Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to determine if the bronchoconstriction and airway hyperresponsiveness (AHR) resulting from aerosolized xanthine (x; 0.1%)-xanthine oxidase (xo; 4.1 U) and the subsequent production of oxygen radicals is mediated by the secondary generation of lipid mediators. In seven conscious sheep, specific lung resistance (SRL) was measured before and after x-xo challenge; approximately 30 min later when SRL had returned to baseline, airway responsiveness to carbachol was determined from dose-response curves by calculating the cumulative provocating dose of carbachol in breath units (BU, defined as one breath of a 1% wt/vol carbachol solution) that increased SRL 400% over baseline (PD400). Inhaled x-xo caused in immediate increase in SRL of 162 +/- 36% (mean +/- SE; p less than 0.05) over baseline and decreased PD400 from a baseline value of 32.5 +/- 5.0 to 16.6 +/- 1.7 BU (p less than 0.05). Pretreatment with the H2O2 scavenger, catalase (CAT,; 38 mg aerosol), methylprednisolone succinate (MS; 1 mg/kg given intravenously), the cyclooxygenase inhibitor, indomethacin (IND; 2 mg/kg given intravenously), and the PAF antagonist, WEB-2086 (3 mg/kg given intravenously) all attenuated the x-xo-induced increase in SRL (p less than 0.05); the leukotriene D4 antagonist, MK-571 (5 mg by aerosol) had no effect. All agents inhibited the x-xo-induced decrease in PD400: mean BUs were 27 after CAT, 32 after WEB-2086, 34 after IND, 31 after MS, and 25 after MK-571 (all p less than 0.05 versus x-xo alone).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lipid mediators contribute to oxygen-radical-induced airway responses in sheep. 174 41

Platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine [PAF]) is a vasoactive ether lipid produced by activated blood cells. To examine the molecular traffic and sites of metabolism of PAF released in the vascular wall, we used a coculture system in which endothelial cells are grown on micropore filters suspended over confluent cultures of vascular smooth muscle cells. The endothelial cells took up PAF 5-7 times more readily from the apical than from the basolateral surface, converting it to 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine (2-acyl-PAF) and other minor metabolites. Intact endothelial monolayers effectively shielded the underlying smooth muscle cells from PAF present in the apical fluid; after a 30-min incubation with [3H]-PAF, only 1% of the radioactivity was transferred to the interstitial fluid. By contrast, PAF readily entered the interstitial fluid when the endothelial monolayers were injured by exposure to xanthine and xanthine oxidase. PAF did not significantly increase the permeability of endothelial monolayers to albumin. Smooth muscle cells took up and metabolized interstitial PAF more quickly and more completely than did endothelial cells; 65% was converted to 2-acyl-PAF in 15 min by the smooth muscle cells. PAF enhanced the proliferative effect of PDGF on smooth muscle cells, as assessed by [3H]-thymidine incorporation. These findings suggest that endothelial cells form a barrier to PAF released at the luminal surface, but PAF released in the vascular intima interacts primarily with smooth muscle cells, possibly stimulating proliferation in these cells.
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PMID:Interaction of platelet-activating factor with endothelial and vascular smooth muscle cells in coculture. 271 86

Oxygen derived free radicals are involved in many pathological processes such as postischemic reperfusion injuries, hepatotoxicity of drugs and inflammatory processes. Thereby these oxygen radicals induce lipid peroxidation and perturbation of cellular membranes. The aim of our present study was to determine whether oxygen radicals generated by the xanthine oxidase/ hypoxanthine system cause a release of histamine in human blood cell cultures. Stimulation of blood cell cultures with oxygen radicals induced a histamine liberation which was mainly due to calcium independent processes during the first 30 min, whereas then calcium requiring processes took part in the release of histamine. The regulation of the leukocyte selection LECAM-1 was altered by oxygen radicals whereas histamine, which is known to modulate vascular selectin expression, did not affect the expression of LECAM-1. Our data indicate that oxygen radicals induce a direct calcium independent release of histamine which is due to membrane pertubating processes during the first phase but also induce a specific reaction leading to a further indirect histamine liberation which is probably mediated by PAF.
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PMID:Release of histamine in whole blood by oxygen radicals: division between specific and unspecific processes. 887 18

