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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ischemia and reperfusion lead to eicosanoid- and neutrophil (PMN)-dependent injury. This study tests the role of ischemia-induced lipoxygenase activity in mediating PMN activation and diapedesis. Anesthetized rabbits (n = 8) underwent 3 hours of bilateral hindlimb ischemia. At 10 minutes of reperfusion, leukotriene B4 (LTB4) levels in femoral venous effluent were 0.49 +/- 0.05 ng/ml compared with 0.04 +/- 0.07 ng/ml in sham-treated animals (n = 10) (p less than 0.05). Intracellular H2O2 production of circulating PMNs assayed flow cytometrically by dichlorofluorescein (DCF) oxidation, increased from a preischemic value of 74 +/- 14 femtomoles DCF/cell to 135 +/- 8 fmol DCF/cell (p less than 0.05). PMNs were treated with phorbol myristate acetate (PMA), 10(-7) mol/L. In contrast to a 162% increase in H2O2 production before ischemia, PMNs at 10 minutes of reperfusion had an enhanced response to PMA of 336% (p less than 0.05). Addition of authentic LTB4 (0.5 ng/ml) to PMN from sham-treated animals led to their activation, manifest by an oxidative burst, 127 +/- 12 fmol DCF/cell, and an enhanced response of 337% to PMA stimulation. To study diapedesis, plasma collected at 10 minutes of reperfusion was introduced into plastic chambers taped atop skin abrasions in rabbits (n = 8). After 3 hours, 1610 +/- 246 PMN/mm3 accumulated and LTB4 levels in blister fluid were 0.83 +/- 0.03 ng/ml, higher than values of 44 +/- 23 PMN/mm3 (p less than 0.05) and 0.04 +/- 0.03 ng LTB4/ml (p less than 0.05) with saline solution and 68 +/- 16 PMN/mm3 (p less than 0.05) and 0.19 +/- 0.02 ng/ml (p less than 0.05) with nonischemic plasma. The introduction of LTB4, 3.3 ng/ml, into the chambers resulted in an accumulation of 536 +/- 352 PMN/mm3 (p less than 0.05). Pretreatment of animals before hindlimb ischemia (n = 5) with the lipoxygenase inhibitor diethylcarbamazine abolished PMN activation (51 +/- 12 fmol DCF/cell) and ischemic plasma-induced diapedesis into the plastic chamber (38 +/- 18 PMN/mm3). Pretreatment of nonischemic animals (n = 13) used for the dermabrasion bioassay with diethylcarbamazine abolished diapedesis into the plastic chambers induced by ischemic plasma (n = 5) (32 +/- 24 PMN/mm3) or LTB4 (n = 3) (36 +/- 28 PMN/mm3). These data indicate that PMN activation after reperfusion of ischemic tissue is mediated by a lipoxygenase product, perhaps LTB4, and that both reperfusion plasma and authentic LTB4 induce diapedesis by stimulating de novo lipoxygenase activity.
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PMID:Ischemia-induced neutrophil activation and diapedesis is lipoxygenase dependent. 215

Reactive oxygen metabolites have been implicated in the pathogenesis of mucosal injury induced by ischemia-reperfusion in adult animals, with recent interest centering on the capacity of polymorphonuclear neutrophil-derived oxidants to mediate this injury. A role for oxidants has also been postulated in the etiology of neonatal necrotizing enterocolitis. Based on evidence that the intrinsic capacity of the neonatal piglet intestine to detoxify hydrogen peroxide (H2O2) is minimal relative to that of older piglets, we characterized the changes in mucosal permeability induced by luminal perfusion with H2O2 and hypochlorous acid at concentrations that can be produced physiologically by activated neutrophils (0.05 mmol/L, 0.1 mmol/L, and 0.5 mmol/L), in the distal ileum of 1-d- and 1-mo-old piglets. Mucosal permeability was quantitated by measurement of blood-to-lumen clearance of 51-labeled chromium EDTA. Luminal perfusion with either H2O2 (0.05 mmol/L and 0.1 mmol/L) or hypochlorous acid (0.1 mmol/L and 0.5 mmol/L) significantly increased mucosal permeability in newborn piglets but did not affect mucosal permeability in 1-mo-old animals. Perfusion with 0.5 mmol/L H2O2 significantly increased mucosal permeability over control values in both age groups, but injury in the newborn intestine was significantly greater than that observed in 1-mo-old animals. Thus, as predicted by the reduced intrinsic capacity of the mucosa of neonatal piglets to detoxify H2O2, the ileum of newborn piglets is more vulnerable to oxidant-induced mucosal injury than is the ileum of older animals.
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PMID:Oxidant-induced increases in mucosal permeability in developing piglets. 216 84

