Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.13.11.12 (lipoxygenase)
8,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reperfusion of ischemic hindlimbs leads to leukotriene B4 (LTB4) and polymorphonuclear neutrophil (PMN)-dependent lung injury. Pulmonary mast cells are capable of synthesizing LTB4 and are potential mediators of this inflammatory response. This study tests their role in PMN sequestration and pulmonary edema after hindlimb ischemia. Anesthetized, mast cell-sufficient mice (n = 8) or their congeneic mast cell-deficient strain (n = 8) were subjected to 3 hours of hindlimb ischemia. After another 3 hours of reperfusion, plasma LTB4 levels rose to 651 pg/ml, higher than sham ischemic control (n = 8) values of 202 pg/ml (p less than 0.05). At this time there was sequestration of neutrophils in the pulmonary microcirculation (54 PMN/10 high-power fields [HPF]) and an increase in lung wet/dry weight ratio (W/D) of 4.4. Both these values were higher (p less than 0.05) than those in sham ischemic animals that showed sequestration of 18 PMN/10 HPF and a lung W/D of 3.1. In contrast, mast cell-deficient mice showed an attenuation of ischemia- and reperfusion-induced rise in plasma LTB4 (507 pg/ml), fewer sequestered neutrophils (34 PMNs/10 HPF), and a reduction in lung W/D to 3.9 (all p less than 0.05). To test the role of lung LTB4 in determining PMN sequestration, rats (n = 78) were subjected to 3 hours of hindlimb ischemia. After 3 hours of reperfusion, plasma and bronchoalveolar lavage (BAL) LTB4 concentrations rose to 956 and 211 pg/ml, respectively--higher than sham values of 460 and 121 pg/ml (both p less than 0.05). After 4 hours, plasma LTB4 levels had returned to baseline, whereas BAL LTB4 had increased further to 658 pg/ml, indicating lung origin. Treatment of other rats by localized lung lavage of the lipoxygenase inhibitor diethylcarbamazine (80 mg/kg in 0.1 ml twice) prevented the ischemia- and reperfusion-induced rise in BAL LTB4 (267 pg/ml) and limited local neutrophil sequestration (from 51 PMN/10 HPF after saline aspiration to 36 PMN/10 HPF) and lung W/D (from 4.5 to 4.1) (all p less than 0.05). The data indicate that after hindlimb ischemia pulmonary mast cells and localized LTB4 synthesis mediate, in part, the lung inflammatory response.
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PMID:Mast cells and leukotrienes mediate neutrophil sequestration and lung edema after remote ischemia in rodents. 132 74

Prostaglandin E2 (PGE2) and leukotriene C4 (LTC4) are the metabolites of arachidonic acid (AA) that increase in forebrain following global ischemia and reperfusion. These mediators are highly potent vasoconstrictors of cerebral arteries leading to enhanced vascular permeability that induces the formation of vasogenic edema. In this study, after developing an experimental animal model simulating the concept of ischemic penumbra in the rat, the levels of PGE2 and LTC4 produced in the forebrain were measured and the effects of these mediators in short duration and prolonged reperfusion were investigated and then correlated with neuropathological findings. We found statistically significant reduction both in PGE2 and LTC4-like activities after just 10 min ischemia (p less than 0.05, p less than 0.05). PGE2-like activity significantly increased in the 4th and 60th min of reperfusion (p less than 0.05, p less than 0.05). In the 15th min of reperfusion, PGE2 was found to be significantly reduced (p less than 0.005) that may be due to the formation of free oxygen radicals by activation of PG hydroperoxidase reaction that inhibits PGE2 production in the cyclooxygenase pathway. LTs were not significantly increased in any reperfused group. Inhibition of the lipoxygenase pathway of AA metabolism may occur as a result of 15-HPETE (15-hydroperoxyeicosatetraenoic acid) production. Pathologically, edema and degeneration of brain tissue were seen beginning from the 4th min of reperfusion that reached a peak in the 60th min of reperfusion which is in accordance with biochemical changes in the damaged tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostaglandin E2 and leukotriene C4 levels following different reperfusion periods in rat brain correlated with morphological changes. 140 66

