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)

Inhaled nitric oxide (NO) may modify surfactant either by interacting with the surfactant complex or by changing the capacity of the proteins of the epithelial lining fluid to inhibit the surface activity. Natural surfactant was exposed to NO (80 parts/million) in air in vitro while the gas-liquid surface was cycled. In the presence or absence of oxidants (Fe2+, xanthine, xanthine oxidase), surfactant exposed to NO retained the high surface activity significantly better than control surfactants exposed to air. Two surfactant inhibitors, hemoglobin (Hb) and albumin, were separately exposed to NO. In contrast to albumin, NO-exposed Hb and methemoglobin (MetHb; 16-125 micrograms/ml) decreased the surface activity at low surfactant concentrations, whereas native Hb had no effect. Surfactant recovered by sedimentation after exposure to MetHb had decreased surface activity and contained MetHb, whereas Hb did not bind to surfactant. Acidic phospholipid phosphatidylglycerol increased the binding of MetHb to surfactant. The MetHb-induced decrease in surface activity was elicited in the presence of surfactant proteins, including a peptide mimicking surfactant protein B. MetHb (but not Hb) added to a low dose of exogenous surfactant decreased the efficacy of surfactant to improve the lung compliance of premature rabbits. We propose that inhaled NO promotes the surface activity of surfactant during tidal ventilation and that, in high-permeability lung edema and surfactant deficiency, inhaled NO increases the inhibition of surface activity by converting Hb to MetHb in the alveolar space.
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PMID:A mechanism of nitric oxide-induced surfactant dysfunction. 880 11

Not all possible mediators of lung I/R injury that have been studied, such as cyclooxygenase and lipoxygenase products, have been presented in this review, but it is very clear that oxygen free radicals are the primary mediators of the damage, regardless of their origin. Oxygen radicals are generated by neutrophils, which are sequestered and activated in the ischemic-reperfused pulmonary tissue, and by xanthine oxidase, which is upregulated by ischemia and/or activated neutrophils. The contributions to lung injury by different species of oxygen radicals may very depending upon the lung model used to study I/R. Also, nitric oxide may be injurious or protective in lung I/R injury, depending upon some critical alveolar PO2 level present either during ischemia or at reperfusion. I/R-induced lung microvascular injury ultimately depends upon some balance between lung metabolic stress, the extent of the I/R-induced inflammatory response, endogenous antioxidant levels, and the timing, magnitude, and duration of oxygen free radical generation during both periods of ischemia and reperfusion. The final common pathway causing microvascular permeability to increase after lung I/R is the activation of the endothelial cell's contractile machinery. Particularly, endothelial contraction may occur in a MLCK-dependent fashion. Endothelial contraction may also be related to an intracellular Ca++ increase and subsequent calmodulin activation. The initiating event causing increased intracellular Ca++ is not known, but may be due to endothelial cell/leukocyte interactions, oxygen radical-mediated Ca++ transients, mobilization of intracellular Ca++ pools by various second messengers, or stimulation of Ca++ influx secondarily to changes in the activity of membrane ion pumps such as the Na+/H+ antiport. Increasing cAMP levels in the postischemic lung can prevent and actually reverse I/R-induced microvascular injury, by affecting MLCK, the endothelial cell cytoskeleton, and/or the function of sequestered leukocytes. Also, cAMP elevation aids the resolution of pulmonary edema by facilitating capillary fluid reabsorption. Whatever the mechanism, elevation of cAMP in the setting of lung I/R injury represents a potentially useful therapy for improving early lung function following lung transplantation. Finally, additional studies are necessary to elucidate the complete mechanisms responsible for producing microvascular injury during lung I/R. Specifically, a better understanding of the relationships between the many factors required to produce lung damage is needed. Many interventions into the lung I/R process provide protection against microvascular injury, suggesting that regulation of the endothelial barrier permeability to fluid, protein, and leukocytes is accomplished by several redundant systems. This situation may be similar to mechanisms reported to regulate the immune response mediated by T cells (62a), where T cell activation depends upon multiple signal inputs for the full immune response to occur. Thus, multiple signals in a correct sequence delivered to the endothelium may be necessary to produce the microvascular injury associated with lung ischemia and reperfusion.
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PMID:Endothelial damage caused by ischemia and reperfusion and different ventilatory strategies in the lung. 890 6