The reaction of xanthine and xanthine oxidase generates superoxide and hydrogen peroxide. In contrast to earlier works, recent spin trapping data (Kuppusamy, P., and Zweier, J.L. (1989) J. Biol. Chem. 264, 9880-9884) suggested that hydroxyl radical may also be a product of this reaction. Determining if hydroxyl radical results directly from the xanthine/xanthine oxidase reaction is important for 1) interpreting experimental data in which this reaction is used as a model of oxidant stress, and 2) understanding the pathogenesis of ischemia/reperfusion injury. Consequently, we evaluated the conditions required for hydroxyl radical generation during the oxidation of xanthine by xanthine oxidase. Following the addition of some, but not all, commercial preparations of xanthine oxidase to a mixture of xanthine, deferoxamine, and either 5,5-dimethyl-1-pyrroline-N-oxide or a combination of alpha-phenyl-N-tert-butyl-nitrone and dimethyl sulfoxide, hydroxyl radical-derived spin adducts were detected. With other preparations, no evidence of hydroxyl radical formation was noted. Xanthine oxidase preparations that generated hydroxyl radical had greater iron associated with them, suggesting that adventitious iron was a possible contributing factor. Consistent with this hypothesis, addition of H2O2, in the absence of xanthine, to "high iron" xanthine oxidase preparations generated hydroxyl radical. Substitution of a different iron chelator, diethylenetriaminepentaacetic acid for deferoxamine, or preincubation of high iron xanthine oxidase preparations with chelating resin, or overnight dialysis of the enzyme against deferoxamine decreased or eliminated hydroxyl radical generation without altering the rate of superoxide production. Therefore, hydroxyl radical does not appear to be a product of the oxidation of xanthine by xanthine oxidase. However, commercial xanthine oxidase preparations may contain adventitious iron bound to the enzyme, which can catalyze hydroxyl radical formation from hydrogen peroxide.
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PMID:Hydroxyl radical is not a product of the reaction of xanthine oxidase and xanthine. The confounding problem of adventitious iron bound to xanthine oxidase. 217 Mar 83

Ischemia-reperfusion heart cell injury may be mediated, at least in part, through the generation of oxy radicals. Therefore, mechanisms of action of two oxidants on a membrane model, partially purified Na,K,ATPase, were investigated. Effects of H2O2, an oxygen intermediate postulated to play a primary role in reperfusion injury, on the function of the enzyme were time-dependent and potentiated by Fe ions. The inhibition of enzyme activity was prevented by chelators, but not by hydroxyl radical scavengers. The results support the view that the possible mode of enzyme modification involves H2O2-derived, Fe ion-catalyzed, localized ("site-specific") hydroxyl radical formation. The action of hypochlorous acid (HOCl), a powerful oxidant postulated to be produced by activated neutrophils, was quantitatively similar to that of H2O2 plus Fe ions in causing enzyme dysfunction. This is partly because relatively large doses of oxidants were required, due to the presence of physiological anti-oxidant defense mechanisms in the membrane. Although a combination of deferoxamine (Fe ion chelator) and dithiothreitol (DTT) (sulfhydryl reducing agent) was most effective in preventing the enzyme modification, once enzyme inactivation by oxidants is in progress, deferoxamine plus DTT could only arrest further deterioration of the enzyme function. Therefore, the oxidant-induced change in membrane dysfunction advances with time; the advance can be stalled, but the enzyme activity cannot be restored to normal.
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PMID:Effect of oxidants on Na,K,ATPase and its reversal. 217 45

The recovery of both contractile performance and metabolic response of rat heart following 1 h of ischemia after equilibration with glucose + insulin (glucose-ischemia) or with pyruvate (pyruvate-ischemia), was tested in normoxic reperfusion in the presence of glucose + insulin, pyruvate, lactate or acetate. In glucose-ischemia only the reperfusion with pyruvate results in a complete recovery of the contractile force (left ventricular pressure, LVP) (170%) and good recovery of high energy phosphate compounds. Lower LVP and tissue energy charge were found in glucose reperfusion and even less in lactate and acetate reperfusion. Disappearance of the IMP accumulated during ischemia is evident only in the pyruvate reperfusion indicating a higher metabolic recovery. On the contrary in pyruvate-ischemia all types of reperfusion tested were effective in reactivating the contractile force (although acetate to a lesser extent); the contractile activity was accompanied by a good recovery of phosphocreatine, ATP, energy charge and by the decrease of IMP. Large decreases of adenine nucleotides and NADP and lower decreases of NAD are observed during ischemia/reperfusion in both systems. Pyruvate-ischemia is quite similar to, if not worse than glucose-ischemia, for all the metabolic parameters considered, but not worse for the possibility of recovery. Some specific effect of pyruvate should be exerted during the ischemic phase. The mechanism of pyruvate protection is discussed in relationship to: (i) the possible activation of pyruvate dehydrogenase, (ii) the activation of NADPH-dependent peroxide scavenging systems, (iii) the direct scavenging action of pyruvate on H2O2.
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PMID:The protective action of pyruvate on recovery of ischemic rat heart: comparison with other oxidizable substrates. 218 87

