Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anisodamine, a Chinese traditional medicine herb, has been used for treatment of adult respiratory distress syndrome effectively, but little is known about its mechanism. We attempted to investigate if anisodamine could protect bovine pulmonary endothelial cell injury induced by exogenous oxygen-free radicals that were generated by xanthine/xanthine oxidase or opsonized zymosan-stimulated polymorphonuclear leukocytes. Results showed that with the addition of xanthine/xanthine oxidase into cultured bovine pulmonary endothelial cells, production of malondialdehyde and release of lactate dehydrogenase in supernatant increased, and synthesis of prostacyclin decreased. Damaged cellular membranes were revealed by scanning electron microscopy. The same was true for the addition of opsonized zymosan-stimulated polymorphonuclear leukocytes. While treatment with anisodamine greatly attenuated all of the above-mentioned parameters, results showed that (1) cultured bovine pulmonary endothelial cells could be damaged by oxygen-free radicals, (2) anisodamine had a protective effect on this injury as effective as that of superoxide dismutase and catalase, and (3) the membrane-stable action might contribute to the mechanism of protective effect against this injury.
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PMID:Protective effect of anisodamine on cultured bovine pulmonary endothelial cell injury induced by oxygen-free radicals. 141 86

Oxygen free radicals (OFR) are thought to mediate ischemia-reperfusion injury to endothelium of heart, lung, brain, liver, and kidney and contribute to development of atherosclerosis, pulmonary O2 toxicity, and adult respiratory distress syndrome. Increased cytosolic free Ca2+ (Cai2+) has been proposed as a mechanism of injury from oxidative stress, yet the pathways by which an increase in Cai2+ may cause OFR-mediated endothelial cell injury remain unknown. Using multiparameter digitized video microscopy and the fluorescent probes, fura-2 acetoxymethyl ester and propidium iodide, we measured Cai2+ and cell viability in human umbilical endothelial cells during oxidative stress with xanthine (50 microM) plus xanthine oxidase (40 mU/ml). Oxidative stress caused a sustained increase in Cai2+ from a resting level of 90-100 nM to near 500 nM, which was preceded by formation of plasma membrane blebs. The increase in Cai2+ was prevented by removal of extracellular Ca2+ (Cao2+). Prevention of the increase in Cai2+ was associated with prolonged cell viability. Readdition of Cao2+ resulted in an immediate large increase in Cai2+ and rapid onset of cell death. The protease inhibitors, leupeptin and pepstatin, delayed the increase in Cai2+ and prolonged cell viability. The results are consistent with the hypothesis that endothelial cell injury due to oxidative stress may be the result of Cai2+ influx and resultant activation of Ca(2+)-dependent proteases.
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PMID:Cytosolic free Ca2+ and proteolysis in lethal oxidative injury in endothelial cells. 195 73

Toxic oxygen metabolites (TOM) have been suggested to be mediators of permeability edema associated with the adult respiratory distress syndrome (ARDS). Because corticosteroids have possible beneficial effects in ARDS, we have examined the effect of methylprednisolone (MP) on TOM-induced lung edema in isolated, plasma-perfused rat lungs. TOM were generated by adding xanthine oxidase (XO) and hypoxanthine (HX) to the perfusate. Microvascular permeability was assessed by fluid filtration rate (FFR). FFR was determined before and 30 min after administration of XO and HX by measuring the weight increase of the lungs for the last 3 min during a standard 5 min elevation of the outlet pressure. MP was administered in two different ways: 1) Added to the perfusate 5 or 60 min before XO and HX (0.1 and 1 mg ml-1), and 2) given as pretreatment to the rats 12 and 2 hr before preparation of the lungs (40 mg kg -1). XO and HX significantly increased FFR compared to lungs perfused with untreated plasma. Pretreatment with MP significantly attenuated the increase in FFR caused by XO and HX. Addition of MP to the perfusate also inhibited the effect of TOM. This latter protection occurred irrespective of when MP was added before XO and HX. However, when the highest dose of MP was added 5 min before XO and HX, there was a loss of the protective effect. In summary, this study provides evidence that MP may directly prevent microvascular injury induced by TOM in isolated perfused rat lungs. The effect was dependent on the dose of MP applied, but not on when MP was administered prior to exposure to TOM.
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PMID:Toxic oxygen metabolites increase microvascular permeability in isolated perfused rat lungs: the effect of methylprednisolone. 206 43

The endothelial cells of pulmonary blood vessel play an significant role in lung vessel permeability, especially in acute lung damage and adult respiratory distress syndrome. In this study, bovine pulmonary endothelial cells were isolated, cultured and identified by means of reverse microscopic, scanning electromicroscopic, transmission electro- microscopic and immunofluorescence microscopic observation. Then they were labeled with 51Cr. Hydrogen peroxide (H2O2), H2O2 with catalase, xanthine oxidase (XO) with hypoxanthine (HX), human neutrophil elastase (HNE), cathepsin-G (C-G) and endotoxin (ET) were incubated with the labeled cells for half hour in various experimental groups respectively. The amount of 51Cr in the suspension released from the damaged cells was counted with r-radiometer. The results show that HNE, ET, H2O2 and superoxide anion (the latter is produced from the reaction between XO and HX) could at some degree damage the membrane of endothelial cells, and the inflammatory mediators of human neutrophils might play an important role in the development of pulmonary edema.
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PMID:[Effect of the products released from the activated human neutrophils and endotoxin on bovine pulmonary endothelial cells]. 208 56

