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)

To determine the mechanisms whereby complement-activated granulocytes induce microvascular dysfunction in skeletal muscle, we examined the effect of antineutrophil serum (ANS), IB4 (a monoclonal antibody that inhibits CD18-dependent neutrophil adherence), xanthine oxidase inhibition or inactivation, deferoxamine, and catalase on the increase in canine gracilis muscle microvascular permeability induced by intravascular administration of zymosan-activated plasma (ZAP). Changes in vascular permeability were assessed by measurement of the solvent drag reflection coefficient (sigma) for total plasma proteins, and the extent of neutrophil infiltration was estimated by assessing muscle myeloperoxidase activity. ZAP infusion was associated with a marked increase in vascular permeability compared with control muscles that received no treatment or to muscles treated with zymosan heat-inactivated plasma (ZIP) (sigma = 0.51 +/- 0.04, 0.89 +/- 0.02, and 0.90 +/- 0.01, respectively). Estimates of sigma in animals rendered neutropenic with ANS, or treated with IB4, deferoxamine, or catalase before ZAP infusion were not significantly different from values obtained in control or ZIP-treated muscles (sigma = 0.96 +/- 0.02, 0.88 +/- 0.03, 0.85 +/- 0.02, and 0.79 +/- 0.01, respectively). However, xanthine oxidase inactivation or inhibition provided no protection from this ZAP-induced microvascular dysfunction (sigma = 0.58 +/- 0.02 and 0.58 +/- 0.01, respectively). In addition, neutropenia and inhibition of neutrophil adherence also prevented ZAP-induced increases in vascular resistance and tissue neutrophil infiltration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxidant-mediated, CD18-dependent microvascular dysfunction induced by complement-activated granulocytes. 167 94

We investigated the interaction between activated cat polymorphonuclear neutrophils (PMNs) and coronary vascular endothelial cells in vitro. It was shown that 1) 90 minutes of low-flow perfusion without reperfusion had no deleterious effects on endothelium-dependent vasodilation, whereas 90 minutes of low-flow perfusion and 20 minutes of reperfusion with a blood cell-free solution induced a 20-25% endothelial dysfunction; 2) activated PMNs produced endothelium-dependent vasoconstriction in coronary artery rings isolated from cat hearts undergoing 90 minutes of low-flow perfusion and 20 minutes of reperfusion with a blood cell-free Krebs-Henseleit solution; 3) addition of the superoxide free radical scavenger, superoxide dismutase (150 micrograms/ml), or an antibody directed against CD18 of PMN adherence glycoprotein complex (MAbR15.7, 20 micrograms/ml) attenuated PMN-induced vasoconstriction significantly, but addition of a hydroxyl radical scavenger [N-(2-mercaptopropionyl)-glycine, 150 micrograms/ml], a cyclooxygenase inhibitor, or a lipoxygenase inhibitor had no protective effect; 4) exposure of rings to a superoxide radical-generating system (i.e., xanthine and xanthine oxidase) produced significant vasoconstriction that was similar to that observed with activated PMNs and was inhibited by superoxide dismutase; and 5) activated PMNs produced a marked coronary endothelial dysfunction characterized by a decreased response to the endothelium-dependent vasodilators acetylcholine and A23187. Addition of either superoxide dismutase or MAbR15.7 protected against endothelial dysfunction. These results indicate that activated PMNs produce significant vasoconstriction and endothelial dysfunction in coronary arteries isolated from low-flow perfusion-reperfused hearts. These effects appear to be mediated primarily by superoxide radicals generated by activated PMNs that either inactivate or inhibit the synthesis and release of endothelium-derived relaxing factor. We conclude that activated PMNs are able to induce endothelial dysfunction by releasing free radicals and possibly other substances.
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PMID:Neutrophil-mediated vasoconstriction and endothelial dysfunction in low-flow perfusion-reperfused cat coronary artery. 205 45

Recent studies indicate that polymorphonuclear neutrophils (PMNs) infiltrate the intestinal mucosa during ischemia and after reperfusion. To determine whether PMNs mediate the increased microvascular permeability produced by ischemia-reperfusion (I/R) we treated cats with either saline, antineutrophil serum (ANS), or a monoclonal antibody specific for the beta-chain of the CD18 complex (MoAb 60.3) that prevents neutrophil adherence and extravasation. Intestinal microvascular permeability to plasma proteins was measured in control preparations (0.08 +/- 0.007), in preparations subjected to 1 h of ischemia then reperfusion (I/R, 0.32 +/- 0.02), I/R preparations treated with ANS (0.13 +/- 0.01), and I/R preparations treated with MoAb (0.12 +/- 0.003). Our results indicate that both PMN depletion (to less than 10% control) and prevention of PMN adherence significantly attenuate the increased microvascular permeability induced by I/R. These findings, coupled to previous results obtained from this model, support the hypothesis that neutrophils, which accumulate in the mucosa in response to xanthine oxidase activation, mediate the oxyradical-dependent injury produced by reperfusion of the ischemic bowel.
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PMID:Role of neutrophils in ischemia-reperfusion-induced microvascular injury. 363 3