Oxidant stress plays a major role in the pathophysiologic processes associated with ischemia-reperfusion injury. Xanthine oxidase (XO) is often implicated as a significant source of oxidants and increases in the circulation after hepatoenteric ischemia-reperfusion. We hypothesized that pulmonary injury is associated with hepatic ischemia-reperfusion resulting from descending thoracic aorta occlusion-reperfusion (AoOR). We also proposed that this remote pulmonary injury is attenuated through inactivation of circulating and tissue XO by tungstate, implicating an XO-dependent mechanism. Aortic occlusion was established in rabbits (standard or tungstate diet) for 40 min by 2 h reperfusion. Sham operated rabbits (standard or tungstate diet) served as controls. Hepatic reperfusion injury, as manifested by release of the hepatocellular enzyme alanine aminotransferase (ALT), was markedly increased after AoOR. Suprarenal-infrahepatic occlusion failed to increase ALT release. Tungstate pretreatment significantly (p < 0.05) reduced XO activity and ameliorated liver and intestinal injury (p < 0.05). Lung injury, manifested by increased bronchoalveolar lavage (BAL) protein concentration, BAL lactate dehydrogenase (LDH) activity and increased lung edema was significantly associated with liver injury (p < 0.05) and circulating XO activity (p < 0.001). XO inactivation significantly decreased BAL protein concentration, BAL LDH activity, and lung edema (p < 0.05). We conclude that remote pulmonary injury is significantly influenced by the extent of liver injury and circulating XO activity.
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PMID:Lung injury after hepatoenteric ischemia-reperfusion: role of xanthine oxidase. 891 49

We determined the effect of the antioxidants superoxide dismutase, desferrioxamine and allopurinol on the survival of male CBA mice infected intranasally with 2-5 LD50 lung influenza virus A/Aichi/2/68. Survival for at least 20 days was observed for 45% of the mice that received 1000 U/day superoxide dismutase prepared from red blood cells on days 5, 6, 7 and 8 after infection, and 75% survival was observed for mice that received the same dose on days 4, 5, 6, 7 and 8. Desferrioxamine, 25 mg/kg per day and 100 mg/kg per day injected subcutaneously, resulted in survival rates of 5 and 0%, respectively, compared to 10% survival observed for saline-injected controls. Allopurinol at doses of 5 to 50 mg/kg per day had no effect on mouse survival. These data demonstrate the efficacy of superoxide dismutase for the protection of mice against hemorrhagic lung edema. The ineffectiveness of allopurinol suggests that the xanthine oxidase system does not play a major role in hemorrhage or lung edema and that caution is necessary when desferrioxamine is administered during an acute inflammatory process accompanied by erythrocyte lysis.
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PMID:Application of various antioxidants in the treatment of influenza. 953 43

LPS and selected cytokines upregulate xanthine dehydrogenase/xanthine oxidase (XDH/XO) in cellular systems. However, the effect of these factors on in vivo XDH/XO expression, and their contribution to lung injury, are poorly understood. Rats were exposed to normoxia or hypoxia for 24 h after treatment with LPS (1 mg/kg) and IL-1beta (100 microg/kg) or sterile saline. Lungs were then harvested for measurement of XDH/XO enzymatic activity and gene expression, and pulmonary edema was assessed by measurement of the wet/dry lung weight ratio (W/D). Although treatment with LPS + IL-1beta or hypoxia independently produced a 2-fold elevation (p < 0. 05 versus exposure to normoxia and treatment with saline) in lung XDH/XO activity and mRNA, the combination of LPS + IL-1beta and hypoxia caused a 4- and 3.5-fold increase in these values, respectively. XDH/XO protein expression was increased 2-fold by hypoxia alone and 1.3-fold by treatment with LPS + IL-1beta alone or combination treatment. Compared with normoxic lungs, W/D was significantly increased by exposure to hypoxia, LPS + IL-1beta, or combination treatment. This increase was prevented by treatment of the animals with tungsten, which abrogated lung XDH/XO activity. In conclusion, LPS, IL-1beta, and hypoxia significantly upregulate lung XDH/XO expression in vivo. The present data support a role for this enzyme in the pathogenesis of acute lung injury.
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PMID:Upregulation of xanthine oxidase by lipopolysaccharide, interleukin-1, and hypoxia. Role in acute lung injury. 965 43