Several experimental and theoretical lines of evidence implicate oxidant mechanisms in the diffuse lung injury which leads to the clinical syndrome called the adult respiratory distress syndrome (ARDS). The fact that the injury is characterized by diffuse lung inflammation and that neutrophils can injure lung cells by producing reactive oxygen species provide all of the events necessary for extracellular oxidant stress as an important mechanism of injury. In experimental models and in the clinical syndrome, biochemical evidence of oxidant injury can be measured in the form of lipid peroxidation products. In some models, antioxidants, even antioxidant enzymes which do not access cell interiors, can protect the lungs from injury. There is also evidence that reactive oxygen species generated within lung cells may provide an additional oxidant mechanism of injury. Gram negative bacterial endotoxin can directly injure lung endothelial cells in culture. This injury is unaffected by superoxide dismutase or catalase (antioxidant enzymes which do not enter cells), but is prevented by several antioxidants which penetrate cells (including dimethyl sulphoxide, dimethyl thiourea and allopurinol). The fact that allopurinol can inhibit direct lung cell injury by endotoxin suggests that xanthine oxidase may be a source of oxidant generation in lung endothelial cells. Current data suggest a two stage oxidant process of lung cell injury where there is both direct injury of the cell by intracellular generation of toxic oxidants and triggering of the inflammatory response. Activated inflammatory cells adherent to lung cells then enhance the injury by the generation and release of extracellular oxidants.
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PMID:Oxidant stress and adult respiratory distress syndrome. 227 7

Pulmonary hypoperfusion/ischemia-reperfusion (I/R) may initiate ARDS (nonhydrostatic pulmonary edema). Endothelial damage via xanthine oxidase (XO)-derived oxygen radicals (O2*) may mediate I/R injury. We previously documented Factor VIII antigen (F8) as a marker for endothelial injury. The purpose of this study was to (1) document I/R-induced nonhydrostatic pulmonary edema, (2) identify whether XO or O2* mediates nonhydrostatic edema, and (3) identify the site of injury (? endothelium). Rat lungs were isolated, ventilated, and perfused (100 min, control, or 40 min at 37 degrees C, I (static vent.), + 60 min, R). Effluent was analyzed for F8 release (ELISA: data relative to control). Tungsten-fed rats had negligible lung XO vs rats fed standard diet (3.6 vs 34.5 mU/g, (P less than 0.05). Catalase (CAT) 50 micrograms/ml) was added to perfusate prior to R. Sectioned lungs were fluorescein anti-F8 photographed (IF) and qualitatively assessed. (Table: see text). We conclude that (1) pulmonary hypoperfusion (I/R) leads to nonhydrostatic pulmonary edema, and (2) the edema results in part from XO-generated O2* directed at the capillary endothelium.
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PMID:Xanthine oxidase-derived oxygen radicals induce pulmonary edema via direct endothelial cell injury. 249 87

In a 1902 American Journal of the Medical Sciences case report, Riesman described "albuminous expectoration" following thoracentesis, a phenomenon that is now recognized as re-expansion pulmonary edema (RPE). Both cellular and biochemical mechanisms that produce lung injury in RPE have been described recently. Pathophysiologically, this unilateral edematous lung injury resembles the adult respiratory distress syndrome (ARDS) because both are characterized by intra-alveolar-activated neutrophils and markedly increased lung capillary permeability. Biochemical mechanisms that operate in RPE are analogous to those in diverse re-oxygenation (reperfusion) injuries that have been described recently in the heart, kidney, brain, and intestine. Re-oxygenated lung tissue appears to produce excess superoxide and other cytotoxic oxygen metabolites, although lung xanthine oxidase, the commonly recognized source of these oxidants, is exceedingly low. Riesman's critical analyses of the re-expansion edema fluid in his case provided an impetus for others to hypothesize that increased permeability pulmonary edema in RPE represented re-oxygenation injury of the lung microvasculature.
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PMID:Re-expansion, re-oxygenation, and rethinking. 266 85