We compared the effects of phorbol 12-myristate 13-acetate (PMA) and thrombin with those of nonlytic concentrations of reactive oxygen species (ROS) generated by hypoxanthine (HX)-xanthine oxidase (XO) on the adhesion properties of human umbilical cord vein endothelial cells (HUVEC) to resting polymorphonuclear neutrophils (PMN). PMN adherence to HX-XO-treated HUVEC was increased approximately twofold to 2.5-fold relative to untreated HUVEC, both immediately and after 2 hours. It was not additive to that induced by PMA or thrombin stimulation of HUVEC. ROS-induced adherence was not due to platelet-activating factor (PAF) or P-selectin expression, as it was neither antagonized by BN52021 (PAF receptor antagonist) nor inhibited by anti-P-selectin monoclonal antibody (MoAb), contrary to the increased adhesion of PMA- and thrombin-stimulated HUVEC. PMN preincubated with mannose-6-P or N-acetylneuraminic acid (sialic acid), but not mannose or galactose-6-P, showed reduced adherence to ROS-treated HUVEC, suggesting that carbohydrate molecules were expressed on the latter and served as the ligand for the PMN L-selectin. Intercellular adhesion molecule (ICAM-1), constitutively present on the surface of resting HUVEC, was involved in the PMN adherence to ROS-treated HUVEC, since this adherence was inhibited by anti-ICAM-1, anti-CD11a, anti-CD11b, and anti-CD18 MoAbs. A non-CD18, non-ICAM-1-dependent mechanism is also involved in this adherence, since effects of these MoAbs were not additive; moreover, combinations of anti-CD18 and anti-ICAM-1 MoAbs with mannose-6-P and sialic acid completely inhibited PMN adherence. The increased binding of PMN to HX-XO-exposed HUVEC observed here involved IC-AM-1, but was independent of its upregulation, and another non-ICAM-1-dependent mechanism, in which carbohydrates expressed on HUVEC recognize L-selectin on PMN.
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PMID:Reactive oxygen species rapidly increase endothelial ICAM-1 ability to bind neutrophils without detectable upregulation. 751 10

The effect of exposure of PMN to extracellular oxidants on the PMN oxidative burst on the subcellular location of CD64 (Fc gamma RI), CD32w (Fc gamma RII), CD16 (Fc gamma RIII), CD35 (complement receptor 1), and CD11b/CD18 (complement receptor 5) was studied. Incubation of PMN with glucose/glucose oxidase resulted in an intracellular shift in Fc gamma receptors from secretory vesicles to plasma membrane fractions while reducing complement receptor expression in plasma membrane fractions. Incubation of PMN with xanthine/xanthine oxidase resulted in an intracellular shift in Fc gamma receptors from specific granules to secretory vesicles. Incubation of PMN with xanthine/xanthine oxidase resulted in an intracellular shift from secretory vesicles to plasma membrane fractions for CD35 and from secretory vesicles and specific granules to plasma membrane fractions for CD11b/CD18. The effects of glucose/glucose oxidase and xanthine/xanthine oxidase on receptor redistribution were blocked by catalase and catalase and superoxide dismutase, respectively. Cytoskeleton stabilization with phalloidin and Taxol blocked the effect of glucose/glucose oxidase and xanthine/xanthine oxidase on Fc gamma and complement receptor relocation. Both H-7 and staurosporine abrogated the effect of glucose/glucose oxidase and xanthine/xanthine oxidase on Fc gamma receptor relocation, while genistein abrogated the effect of glucose/glucose oxidase and xanthine/xanthine oxidase on complement receptor relocation. Increases in CD64, CD32w, CD16, CD35, and CD11b/CD18 expression associated with plasma membrane fractions corresponded to functional increases in monomeric IgG binding, E-IV.3, (sheep erythrocyte opsonized with monoclonal antibody IV.3 directed against CD32w) E-Con A, EC3b, and EC3bi rosetting. These studies indicate that exposure of PMN to extracellular oxidants does not occur as an isolated event but results in a coordinated subcellular relocation of opsonic receptors which corresponds to changes in PMN function.
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PMID:Subcellular location of neutrophil opsonic receptors is altered by exogenous reactive oxygen species. 758 83