Considerable evidence has accumulated that oxygen free radicals play a major role in ischemic injury, particularly when followed by reperfusion. Few reports have demonstrated the occurrence of oxidative damage during the ischemic period, itself. Our laboratory has demonstrated that events occurring during an ischemic period with adequate oxygen supply can mimic the "oxygen paradox," using lipid peroxidation as an index of oxidative stress and lung edema as an index of tissue injury. The present study compares lipid peroxidation and oxidation of soluble (100,000g supernatant) protein during ischemia and reperfusion in isolated rat lung model perfused with artificial medium and ventilated with varying alveolar oxygen tension. Protein oxidation was determined by a modified dinitrophenylhydrazine (DNPH) method using Sephadex G-25 column chromatography to isolate the DNPH bound proteins. Global ischemia was produced by discontinuing perfusion while ventilation continued with gas mixtures containing 5% CO2 and a fixed oxygen concentration between 0 and 95%. After 1 h ischemia in the isolated rat lung ventilated with 20% oxygen, protein carbonyls and thiobarbituric acid reactive substances (TBARS) increased significantly compared with controls. These changes were more pronounced after 60 min of reperfusion with 95% oxygen in the ventilation gas. With 0% oxygen (95% nitrogen and 5% CO2) content of the ventilating gas during ischemia, TBARS and protein carbonyls remained at the control level. The wet/dry weight ratio showed changes parallel to the indices of tissue oxidation. The presence of 5,8,11,14-eicosatetraynoic, an inhibitor of cyclooxygenase and lipoxygenase pathways, in the perfusate had no effect on the generation of protein carbonyls although inhibition of lipid peroxidation was demonstrated. This implies that the oxidation of soluble protein is not mediated by the eicosanoid metabolic cascade. These data indicate that oxidative processes occur during ischemia and are dependent on the alveolar oxygen concentration. Oxidation of soluble protein can be used as an index of oxidative damage during lung ischemia and reperfusion.
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PMID:Role of oxygen in oxidation of lipid and protein during ischemia/reperfusion in isolated perfused rat lung. 160 29

We characterized the release of arachidonic acid (AA) metabolites in lung effluent following lung ischemia-reperfusion since they may contribute to the pathophysiology of reperfusion lung injury. The left pulmonary artery of rabbits (N = 5) was occluded for 24 hrs with a surgically implanted vascular clip. At 24 hrs, the heart and lungs were removed en bloc and perfused with Ringers-albumin (0.5 gm%) at 60 ml/min while statically inflated with 95% O2-5% CO2. The lipid fraction of the lung effluent was concentrated using the Bligh-Dyer extraction and analyzed by gradient RP-HPLC. Samples obtained in the first minute of reperfusion showed significant increases in LTB4 (+180%), LTC4 (+3600%), 15-HETE (+370%), 5-HPETE (+270%), PGE2 (+140%), 6-keto-PGF1 alpha (+110%) and 12-HHT (+160%) compared to the effluent from the right control lung. The reperfusion-induced increases in LTB4, LTC4, LTD4 and 15-HETE were inhibited greater than or equal to 70% by pretreatment with the 5-LO inhibitors L663,536 or L651,392. The increases in lipid concentrations corresponded to significantly increased pulmonary arterial pressure from a baseline value of 9.5 +/- 0.3 to 29.3 +/- 2.9 (cmH2O) during the first min of reperfusion. The pulmonary arterial pressure remained elevated for at least 20 min of reperfusion. Reperfusion also resulted in PMN uptake (assessed by lung tissue myeloperoxidase content) in the reperfused lung versus control lung (25.0 +/- 2.4 vs. 10.5 +/- 2.5 units). The generation of lipoxygenase metabolites during the initial phase of reperfusion may contribute to post-reperfusion PMN uptake and pulmonary vasoconstriction.
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PMID:Generation of 5-lipoxygenase metabolites following pulmonary reperfusion in isolated rabbit lungs. 160 20