Neutrophil-derived reactive oxygen metabolites have been implicated as one mechanism for the cellular injury in the adult respiratory distress syndrome. Previous studies have demonstrated that alveolar lung fluid of patients with adult respiratory distress syndrome has abnormal composition and surface active properties. To examine the effects of oxygen metabolites on the viability and metabolism of type II alveolar pneumocytes, the cellular source of surfactant, isolated rat type II pneumocytes were exposed to reactive oxygen metabolites generated by the enzymatic action of xanthine oxidase upon hypoxanthine. Utilizing a 51Cr release assay to detect cellular death, we found that oxygen metabolites were lethal to type II cells in a dose-dependent manner. To demonstrate that oxygen metabolites were responsible for the toxicity, we assessed the protective effects of catalase and superoxide dismutase, scavengers of hydrogen peroxide and the superoxide anion, respectively. At a xanthine oxidase concentration of 50 mU/ml, catalase reduced the percentage of 51Cr release from 58.9 +/- 3.1% (SEM) to 7.2 +/- 2.3% (p less than 0.0001), whereas superoxide dismutase was without protection (58.9 +/- 3.1% versus 54.2 +/- 1.8% (p greater than 0.05). To determine whether oxygen metabolites also impair surfactant metabolism, we measured the incorporation of [3H]palmitate into the surfactant component disaturated phosphatidylcholine by type II pneumocytes. We found that sublethal amounts of generated oxygen metabolites caused a progressive decrease in the amount of [3H]palmitate incorporated into disaturated phosphatidylcholine. For example, using a xanthine oxidase concentration of 5 mU/ml (which causes no increased 51Cr release), we found that [3H]palmitate incorporation into disaturated phosphatidylcholine fell from a control level of 3.53 +/- 0.22 X 10(5) to 0.66 +/- 0.10 X 10(5) dpm/10(6) cells/4 hours (p less than 0.0001). Both catalase and superoxide dismutase protected the [3H]palmitate incorporation of oxygen metabolite-exposed type II cells. We conclude that reactive oxygen metabolites are injurious to type II pneumocytes and may result in impaired surfactant synthesis even at sublethal doses. Thus, oxygen metabolites generated by stimulated phagocytic cells may be responsible in part for the decreased surfactant that has been observed in adult respiratory distress syndrome.
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PMID:Effects of oxygen metabolites on rat alveolar type II cell viability and surfactant metabolism. 283 58

Free reactive oxygen species (ROS) are generated during cell respiration and by various metabolic processes, after reoxigenation of infarctions and to a large extent by activated phagocytes. In- and extracellular physiologic radical scavengers control the multiple reactions of ROS to prevent the generation of the highly damaging hydroxyl radical (OH). ROS damage after reoxigenation of an infarct can be reduced by employing the xanthine oxidase inhibitor allopurinol. ROS generated by activated phagocytes are both defensive and noxious. ROS reduction is achieved by applying physiologic radical scavengers as the superoxide dismutase, which are of therapeutic interest for the treatment of inflammatory joint and vascular diseases and the adult respiratory distress syndrome. Known drugs e.g. benzydamine (Tantum) are increasingly recognized to act via ROS mediated mechanisms and a ROS-targeted pharmacological research appears now possible.
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PMID:[Pathophysiology and pharmacology of reactive oxygen species in inflammation]. 361 80

Adult Respiratory Distress Syndrome (ARDS) is a feared complication of trauma or sepsis, characterized by an interstitial and alveolar edema due to increased pulmonary microvascular permeability. In ARDS polymorphonuclear granulocytes (PMN) aggregate and accumulate in the pulmonary microvessels and activation of the complement system, especially C5a, is suggested to be of importance supporting this aggregation. Such complement activated PMN can increase vascular permeability, probably by initiating endothelial cell (EC) damage. Addition of PMN and C5a to cultured EC monolayers in vitro produced both morphological and functional EC damage. A similar EC damage could be reproduced in the absence of white cells by exposing EC monolayers to oxygen free radicals induced by xanthine and xanthine oxidase or hydrogen peroxide. High dose corticosteroid (HDC) administration has been advocated in shock and ARDS and it has been experimentally demonstrated that methylprednisolone or hydrocortisone at a concentration corresponding approximately to a dose of 30 mg/kg i.v. inhibited both PMN aggregation and adhesion to the endothelium. On the other hand, no effect of HDC on PMN thromboxane synthesis or cell membrane morphology alterations was found. It has been suggested that HDC increases PMN hydrophobicity and thus reduces the tendency of the white cells to adhere to the endothelium of the microvasculature. Furthermore, it has been demonstrated that HDC can inhibit PMN production of oxygen free radicals. Platelets seem to play a role in ARDS. Serotonin released from platelets increased the cytotoxic effect of PMN on EC more than 100% in vitro, and activated PMN seemed to recruit platelets and release vasoactive substances. On the other hand, platelet serotonin enhanced the adhesion of complement stimulated PMN to EC, thus creating a vicious circle. To conclude, complement activated PMN aggregate and adhere to the pulmonary microvascular EC which are injured by e.g. PMN-generated oxygen free radicals. Platelet aggregation and release of serotonin augments this injury and activated PMN probably stimulate platelet aggregation and release. Agents capable of diminishing PMN activation and aggregation, e.g. HDC, might be of value in attenuating these cell-cell interactions in ARDS.
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PMID:High dose corticosteroids and cell-cell interactions. 391 7


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