To clarify the mechanism of vascular endothelial cell injury induced by activated leukocytes, we examined the effects of antibodies against adhesion molecules on the injury and on the intracellular peroxide level in endothelial cells. Treatment of leukocytes with phorbol myristate acetate (PMA) caused significant increases in the expression of adhesion molecules, CD11a, CD11b, CD11c, and CD18, on the surface of the leukocytes. Monoclonal antibodies against CD11a, CD11b and CD18, and ICAM-1, an adhesion molecule in the side of endothelial cells, abolished significantly the endothelial cell injury induced by PMA-stimulated leukocytes. These antibodies affected neither the production of active oxygen species by the leukocytes nor the rate of adhesion of leukocytes to endothelial cells. These data indicated that adhesion through CD11/CD18-ICAM-1 is necessary for leukocytes to induce endothelial cell injury. To investigate the phenomenon that occurred after the specific adhesion, the change in the intracellular peroxide level was measured using fluorescence of 2,7-dichlorofluorescein diacetate. The fluorescence intensity of the endothelial cells exposed to PMA-stimulated leukocytes increased with time up to 15 minutes, although neither PMA alone nor unstimulated leukocytes alone showed such activity at all. The monoclonal antibodies against CD11a, CD11b, CD18, and ICAM-1 also showed inhibitory effects on the increase in intracellular fluorescence intensity of the endothelial cells exposed to PMA-stimulated leukocytes. In contrast, CD11c could block neither the cell injury nor the increase in intracellular fluorescence in endothelial cells exposed to PMA-stimulated leukocytes. Thus, the addition of PMA-stimulated leukocytes to an endothelial cell monolayer caused a significant increase in the intracellular peroxide level in the endothelial cells after 15 minutes and severe endothelial cell injury after 5 hours. Both the early increase in peroxide production and late cell lysis were abolished by specific antibodies against CD11a, CD11b, CD18, and ICAM-1, but not CD11c. There seems to be a close relationship between the early and late events. Both events were only partially blocked by catalase (approximately 40%), but almost completely abolished by deferoxamine, a chelator of ferrous ions, suggesting that hydroxyl radicals produced in endothelial cells themselves from xanthine oxidase may injure the cells from their inside. Therefore, the effect of allopurinol, a specific inhibitor of xanthine oxidase, was examined. Pretreatment of endothelial cells with allopurinol caused significant but not complete inhibition (approximately 60%) of both the early and the late events, suggesting that influx of hydrogen peroxide may also be important.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Adhesion molecule mediated endothelial cell injury elicited by activated leukocytes. 769 61

We have demonstrated that the endothelial cell-derived superoxide anion is deeply involved in the endothelial cell injury induced by activated neutrophils (Fujita, H., Morita, I. and Murota, S. (1994) Arch. Biochem. Biophys. 309, 62-69). To clarify the mechanism underlying the increase in the endothelial cell-derived superoxide anion induced by activated neutrophils, the conversion of xanthine dehydrogenase (XD) to xanthine oxidase (XO) in cultured endothelial cells isolated from bovine carotid arteries was investigated. Although the endothelial cells expressed both XD and XO activity, the XO activity of unstimulated cells comprised about 12% of the total (XD + XO) activity. When endothelial cells were exposed to neutrophils activated with phorbol 12-myristate 13-acetate (PMA), XO activity rapidly increased about 3-fold over the control. Whereas treatment of endothelial cells with PMA alone or unstimulated neutrophils alone did not increase the XO activity at all. The increase in XO activity in endothelial cells was also observed on the treatment of the cells with neutrophils activated with leukotriene B4 or thrombin. To determine whether or not proteases released from activated neutrophils are involved in the increased conversion of XD to XO in endothelial cells, the effects of the elastase specific inhibitor, ONO-5046, and protease inhibitors, such as aprotinin, gabexate mesylate and urinastatin, were examined. However, these protease inhibitors did not suppress the conversion of XD to XO induced by PMA-activated neutrophils. Moreover, the treatment of endothelial cells with purified human neutrophil elastase and H2O2 also did not affect the conversion at all. In contrast, monoclonal antibodies against CD11a and CD18 significantly inhibited the increased conversion of XD to XO induced by PMA-activated neutrophils. Moreover, tyrosine kinase inhibitors such as staurosporin and herbimysine also inhibited the increased conversion of XD to XO induced by PMA-activated neutrophils. These results indicate that the adhesion of activated neutrophils to endothelial cells via CD11a/CD18-ICAM-1 is involved in the conversion of XD to XO in endothelial cells induced by activated neutrophils.
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PMID:Conversion of xanthine dehydrogenase to xanthine oxidase in bovine carotid artery endothelial cells induced by activated neutrophils: involvement of adhesion molecules. 769 38

