Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ischemic alterations in the glutathione (GSH) redox system of the blood-brain barrier (BBB) may facilitate oxidative injury and formation of vasogenic brain edema. In this study, both the intra- and extracellular GSH contents of human cerebromicrovascular endothelial cells (HCEC) were reduced by 35% after exposing the cells to 4 h in vitro ischemia and 24 h-recovery. The intracellular/extracellular GSH ratio was not affected, indicating a constant rate of GSH efflux. The activities of the peroxide detoxifying enzymes, glutathione peroxidase and glutathione S-transferase, increased by 35%-50%, whereas the GSH regenerating enzyme, glutathione reductase, remained unchanged in ischemic HCEC. gamma-glutamyl transpeptidase (GGTP), a GSH catabolizing enzyme enriched in brain capillaries, was reduced by 30-50% in ischemic HCEC. The effect of in vitro ischemia on HCEC permeability was assessed by measuring sodium fluorescein clearance across a compartmentalized in vitro BBB model. Sodium fluorescein clearance across HCEC monolayers exposed to leukotriene C4 in the presence of the GGTP inhibitor, acivicin (1 microM), or after in vitro ischemia was increased by 60% and 30%, respectively, suggesting that oxidative stress and loss of GGTP may 'unmask' BBB permeabilizing actions of leukotrienes. These results indicate that oxidative stress and loss of GGTP activity in HCEC contribute to ischemic BBB disruption and vasogenic brain edema.
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PMID:Glutathione homeostasis and leukotriene-induced permeability in human blood-brain barrier endothelial cells subjected to in vitro ischemia. 1145 27

The limits of organ donation from heart-beating (HB) donors reached a plateau illustrated by the number of postmortem kidneys for transplantation. Programs such as the European Donor Hospital Education Program (EDHEP) and Donor Action have helped to stop a further decrease in the number instead of an expected increase. For kidneys, heart, liver, and lungs one must also explore the use of marginal donors as a possible additional source. Examples are donors with a horseshoe kidney, those at both ends of the age spectrum, and those with medical contraindication such as diabetes. We have enlarged our kidney donor pool considerably with non-heart-beating(NHB) donors. Because we preserve these kidneys in a preservation machine, we are able to perform viability testing. With glutathione S-transferase (GST) as a measure of tubular damage, we now decide whether to transplant based on GST values. For other organs, NHB donation does not seem to be an option other than for the liver when the warm ischemia time is short.
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PMID:Organ donors: heartbeating and non-heartbeating. 1186 48

Rho GTPases are critical for actin cytoskeletal regulation, and alterations in their activity may contribute to altered cytoskeletal organization that characterizes many pathological conditions, including ischemia. G protein activity is a function of the ratio of GTP-bound (active) to GDP-bound (inactive) protein, but the effect of altered energy metabolism on Rho protein activity has not been determined. We used antimycin A and substrate depletion to induce depletion of intracellular ATP and GTP in the kidney proximal tubule cell line LLC-PK10 and measured the activity of RhoA, Rac1, and Cdc42 with GTPase effector binding domains fused to glutathione S-transferase. RhoA activity decreased in parallel with the concentration of ATP and GTP during depletion, so that by 60 min there was no detectable RhoA-GTP, and recovered rapidly when cells were returned to normal culture conditions. Dissociation of the membrane-actin linker ezrin, a target of RhoA signaling, from the cytoskeletal fraction paralleled the decrease in RhoA activity and was augmented by treatment with the Rho kinase inhibitor Y27632. The activity of Cdc42 did not decrease significantly during depletion or recovery. Rac1 activity decreased moderately to a minimum at 30 min of depletion but then increased from 30 to 90 min of depletion, even as ATP and GTP levels continued to fall. Our data are consistent with a principal role for RhoA in cytoskeletal reorganization during ischemia and demonstrate that the activity of Rho GTPases can be maintained even at low GTP concentrations.
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PMID:Rho GTPases show differential sensitivity to nucleotide triphosphate depletion in a model of ischemic cell injury. 1262 Aug 11