This study was designed to clarify the role of leukotrienes (LTs) in gastric injury induced by ischemia-reperfusion in rats. Gastric lesions were produced by clamping of the celiac artery and by reoxygenation following clamping. Administration of AA-861, a lipoxygenase inhibitor, significantly inhibited the increase in the total area of the gastric erosions and the increase in thiobarbituric acid-reactive substances in the gastric mucosa. Administration of YM-638, a peptide LT antagonist, showed protective effects similar to AA-861. These results suggest that the protective effects of AA-861 and YM-638 against ischemia-reperfusion-induced gastric injury were due to their antioxidative action.
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PMID:Role of leukotrienes in gastric mucosal injury induced by ischemia-reperfusion in rats. 162 80

The last two decades of research have produced detailed information not only on how ischemia causes degradation of phospholipids and accumulation of potentially cytotoxic breakdown products of such lipids, but also on reactions elicited by the subsequent conversion of these products into a series of lipids, mediating an array of cellular and intercellular reactions. It now seems clear that PAF, as well as several of the cyclooxygenase and lipoxygenase products of arachidonic acid, can induce changes, particularly in the microvasculature, which jeopardize cell survival in reperfused tissue. It is equally clear that, at least following long periods of ischemia, free radicals generated in reactions that are interacting with those producing eicosanoids and PAF play a similar role. A somewhat more speculative mechanism links sustained activation and membrane translocation of PKC to delayed neuronal death following transient ischemia. All of these interactions underscore the importance of lipolytic events for cell damage in ischemia and other conditions with a compromised cellular energy metabolism.
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PMID:Ischemic brain damage: focus on lipids and lipid mediators. 163 6

Leukotriene B4 (LTB4) is a potent chemotactic compound for neutrophils and is thought to be an important mediator of myocardial ischemia-reflow injury. We have measured LTB4 in rabbit cardiac tissue following ischemia-reflow using a sensitive and specific gas chromatographic-mass spectrometric (GC-MS) assay. The concentration of LTB4 in rabbit myocardium following 45 min ischemia and 3 h reflow was 48.7 +/- 12.5 pg/g, significantly higher than in non-ischemic tissue from the same animal (17.5 +/- 3.9 pg/g). These concentrations were at least an order of magnitude lower than previously reported values assessed by radioimmunoassay (RIA). Compared with the GC-MS method, RIA greatly overestimated LTB4 concentrations in cardiac tissue. The capacity of post-ischemic myocardium to produce lipoxygenase products, LTB4, 5-, 12- and 15-HETEs was also assessed following incubation of myocardium ex vivo with calcium ionophore. In all animals ischemic cardiac tissue produced greater amounts of LTB4, 5-, and 12-HETEs than non-ischemic myocardium and 12-HETE was the major product. Neutrophils that have accumulated in the injured tissue may be a major source of these products. However, in contrast to cardiac tissue, isolated rabbit neutrophils stimulated with A23187 produced 5-HETE as the major product with very little 12-HETE formed. These latter findings suggest that cells other than neutrophils may contribute to the production of lipoxygenase products during myocardial ischemia-reflow injury.
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PMID:Gas chromatographic-mass spectrometric analysis of lipoxygenase products in post-ischemic rabbit myocardium. 165 11