Efforts to reduce reperfusion injury have focused on exogenous therapies; however, endogenous attenuation of reperfusion injury can be induced by a single sublethal dose of endotoxin (ETX) prior to ischemia. The purposes of this study were to investigate (i) the early neutrophil-endothelial (PMN-EC) adherence, (ii) the associated myocardial oxidant stress, (iii) the relationship of oxidant stress to antioxidant enzyme activity, and (iv) the correlation of increased antioxidant enzyme activity to myocardial recovery following ischemia/reperfusion (I-R) injury at 36 hr. Rats were administered a sublethal dose (2% of LD50) of endotoxin (500 micrograms/kg, ip, Salmonella typhimurium). At 6 hr, myocardial neutrophil accumulation (histology), hydrogen peroxide (H2O2) levels, and myocardial tissue glutathione (glutathione and oxidized glutathione) levels were determined. At 24 hr myocardial tissue glutathione levels and catalase (CAT) activity were assayed. At 36 hr, myocardial tissue superoxide dismutase, glutathione peroxidase, glutathione reductase, catalase, and glucose-6-phosphate dehydrogenase (G-6-PD) were assayed. At 36 hr, hearts were subjected to a standard (20 min, global, 37 degrees C) ischemic insult followed by reperfusion. At 40 min of reperfusion, ventricular function was assessed (ventricular balloon; ventricular developed pressure +dP/dt, and -dP/dt).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Induction of endogenous tissue antioxidant enzyme activity attenuates myocardial reperfusion injury. 219 33

We occluded the left anterior descending coronary artery of anesthetized, open-chest dogs, for 1 or 2 h. Some hearts were reperfused for 1 h after 1 h of ischemia. We isolated mitochondria from the central ischemic zone (CIZ) and a surrounding nonischemic zone (NIZ) of the left ventricle, and assayed H2O2 production using a horseradish peroxidase-dual wavelength spectrophotometric technique. Mitochondria, studied in the absence of exogenous respiratory chain inhibitors, generated H2O2 during State 4 respiration with succinate as the substrate. NIZ mitochondria in all groups produced ca. 1.5 nmols H2O2/min/mg protein (no significant differences between groups). The State 4 O2 consumption rates of NIZ mitochondria from hearts subjected to 1 h ischemia plus reperfusion, or 2 h of ischemia (ca. 30 nmols/min/mg) were significantly higher than that of NIZ mitochondria of hearts subjected to only 1 h of ischemia (23 nmols/min/mg). Thus, the ratio between H2O2 produced and State 4 O2 consumption fell from 6.5% to 5%. Mitochondria from all CIZ samples had State 4 O2 consumption rates that were not different from corresponding NIZ values. However CIZ mitochondria of hearts subjected to 1 h ischemia without reperfusion produced less H2O2 (1.1 +/- 0.1 nmols/min/mg), and had a slightly reduced H2O2/O2 ratio (4.4 +/- 0.7%), compared with their NIZ samples (1.5 +/- 0.1 nmols/min/mg; 5.3%). Reperfusion after 1 h of ischemia abolished these regional differences. The CIZ mitochondria from hearts subjected to 2 h ischemia produced only 0.75 +/- 0.22 nmols H2O2/min/mg (2.5% of State 4 O2 consumption). These values were 50% of corresponding NIZ values, and were significantly less than for any other group or tissue region. If similar phenomena occur in conscious animals subjected to incomplete regional ischemia, especially of relatively brief duration or if accompanied by reduced intracellular defenses against oxidants such as H2O2, they suggest that mitochondria persist as H2O2 sources and so may contribute to the oxidant load and myocardial dysfunction.
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PMID:Hydrogen peroxide generation by mitochondria isolated from regionally ischemic and nonischemic dog myocardium. 224 65