Nonspecific investigations resulting in treatment delays contribute to the 30 per cent mortality associated with acute mesenteric ischemia (AMI). As preliminary studies indicate that alpha-glutathione S-transferase (alpha-GST) is elevated in AMI we compare the ability of alpha-GST against conventional biochemical tests to predict AMI. There were 58 patients prospectively evaluated for AMI. Samples for alpha-GST (Biotrin International, Dublin, Ireland), lactate, pH, amylase, base excess, and white blood cell count (WBC) were evaluated. Intestinal ischemia was confirmed by colonoscopy, angiography, or laparotomy. Ischemia was present in 35 (60%) patients: small bowel (n = 14), colonic (n = 17), and global (n = 4). Four patients without autopsy were excluded. Alpha-GST was elevated in those with AMI [22.2 (7-126) ng/mL vs 2.2 (1-3) (P = 0.001)]. Alpha-GST was more accurate at predicting intestinal ischemia (74%) than conventional tests (47-69% accuracy). Accuracy was increased to 80 per cent by combination with lactate or WBC, which increased sensitivity to 97 to 100 per cent. Alpha-GST monitoring is a useful tool for the diagnosis of intestinal ischemia. A normal alpha-GST and WBC may exclude the presence of AMI.
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PMID:Prospective assessment of the predictive value of alpha-glutathione S-transferase for intestinal ischemia. 1271 91

The hepatic ischemia-reperfusion syndrome was investigated in 28 patients undergoing elective partial liver resection with intraoperative occlusion of hepatic inflow (Pringle maneuver) using the technique of liver vein catheterization. Hepatic venous oxygen saturation (ShvO2) was monitored continuously up to 24 hours after surgery. Aspartate aminotransferase, glutamate dehydrogenase, gamma-glutamyl transpeptidase, pseudocholinesterase, alpha-glutathione S-transferase, reduced and oxidized glutathione, procalcitonine, and interleukin-6 were serially measured both before and after Pringle maneuver during the resection and postoperatively in arterial and/or hepatic venous blood. ShvO2 measurement demonstrated that peri- and postoperative management was suitable to maintain an optimal hepatic oxygen supply. As expected, we were able to demonstrate a typical enzyme pattern of postischemic liver injury. There was a distinct decrease of reduced glutathione levels both in arterial and hepatic venous plasma after LR accompanied by a strong increase in oxidized glutathione concentration during the phase of reperfusion. We observed increases in procalcitonin and interleukin-6 levels both in arterial and hepatic venous blood after declamping. Our data support the view that liver resection in man under conditions of inflow occlusion resulted in ischemic lesion of the liver (loss of glutathione synthesizing capacity with disturbance of protection against oxidative stress) and an additional impairment during reperfusion (liberation of reactive oxygen species, local and systemic inflammation reaction with cytokine production). Additionally, we found some evidence for the assumption that the liver has an export function for reduced glutathione into plasma in man.
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PMID:Hepatic ischemia-reperfusion syndrome after partial liver resection (LR): hepatic venous oxygen saturation, enzyme pattern, reduced and oxidized glutathione, procalcitonin and interleukin-6. 1287 55

Hypoxia/reoxygenation (H/R)-induced intestinal injury plays a significant role in the development of necrotizing enterocolitis (NEC). We experimentally explored the effect of pentoxifylline (PTX) on an NEC model. Twenty-one newborn rabbits were divided into three groups: group 1 (control), group 2 (H/R) and group 3 (H/R + PTX). Five minutes of reoxygenation following 5 min of hypoxia was performed three times a day during 3 days. Before each H/R procedure in the H/R + PTX group, the rabbits were treated with PTX 25 mg/kg intraperitoneally. Animals were sacrificed on the third day and ileum samples were taken for histopathological examination and biochemical enzyme studies [superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S-transferase (GST)]. There was a significant difference in the grade and number of the intestinal lesions between controls and the H/R and H/R + PTX groups (p < 0.001), but no significant difference was found between the H/R and the H/R + PTX groups (p > 0.05). Intestinal SOD, GR and GST activities in the H/R and H/R + PTX groups were significantly higher than in the control group (p < 0.05); however, there was no significant difference between the H/R and H/R + PTX groups (p > 0.05). Significantly reduced GPx activity was found in the H/R and H/R + PTX groups compared with the controls (p < 0.05). No significant difference in GPx activity existed between the H/R group and the H/R + PTX group (p > 0.05). Ischemia/reperfusion injury was responsible for mediating hypoxia-induced intestinal necrosis in NEC and PTX pretreatment did not have a protective effect on NEC.
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PMID:Pentoxifylline does not prevent hypoxia/reoxygenation-induced necrotizing enterocolitis. An experimental study. 1501 17