To clarify the mechanism of vascular endothelial cell injury induced by activated leukocytes, we investigated the intracellular peroxide level in endothelial cells and the effect of antibodies against adhesion molecules on it. The change in the intracellular peroxide level was measured using the fluorescence of 2,7-dichlorofluorescein diacetate. The fluorescence intensity of the endothelial cells exposed to PMA-stimulated leukocytes increased with time up to 15 min, although neither PMA alone nor unstimulated leukocytes alone showed such increase at all. When catalase, which degrades hydrogen peroxide produced by leukocytes, was added to this system, the peroxide level in endothelial cells decreased significantly. On the other hand, pretreatment of endothelial cells with allopurinol, a specific inhibitor of xanthine oxidase, also caused significant inhibition of the increase in peroxide level in the endothelial cells. The monoclonal antibodies against CD11a, CD11b, CD18, and ICAM-1 showed almost complete inhibition of the increase in intracellular peroxide levels of the endothelial cells exposed to PMA-stimulated leukocytes. In contrast, the anti-CD11c antibody could not block the increase in fluorescence intensity due to peroxides. The endothelial injury elicited by activated leukocytes was partially inhibited by catalase alone (approximately 40%) and allopurinol alone (approximately 60%), but it was completely inhibited by the concomitant treatment of endothelial cells with catalase and allopurinol. The specific antibodies against such adhesion molecules as ICAM-1 and CD11/CD18 except CD11c/CD18 also blocked the endothelial cell injury significantly. These data suggest that there is a good correlation between the early increase in intracellular peroxides and endothelial cell injury elicited by PMA-stimulated leukocytes and that the adhesion of activated leukocytes to endothelial cells via CD11a/CD18-ICAM-1 must be deeply involved in these phenomena.
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PMID:A possible mechanism for vascular endothelial cell injury elicited by activated leukocytes: a significant involvement of adhesion molecules, CD11/CD18, and ICAM-1. 790 37

Intravital microscopy was used to monitor leukocyte adherence, flux, rolling velocity, and number of rolling leukocytes (flux/velocity) in venules 25-40 microns in diameter. The superoxide-generating system, hypoxanthine and xanthine oxidase (HX/XO), was infused into the mesenteric circulation in untreated animals or in animals pretreated with either catalase (a hydrogen peroxide scavenger), WEB-2086 [a platelet-activating factor (PAF) receptor antagonist], or monoclonal antibodies directed against adhesion molecules CD18 (CL26) or P-selectin (PB1.3). HX/XO infusion caused a decrease in leukocyte rolling velocity and an increase in the number of rolling and adherent leukocytes. WEB-2086 prevented the increase in leukocyte adhesion and markedly increased leukocyte rolling velocity. PB1.3 abolished the HX/XO-associated rise in the flux of rolling leukocytes and proportionally decreased the number of adherent leukocytes. CL26 abolished HX/XO-induced leukocyte adhesion and also reduced the number of rolling leukocytes. In conclusion, P-selectin mediates the increased leukocyte flux induced by superoxide, whereas PAF and CD18 modulate leukocyte adhesion. PAF also reduces leukocyte rolling velocity, possibly as a result of CD18, but not P-selectin.
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PMID:Molecular mechanisms involved in superoxide-induced leukocyte-endothelial cell interactions in vivo. 790 74

Addition of PMA (phorbol myristate acetate)-stimulated neutrophils to an endothelial cell monolayer caused a significant increase in the intracellular peroxide level of the endothelial cells after 15 minutes and endothelial cell injury after 5 hours. Both the early and the late events were abolished in the presence of specific antibodies against CD (cluster of differentiation) 11a, CD11b, CD18 and ICAM (intercellular adhesion molecule) 1, but not CD11c. These antibodies affected neither the production of active oxygen species by the neutrophils nor the rate of adhesion of neutrophils to endothelial cells. Pretreatment of endothelial cells with allopurinol caused significant inhibition of both the early and the late events, suggesting that the binding of adhesion molecules may trigger the activation of XO (xanthine oxidase) of endothelial cells, and have the cells produce more hydrogen peroxide and ferrous ions, followed by producing more hydrogen peroxide. The hydrogen peroxide produced by endothelial cells themselves and by neutrophils may be converted to hydroxyl radicals by ferrous ions, which may cause lethal cell damage. Examination of XO activity in endothelial cells showed that the enzyme activity increased double within 15 minutes after the addition of PMA activated neutrophils. Monoclonal antibodies against CD11a and CD18 significantly inhibited the increased conversion of XD (xanthine dehydrogenase) to XO induced by PMA-activated neutrophils. Moreover, tyrosine kinase inhibitors also inhibited the increased conversion of XD to XO. These results indicate that the adhesion of activated neutrophils to endothelial cells via CD11a/CD18-ICAM-1 is involved in the conversion of XD to XO in endothelial cells, which results in endothelial cell injury.
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PMID:Cell adhesion molecule mediates endothelial cell injury caused by activated neutrophils. 889 63


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