In the presence of O2, Fe(III) or Cu(II), and an appropriate electron donor, a number of enzymic and nonenzymic oxygen free radical-generating systems are able to catalyze the oxidative modification of proteins. Whereas random, global modification of many different amino acid residues and extensive fragmentation occurs when proteins are exposed to oxygen radicals produced by high energy radiation, only one or a few amino acid residues are modified and relatively little peptide bond cleavage occurs when proteins are exposed to metal-catalyzed oxidation (MCO) systems. The available evidence indicates that the MCO systems catalyze the reduction of Fe(III) to Fe(II) and of O2 to H2O2 and that these products react at metal-binding sites on the protein to produce active oxygen (free radical?) species (viz; OH, ferryl ion) which attack the side chains of amino acid residues at the metal-binding site. Among other modifications, carbonyl derivatives of some amino acid residues are formed; prolyl and arginyl residues are converted to glutamylsemialdehyde residues, lysyl residues are likely converted to 2-amino-adipylsemialdehyde residues; histidyl residues are converted to asparagine and/or aspartyl residues; prolyl residues are converted to glutamyl or pyroglutamyl residues; methionyl residues are converted to methionylsulfoxide residues; and cysteinyl residues to mixed-disulfide derivatives. The biological significance of these metal ion-catalyzed reactions is highlighted by the demonstration: (i) that oxidative modification of proteins "marks" them for degradation by most common proteases and especially by the cytosolic multicatalytic proteinase from mammalian cells; (ii) protein oxidation contributes substantially to the intracellular pool of catalytically inactive and less active, thermolabile forms of enzymes which accumulate in cells during aging, oxidative stress, and in various pathological states, including premature aging diseases (progeria, Werner's syndrome), muscular dystrophy, rheumatoid arthritis, cataractogenesis, chronic alcohol toxicity, pulmonary emphysema, and during tissue injury provoked by ischemia-reperfusion. Furthermore, the metal ion-catalyzed protein oxidation is the basis of biological mechanisms for regulating changes in enzyme levels in response to shifts from anaerobic to aerobic metabolism, and probably from one nutritional state to another. It is also involved in the killing of bacteria by neutrophils and in the loss of neutrophil function following repeated cycles of respiratory burst activity.
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PMID:Metal ion-catalyzed oxidation of proteins: biochemical mechanism and biological consequences. 228 87

Since hydrogen peroxide (H2O2) can react with ferrous iron (FE++) to form the more toxic hydroxyl radical (OH) in vitro, and since H2O2 is generated brain xanthine oxidase (XO) during ischemia/reperfusion (I/R), we hypothesized that gerbils depleted of iron by dietary restriction or treated with iron chelators would be less susceptible to I/R injury. We found that gerbils fed a low iron diet for 8 weeks had decreased brain and serum iron levels, less neurologic deficits, and decreased brain edema after temporary unilateral carotid ligation (ischemia) and then reperfusion than gerbils fed a control standard iron diet. In addition, brains from gerbils treated with iron-free deferoxamine (an iron chelator), but not iron-loaded deferoxamine, had decreased (P less than .05) brain edema following ischemia and reperfusion. The results indicate that iron may contribute to cerebral ischemia/reperfusion damage.
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PMID:Iron depletion or chelation reduces ischemia/reperfusion-induced edema in gerbil brains. 230 92

Hydrogen peroxide (H2O2) has been implicated in cardiac damage due to ischemia and reperfusion. We adapted an electron microscopic, histochemical method for demonstrating H2O2 produced by isolated cells to isolated, buffer-perfused rabbit hearts. The method involves formation of an electron-dense precipitate when H2O2 reacts with cerium chloride (CeCl3). We perfused hearts retrograde via the aorta with well-oxygenated bicarbonate-buffered solution, followed by one in which bicarbonate was replaced with imidazole (IPSS) to prevent precipitation of bicarbonate and CeCl3. Some hearts were made globally ischemic (30 min, 37 degrees C), reperfused 5 min with well-oxygenated IPSS containing 1 mM CeCl3, then processed for electron microscopy. Others were perfused with IPSS containing catalase (300 U/ml) or albumin before ischemia and upon reperfusion, followed by CeCl3 administration. Nonischemic control hearts perfused with IPSS (+/- catalase) were also studied. Electron micrographs were assessed visually and by computer for precipitate localization and amount. There was abundant precipitate on the luminal face of the coronary vascular endothelium in ischemic-reperfused, cerium-treated hearts, including those treated with albumin. There was significantly less in reperfused catalase-treated or nonischemic control hearts. X-ray microbeam analysis of the endothelial precipitate indicated the presence of Ce. This appears to be the first visual demonstration of a CeCl3-H2O2-dependent reaction product in intact isolated ischemic hearts. The data indicate that at the time of reperfusion some H2O2 is accessible to the vascular space, and that its amount can be reduced by perfused catalase. Further modifications this technique may be useful for assessing the sites and pathways by which H2O2 is generated by hearts or other buffer-perfused organs subjected to stresses such as ischemia or hypoxia.
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PMID:Cerium chloride as a histochemical marker of hydrogen peroxide in reperfused ischemic hearts. 232 33


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