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)

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

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

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

Reactive oxygen metabolites (ROMs) have been implicated in the pathogenesis of the inflammatory response to ischemia/reperfusion (I/R), which is exacerbated in diabetes. This study revealed an increased (P < 0.01) ROMs production in mesenteric tissue (measured using the oxidant-sensitive fluorochrome dihydrorhodamine 123) after I/R in control and diabetic rats, with larger increments (P <0.0001) observed in the latter group, that was associated with an increased inflammatory response measured by intravital microscopy. Either xanthine oxidase inhibition, superoxide scavenging, ICAM-1 immunoneutralization, or blockade of platelet-activating factor or leukotrienes effectively reduced leukocyte recruitment and ROMs production in control and diabetic rats. Moreover, neutrophils from diabetic rats showed an enhanced production of ROMs in vitro in basal and stimulated conditions. We conclude that the oxidative stress during reperfusion is markedly enhanced in diabetes and this appears to result from increased leukocyte recruitment and a higher capacity of diabetic leukocytes to generate ROMs in response to stimulation.
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PMID:Reperfusion-induced oxidative stress in diabetes: cellular and enzymatic sources. 1041 Sep 90

Using a retrograde infusion sodium taurocholate pancreatitis model in the rat treatment with oxygen radical scavengers or monoclonal anti-ICAM-1 antibody decreased tissue damage and polymorphonuclear leukocytes (PMN) infiltration. Scavengers or anti-ICAM-1 treatment attenuated the activating capacity of blood PMNs following zymosan stimulation. The local production of oxygen free radicals in the pancreas by systemic infusion of hypoxanthine and regional infusion of xanthine oxidase did not induce acute pancreatitis, although an increase of infiltrating PMNs was observed. Our data suggest that oxygen free radicals and infiltrating PMNs aggravate acute pancreatitis and that both are important mediators of local destruction and systemic activation of PMNs.
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PMID:The role of polymorphonuclear leukocytes and oxygen-derived free radicals in experimental acute pancreatitis: mediators of local destruction and activators of inflammation. 1056 9

This study evaluated the changes in the biomechanical properties of endothelial cells (ECs) induced by neutrophil adhesion and the roles of ICAM-1 and reactive oxygen species (ROS) in modulating these changes. Neutrophil adherence to 24-h TNF-alpha-activated pulmonary microvascular ECs induced an increase in the apparent stiffness of ECs within 2 min, measured with magnetic twisting cytometry. An anti-ICAM-1 Ab blocked the EC stiffening response without inhibiting neutrophil adherence. Moreover, cross-linking ICAM-1 mimicked the stiffening response induced by neutrophils. The neutrophil-induced increase in the apparent stiffness of ECs was inhibited with 1% DMSO (a hydroxyl radical scavenger), allopurinol (a xanthine oxidase inhibitor), or deferoxamine (an iron chelator), suggesting that ROS may be involved in mediating the EC stiffening response. The cellular sources of ROS were determined by measuring the oxidation of dichlorofluorescein. Neutrophil adherence to TNF-alpha-activated ECs induced ROS production only in ECs, and not in neutrophils. This ROS production in ECs was completely prevented by the anti-ICAM-1 Ab and partially inhibited by allopurinol. These results suggest that ICAM-1-mediated signaling events during neutrophil adherence may activate xanthine oxidase, which in turn mediates the ROS production in ECs that leads to stiffening. ROS generated in ECs on neutrophil adherence appear to mediate cytoskeletal remodeling, which may modulate subsequent inflammatory responses.
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PMID:Neutrophil-induced changes in the biomechanical properties of endothelial cells: roles of ICAM-1 and reactive oxygen species. 1084 6

Changes in the cytoskeleton of endothelial cells (ECs) play important roles in mediating neutrophil migration during inflammation. Previous studies demonstrated that neutrophil adherence to TNF-alpha-treated pulmonary microvascular ECs induced cytoskeletal remodeling in ECs that required ICAM-1 ligation and oxidant production and was mimicked by cross-linking ICAM-1. In this study, we examined the role of ICAM-1-induced signaling pathways in mediating actin cytoskeletal remodeling. Cross-linking ICAM-1 induced alterations in ICAM-1 distribution, as well as the filamentous actin rearrangements and stiffening of ECs shown previously. ICAM-1 cross-linking induced phosphorylation of the p38 mitogen-activated protein kinase (MAPK) that was inhibited by allopurinol and also induced an increase in the activity of the p38 MAPK that was inhibited by SB203580. However, SB203580 had no effect on oxidant production in ECs or ICAM-1 clustering. ICAM-1 cross-linking also induced phosphorylation of heat shock protein 27, an actin-binding protein that may be involved in filamentous actin polymerization. The time course of heat shock protein 27 phosphorylation paralleled that of p38 MAPK phosphorylation and was completely inhibited by SB203580. In addition, SB203580 blocked the EC stiffening response induced by either neutrophil adherence or ICAM-1 cross-linking. Moreover, pretreatment of ECs with SB203580 reduced neutrophil migration toward EC junctions. Taken together, these data demonstrate that activation of p38 MAPK, mediated by xanthine oxidase-generated oxidant production, is required for cytoskeletal remodeling in ECs induced by ICAM-1 cross-linking or neutrophil adherence. These cytoskeletal changes in ECs may in turn modulate neutrophil migration toward EC junctions.
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PMID:The p38 mitogen-activated protein kinase mediates cytoskeletal remodeling in pulmonary microvascular endothelial cells upon intracellular adhesion molecule-1 ligation. 1135 48

Endothelial cell ICAM-1 upregulation in response to TNF-alpha is mediated in part by reactive oxygen species (ROS) generated by the endothelial membrane-associated NADPH oxidase and occurs maximally after 4 h as the synthesis of new protein is required. However, thrombin-stimulated P-selectin upregulation is bimodal, the first peak occurring within minutes. We hypothesize that this early peak, which results from the release of preformed P-selectin from within Weibel-Palade bodies, is mediated in part by ROS generated from the endothelial membrane-associated xanthine oxidase. We found that this rapid expression of P-selectin on the surface of endothelial cells was accompanied by qualitatively parallel increases in ROS generation. Both P-selectin expression and ROS generation were inhibited, dose dependently, by the exogenous administration of disparate cell-permeable antioxidants and also by the inhibition of either of the known membrane-associated ROS-generating enzymes NADPH oxidase or xanthine oxidase. This rapid, posttranslational cell signaling response, mediated by ROS generated not only by the classical NADPH oxidase but also by xanthine oxidase, may well represent an important physiological trigger of the microvascular inflammatory response.
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PMID:Rapid upregulation of endothelial P-selectin expression via reactive oxygen species generation. 1238 85


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