Endothelin (ET) contributes to disturbances of hepatic microcirculation after ischemia/reperfusion (I/R) by causing vasoconstriction and enhancing leukocyte- and platelet-endothelium interactions. The aim of this study was to investigate a possible protective role of a selective endothelin(A) receptor antagonist (ET(A)-RA) in this setting. In a rat model, warm ischemia of the left lateral liver lobe was induced for 90 minutes under intraperitoneal anesthesia with xylazine and ketamine. Groups of rats consisted of sham-operated (SO, n=14), untreated ischemia (n=14), and treatment with BSF208075 (5 mg/kg body weight IV, n=14). The effect of the ET(A)-RA on I/R was assessed by in vivo microscopy 20 to 90 minutes after reperfusion; by measurement of local tissue Po(2), serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glutathione S-transferase alpha levels, and by histologic investigation. In the untreated group, sinusoidal constriction to 69.4+/-6.7% of diameters of SO rats was observed, leading to a significant decrease in perfusion rate (74.3+/-2.1% of SO) and liver tissue Po(2) (43.5+/-3.2% of SO) (P < 0.05). In addition, we found an increased percentage of stagnant leukocytes (142.9+/-11.9%) and platelets (450.1+/-62.3%) in sinusoids and in postsinusoidal venules (P < 0.05). Hepatocellular damage (AST and ALT increase to 1330+/-157 U/L and 750+/-125 U/L respectively; previously, 27.1+/-3.5 U/L and 28.5+/-3.6 U/L) was detected 6 hours after reperfusion (P < 0.05). Administration of the ET(A)-RA before reperfusion significantly reduced I/R injury. Sinusoidal diameters were maintained (108.5+/-6.6%), and perfusion rate (93.1+/-1.8%) and tissue Po(2) (95.3+/-5.7%) were significantly increased (P < 0.05). According to reduced leukocyte-endothelium interactions after therapy, both platelet rolling and adhesion were significantly reduced (P < 0.05). The number of stagnant platelets in sinusoids was 199.5+/-12.3% of 50 (P < 0.05). After treatment, hepatocellular damage was decreased (AST and ALT levels after 6 hours of reperfusion: 513+/-106 U/L and 309+/-84 U/L, respectively; P < 0.05), and histologic changes were reduced in the long term. Our results provide evidence that the new therapeutic approach with an ET(A)-RA is effective in reducing hepatic I/R injury. In addition to reduced leukocyte-endothelium interactions, the number of stagnant and rolling platelets in sinusoids and venules was significantly reduced. The reduction in microcirculatory damages is responsible for better organ outcome.
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PMID:Improvement of postischemic hepatic microcirculation after endothelinA receptor blockade--endothelin antagonism influences platelet-endothelium interactions. 1569 14