The antioxidant and anti-inflammatory activities of two transition metal complexes of bioflavonoid rutin, Fe(rut)Cl(3) and Cu(rut)Cl(2), were studied. It was found that Cu(rut)Cl(2) was a highly efficient in vitro and ex vivo free radical scavenger that sharply decreased (by 2-30 times compared to the parent rutin): oxygen radical production by xanthine oxidase, rat liver microsomes, and rat peritoneal macrophages; the formation of thiobarbituric acid-reactive products in microsomal lipid peroxidation; and the generation of oxygen radicals by broncho-alveolar cells from bleomycin-treated rats. The copper-rutin complex was also a superior inhibitor of inflammatory and fibrotic processes (characterized by such parameters as macrophage/neutrophil ratio, wet lung weight, total protein content, and hydroxyproline concentration) in the bleomycin-treated rats. The antioxidant activity of Fe(rut)Cl(3) was much lower and in some cases approached that of rutin. Fe(rut)Cl(3) also stimulated to some degree spontaneous oxygen radical production by macrophages. We suggested that the superior antioxidant and anti-inflammatory activity of the copper-rutin complex is a consequence of its acquiring the additional superoxide-dismuting copper center. The inhibitory activity of Fe(rut)Cl(3) was lower, probably due to the partial reduction into Fe(rut)Cl(2) in the presence of biological reductants; however, similarly to the copper-rutin complex, this complex efficiently suppressed lung edema.
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PMID:Enhancement of antioxidant and anti-inflammatory activities of bioflavonoid rutin by complexation with transition metals. 1126 52

Compelling evidence indicates that the small intestine is the primary source of factors inducing lung injury after major surgery and that the lymphatic system is the major route by which these gut-derived factors reach the pulmonary circulation. This study investigated the mechanism of lung edema induced by surgical stress. After subjecting male, fasted, pathogen-free Sprague-Dawley rats to surgical stress (laparotomy and intestinal handling for 5 min), followed by ventilation for 5 h, we measured H2O2 production in the mucosa of small intestine and in the lung using 2',7'-dichlorofluorescein and intravital fluorescence microscopy. In addition, H2O2 in mesenteric lymph was measured using a quantitative assay; lung permeability was assessed as a function of extravasation of Evans blue dye; neutrophil accumulation was visualized by intravital fluorescence microscopy and assessed as a function of myeloperoxidase activity; and TNF-alpha levels were measured using a specific ELISA. The intensity of 2',7'-dichlorofluorescein fluorescence in the mucosa of small intestine, H2O2 levels of mesenteric lymph, and lung permeability were all significantly higher in rats subjected to surgical stress than in control animals. Moreover, all of these effects were blocked by pretreatment with a specific xanthine oxidase inhibitor. Surgical stress did not increase neutrophil accumulation or TNF-alpha production in the lung. In conclusion, surgical stress induces xanthine oxidase-dependent H2O2 production in the small intestine. The H2O2 then enters the mesenteric lymph and travels to the lung, where it increases capillary permeability and thus induces edema.
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PMID:Hydrogen peroxide derived from intestine through the mesenteric lymph induces lung edema after surgical stress. 1475 90