The relationship between leukocyte migration and parenchymal cell death in vivo remains poorly documented. Accordingly, cell killing in the rat mesentery, as recorded by propidium iodide staining, was investigated with an intravital approach. Superfusion of platelet-activating factor (PAF, 10(-8) M) or N-formyl-methionyl-leucyl-phenylalanine (fMLP, 10(-8) M) led to extensive leukocyte extravasation but no significant cell death. In contrast, pretreatment with 10(-8) M PAF or fMLP for 1 h, followed by superfusion of PAF in combination with fMLP (both at 10(-8) M) led to an increase in cell death. Mesenteric parenchymal cells but no endothelial cells were killed. Some of the dead cells were identified as granulocytes/monocytes that were already in the tissue at the start of the experiment. The incidence of cell death was lower but not eliminated when leukocyte migration was blocked with a monoclonal antibody against CD18. A xanthine oxidase inhibitor, BOF-4272, failed to diminish cell death, whereas a hydroxyl radical scavenger, dimethylthiourea, attenuated cell killing without an effect on the number of adhering and migrating leukocytes. These observations demonstrate that leukocytes serve as a factor in the killing of extravascular cells only after the development of a level of stimulation that differs from that required to induce a migratory stimulus into the extravascular space.
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PMID:Leukocyte contribution to parenchymal cell death in an experimental model of inflammation. 926 30

P-selectin and circulating xanthine oxidase are involved in the process of neutrophil infiltration into the lung associated with acute pancreatitis. This study investigated the mediators that trigger the upregulation of P-selectin in this process. Pancreatitis was induced in rats by intraductal administration of 5% sodium taurocholate. P-selectin expression was measured using radiolabeled antibodies. Neutrophil infiltration and PAF levels were also evaluated. The role of superoxide radical, H(2)O(2), or the enzyme poly (ADP-ribose) synthetase (PARS) on these processes was determined in groups of animals treated with the corresponding inhibitors. Pancreatitis was associated with an increase in P-selectin expression in the lung. Inhibition of PARS or H(2)O(2) abrogated P-selectin upregulation, PAF generation, and neutrophil recruitment. Superoxide dismutation prevented neutrophil recruitment and PAF generation, but had no effect on P-selectin expression. We conclude that during acute pancreatitis, upregulation of P-selectin in the pulmonary endothelium is triggered by H(2)O(2) and PARS activity.
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PMID:H(2)O(2) and PARS mediate lung P-selectin upregulation in acute pancreatitis. 1088 59

1. The present study has evaluated the effect of two phenanthrene alkaloids, uvariopsine and stephenanthrine, on angiotensin II (Ang-II)-induced leukocyte-endothelial cell interactions in vivo and the mechanisms involved in their activity. Intravital microscopy within the rat mesenteric microcirculation was used. 2. A 60 min superfusion with 1 nm Ang-II induced a significant increase in the leukocyte-endothelial cell interactions that were completely inhibited by 1 microm uvariopsine cosuperfusion. A lower dose of 0.1 microm significantly reduced Ang-II-induced leukocyte adhesion by 75%. 3. When Ang-II was cosuperfused with 1 and 0.1 microm stephenanthrine, Ang-II-induced leukocyte responses were significantly diminished. A lower dose of 0.01 microm only affected Ang-II-induced leukocyte adhesion. 4. Both alkaloids inhibited Ang-II-induced endothelial P-selectin upregulation and the generation of reactive oxygen species (ROS) in endothelial cells stimulated with Ang-II, in fMLP-stimulated human neutrophils (PMNs) and in the hypoxanthine-xanthine oxidase system. However, cyclic AMP levels in PMNs stimulated with fMLP were not affected. 5. Uvariopsine and stephenanthrine inhibited PAF-induced elevations in intracellular calcium levels in PMNs (IC50 values: 15.1 and 6.1 microm respectively) and blocked the binding of [3H]PAF to these leukocytes. They also reduced PAF-induced increases in intracellular levels of superoxide anion and hydrogen peroxide. 6. In conclusion, stephenanthrine and uvariopsine are potent inhibitors of Ang-II-induced leukocyte accumulation in vivo. This effect appears to be mediated through ROS scavenging activity and blockade of PAF receptor. Thus, they have potential therapeutic interest for the control of leukocyte recruitment that occurs in cardiovascular disease states in which Ang-II is involved.
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PMID:Effect of two phenanthrene alkaloids on angiotensin II-induced leukocyte-endothelial cell interactions in vivo. 1455 57