Organ dysfunction following liver resection is one of the major postoperative complications of liver surgery. The Pringle maneuver is often applied during liver resection to minimize bleeding, which in turn complicates the postoperative course owing to liver ischemia and reperfusion. Routinely, hepatocellular damage is diagnosed by, for example, abnormal aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and the prothrombin time (PT). The cytosolic liver enzyme alpha-glutathione S-transferase (alpha-GST) has recently been shown to have good sensitivity for detecting hepatic injury after acetaminophen poisoning or liver transplantation, but its role in non-transplantation liver surgery has not been assessed. In this prospective randomized clinical study, the diagnostic role of plasma alpha-GST following warm ischemia and reperfusion is reported. A total of 75 patients who underwent liver resection were randomly assigned to three groups: (1) without Pringle (NPR); (2) with Pringle (PR); (3) with ischemic preconditioning by 10 minutes of ischemia and reperfusion each prior to the Pringle manuever (IPC). The major findings are as follows: (1) ALT, AST, and alpha-GST increased upon liver manipulation as early as prior to resection, with a rapid return of alpha-GST values to preoperative levels, whereas ALT and AST further increased on the first postoperative day. (2) In the PR group, alpha-GST, but not ALT and AST, was significantly elevated compared with that in the NPR group at 15 and 30 minutes and 2 hours after resection/reperfusion. In addition, only levels of alpha-GST significantly correlated with the Pringle duration. (3) The ischemia/reperfusion-induced early rise in alpha-GST was completely prevented by ischemic preconditioning. Moreover, only alpha-GST concentrations (> 490 microg L(-1)) determined early after resection (2 hours) predicted postoperative liver dysfunction (24 hours PT < 60%) with a positive predictive value of 74% and a negative predictive value of 76%. Thus alpha-GST seems to be a sensitive, predictive marker of ischemia/reperfusion-induced hepatocellular injury and postoperative liver dysfunction.
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PMID:Alpha-gluthathione S-transferase as an early marker of hepatic ischemia/reperfusion injury after liver resection. 1577 1

Prostaglandin E1 (PGE1) has several potential therapeutic effects, including cytoprotection, vasodilation, and inhibition of platelet aggregation. This study investigates the protective action of PGE1 against hepatic ischemia/reperfusion injury in vivo using a complementary DNA microarray. PGE1 or saline was continuously administered intravenously to mice in which the left lobe of the liver was made ischemic for 30 minutes and then reperfused. Livers were harvested 0, 10, and 30 minutes postreperfusion. Messenger RNA was extracted, and the samples were labeled with two different fluorescent dyes and hybridized to the RIKEN set of 18,816 full-length enriched mouse complementary DNA microarrays. Serum alanine aminotransferase and aspartate aminotransferase levels at 180 minutes postreperfusion were significantly lower in the PGE1-treated group than in the saline-treated group. The cDNA microarray analysis revealed that the genes encoding heat-shock protein (HSP) 70, glucose-regulated protein 78, HSP86, and glutathione S-transferase were upregulated at the end of the ischemic period (0 minutes postreperfusion) in the PGE1 group. Our results suggested that PGE1 induces HSPs immediately after ischemia reperfusion. HSPs might therefore play an important role in the protective effects of PGE1 against ischemia/reperfusion injury of the liver.
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PMID:Pharmacologic preconditioning effects: prostaglandin E1 induces heat-shock proteins immediately after ischemia/reperfusion of the mouse liver. 1598 30

We have evaluated the involvement of hepatic preconditioning mediators (adenosine, adenosine A1 and A2 receptors) during normothermic recirculation (NR) in a model of liver transplantation from non-heart-beating donor (NHBD) pigs. Application of NR after 20 min of warm ischemia (WI) reversed the lethal injury associated with transplantation of NHBD livers (achieving 5-day survival and diminishing glutathione S-transferase (GST), aspartate aminotransferase (AST) and hyaluronic acid (HA)). Adenosine administration prior to WI simulated the effect of NR. Measuring adenosine, we found that during NR, hepatic adenosine levels increased and xanthine levels decreased. Then when we blocked A2 receptors the effect of NR was abolished, whereas the blocking of A1 receptors further protected the liver. Furthermore, A2 blocking improved hepatic perfusion during NR whereas A1 blocking reduced it. The study suggests that NR has a preconditioning effect by maintaining adequate adenosine and xanthine levels. During NR, adenosine protects the liver through A2 activation and damages it through A1 activation although simultaneous stimulation of both receptors exerts a clear beneficial effect. The possible relation of NR mechanism with other preconditioning mediators such as cAMP and nitric oxide synthesis are discussed.
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PMID:The effect of normothermic recirculation is mediated by ischemic preconditioning in NHBD liver transplantation. 1616 86


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