various clinical and experimental studies. Research on traumatic brain injury and ischemia/reperfusion are briefly outlined here as they have been recently reviewed elsewhere, whereas the studies on different animal models of the experimental spinal cord injury have been extensively covered in this mini review for the first time. [source] | ||||||||||||||||||||||||||||||||||