The dramatic increase in the arachidonic acid (AA) level in the brain is a well-known molecular event during cerebral ischemia. As mitochondria are known to be one possible site of the cell damage, the effects of AA on the respiratory activity of rat brain mitochondria were investigated in vitro using an oxygen electrode. In NAD-linked respiration, respiratory control ratio was decreased significantly by AA, with an IC50 of 6.0 microM. AA had the dual effect on mitochondrial respiration, a decrease in state 3 and uncoupled state and an increase in state 4 (i.e., uncoupling) as reported by Hillered and Chan (J. Neurosci. Res. 19, 94-100, 1988). Furthermore, we found that other unsaturated long-chain free fatty acids (C18:1-C18:3, C20:1-C20:5) also showed such a dual effect. Cyclooxygenase metabolites of AA such as prostaglandins (D2, E2, F2 alpha, E1) and thromboxane B2, and lipoxygenase metabolites such as leukotrienes (D4, B4) and 5- or 12-hydroperoxyeicosatetraenoic acid had no significant effect. The inhibition of the uncoupled state by AA was more marked in NAD-linked than that in FAD-linked respiration, while the degree of uncoupling by AA were the same in both respirations. In spectrophotometrical measurement, the reduction of cytochromes and flavo-protein was markedly inhibited by AA in NAD-linked respiration, but not in the FAD-linked one. In addition, the activity of cytochrome c oxidase was scarcely inhibited by AA. These data suggest that AA itself, not its metabolites, may inhibit mitochondrial ATP production during brain ischemia and that AA may act on the site(s) closely related to NAD-linked respiration, but not the FAD-linked one, in addition to its uncoupling effect.
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PMID:A possible mechanism of mitochondrial dysfunction during cerebral ischemia: inhibition of mitochondrial respiration activity by arachidonic acid. 165 47

Derivatives of arachidonic acid have been found to play a role in the reperfusion injury of various tissues. These compounds have a broad spectrum of activity, including modulation of white blood cell response to injured tissue. This study was designed to determine the effect of thromboxane and lipoxygenase derivatives on the local and systemic response to ischemia and reperfusion of skeletal muscle. Fifteen dogs were separated into three groups and subjected to gracilis muscle ischemia followed by 2 hours of reperfusion. One group served as controls, one group was treated with OKY-046 (a thromboxane synthetase inhibitor), and one group was treated with diethylcarbamazine (a lipoxygenase inhibitor). White blood cell activation as measured by superoxide anion production, and eicosanoid levels were measured both in the gracilis venous effluent and central venous circulation. These results were compared to infarct size in the gracilis muscle. OKY-046 significantly reduced thromboxane production in both the central venous (102 +/- 30 to 31 +/- 9 pg/ml, p less than 0.05) and gracilis samples (107 +/- 22 to 25 +/- 6 pg/ml, p less than 0.005). This was accompanied by a reduced white cell activation in the central venous blood (15 +/- 1 to 10 +/- 1 nmol O2-, p less than 0.05), but did not affect infarct size or white cell activation in the gracilis. Conversely, diethylcarbamazine significantly reduced both white cell activation (16 +/- 1 to 10 +/- 1 nmol O2-, p less than 0.005) and infarct size in the gracilis muscles (61.6% +/- 4.5% to 28.5% +/- 8.6%, p less than 0.01), as well as reduced systemic white blood cell activation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The influence of arachidonic acid metabolites on leukocyte activation and skeletal muscle injury after ischemia and reperfusion. 165 4

Although removal of neutrophils from the arterial blood by mechanical filtration has been reported to prevent or reduce the severity of myocardial stunning caused by a 15 minute coronary artery occlusion in the dog, neutrophil filtration does not protect against myocardial dysfunction following a 10-minute occlusion. Nonfilter methods to reduce neutrophil numbers or effectiveness with anti-neutrophil serum, monoclonal anti-CD11b antibodies, or the lipoxygenase inhibitor nafazatrom fail to modify myocardial dysfunction after brief ischemia, even though they effectively reduce infarct size after more prolonged ischemia. The brief durations of ischemia required to produce myocardial stunning but to avoid necrosis are insufficient to produce local activation of complement, formation of chemotactic factors, or activation or infiltration of neutrophils. Microvascular plugging with neutrophils cannot be demonstrated in stunned myocardium, and abnormalities of microvascular function can be dissociated from impaired postischemic myocardial function. Based on the weight of accumulated evidence, neutrophils appear to have no important role in the production of stunned myocardium.
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PMID:Do neutrophils contribute to myocardial stunning? 175 37


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