The pathogenesis of reexpansion pulmonary edema is not yet fully understood. We therefore studied its mechanism in a rat model in which the left lung was collapsed by bronchial occlusion for 1 h and then reexpanded and ventilated for an additional 3 h. We then evaluated the production of reactive oxygen species in the lungs using fluorescent imaging and cerium deposition electron microscopic techniques and the incidence of apoptosis using the TdT-mediated dUTP-digoxigenin nick end labeling (TUNEL) method. We found that pulmonary reexpansion induced production of reactive oxygen species and then apoptosis, mainly in endothelial and alveolar type II epithelial cells. Endothelial cells and alveolar type I and II epithelial cells in the reexpanded lung were positive for TUNEL and cleaved caspase-3. DNA fragmentation was also observed in the reexpanded lung. In addition, wet-dry ratios obtained with reexpanded lungs were significantly higher than those obtained with control lungs, indicating increased fluid content. All of these effects were attenuated by pretreating rats with a specific xanthine oxidase inhibitor, sodium (-)-8-(3-methoxy-4-phenylsulfinylphenyl) pyrazolo[1,5-a]-1,3,5-triazine-4(1H)-one. It thus appears that pulmonary reexpansion activates xanthine oxidase in both endothelial and alveolar type II epithelial cells and that the reactive oxygen species produced by the enzyme induce apoptosis among the endothelial and alveolar type I and II epithelial cells that make up the pulmonary water-air barrier, leading to reexpansion pulmonary edema.
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PMID:Pulmonary reexpansion causes xanthine oxidase-induced apoptosis in rat lung. 1587 59

Generation of oxygen free radicals (OFR) via intravenous administration of xanthine plus xanthine oxidase [X + XO], to Inactin(R) anesthetized rats produced intense respiratory distress. This effect led to death of more than 90% of the animals within a 120 min observation period. Several reports documented that the two autocoids, 5-hydroxytryptamine (5-HT) and histamine (H), can induce pulmonary and bronchiolar constriction and pulmonary edema. Hence, our present studies were conducted to investigate whether antagonists of 5-HT and histamine could provide protection from the lethal toxicity of the free radicals. Pretreatment of the rats with pyrilamine and cimetidine, H1 and H2 receptor antagonists, respectively, prolonged the duration of survival, but it failed to enhance net survival rate. In contrast, pretreatment of the rats with nonspecific 5-HT antagonists, methysergide and cyproheptadine, and a selective 5-HT(2) receptor antagonist, ketanserin, markedly enhanced the survival rate to 80-90%. These observations are consistent with data showing that 5-HT levels in the systemic arterial blood doubled within 5-10 min after administration of [X + XO]. These studies support the view that OFR-mediated respiratory distress is caused predominantly by 5-hydroxytryptamine and to a lesser extent by histamine.
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PMID:Evaluation of the protective effects of histamine and 5-hydroxytryptamine receptor antagonists against the lethal toxicity induced by oxygen free radicals in rats. 1654 37

Lung N-methyl-D-aspartate receptors (NMDAR) may cause excitotoxic pulmonary edema if activated. Acute lung injury may be mediated by oxidative stress, frequently generated by local or remote ischemia and reperfusion (IR). This experimental study assessed the effects of intravenous dextromethorphan, an NMDAR antagonist, on reperfusion lung injury following superior mesenteric artery (SMA) clamping/unclamping. SMA of 48 (12 per group) anesthetized adult male Wistar rats was clamped for 90 min (IR); 48 additional rats underwent a sham laparotomy (control). The experimental timeframe was identical in all groups. Ten minutes before unclamping, three dextromethorphan doses were administered intravenously in three IR and three control groups, followed by 3 h of respiratory and hemodynamic assessment and postexperimental assessment of survival. Intravenous 10 and 20 mg/kg dextromethorphan attenuated an 85% increase in peak ventilatory pressure, a 45% reduction in PO(2)/FiO(2), 4-12-fold increase in bronchoalveolar lavage-retrieved volume, and polymorphonuclear leukocytes/bronchoalveolar cells ratio, all associated with SMA unclamping in the IR-nontreated and the IR-40 mg/kg dextromethorphan-treated rats. Lung tissue polymorphonuclear leukocyte count, total xanthine oxidase activity, reduced glutathione, and wet-to-dry weight ratio were all within normal ranges in the two lower-dose-treated groups. These effective regimens were also associated with longer postexperimental animal survival. Dextromethorphan was not associated with changes in three control groups. Thus, Intravenous dextromethorphan mitigates lung reperfusion injury following SMA clamping/unclamping in a dose-dependent manner. This is a novel potential use of dextromethorphan in vivo.
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PMID:Mesenteric artery clamping/unclamping-induced acute lung injury is attenuated by N-methyl-D-aspartate antagonist dextromethorphan. 1710 8


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