Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.17.3.2 (xanthine oxidase)
8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Xanthine oxidase was given intratracheally in a single dose to guinea pigs. Lung compliance was measured after 4 h and 14 days respectively. Lung-thorax compliance was significantly lower compared with saline-treated controls both 4 h and 14 days after application of fluid. At 14 days there was a dose-related response between lung-thorax compliance and xanthine oxidase administered in the range 0-1.0 U. Superoxide dismutase (SOD) had a protective effect on xanthine oxidase action at 4 h, but not after 14 days. We suggest that the decreased lung-thorax compliance was caused by superoxide radicals, produced by the hypoxanthine-xanthine oxidase system, damaging lung tissue. We speculate that free oxygen radicals produced by the hypoxanthine-xanthine oxidase system could be an important contributory pathogenetic factor in producing both acute and chronic lung damage in, for instance, premature babies or adults, with respiratory distress syndrome.
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PMID:Acute and chronic effects of xanthine oxidase on lung thorax-compliance in guinea pigs. 355 33

A randomized prospective study of the effectiveness of allopurinol (Ap), a potent and specific inhibitor of the enzyme xanthine oxidase, was performed in premature infants endangered by hypoxia. The drug was given at a dose of 20 mg/kg/day orally for 3 days. In the Ap-treated group the expected decrease in the serum concentration and urinary excretion of uric acid was accompanied by a decrease in the mortality rate of infants with idiopathic respiratory distress syndrome. In these patients a concomitant improvements in renal function, as indicated by an increased urinary flow rate and creatinine output, was also obvious. It is suggested that the observed beneficial effect is due to the specific inhibition of xanthine oxidase associated with Ap therapy leading to reduced generation of superoxide radicals and decreased urinary loss of purine.
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PMID:Effect of allopurinol treatment in premature infants with idiopathic respiratory distress syndrome. 654 60

Activation of the kallikrein-kinin system was demonstrated in experimental lung failure in dogs and respiratory distress syndrome (RDS) in newborns. Further lung damage was found in rats after intravenous infusion of hypoxanthine during exposure to 100% oxygen for 48 h. It is discussed whether such damage was mediated through free oxygen radicals produced by the hypoxanthine-xanthine oxidase system. Newborn babies with RDS had high serum myoinositol levels and the role of myoinositol as regulator of surfactant synthesis is discussed. These three different approaches demonstrate the complexity of pathogenesis of RDS in newborn babies and adults.
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PMID:Pathogenetic aspects of respiratory distress syndrome in adults and newborns. Experimental and clinical data. 656 62

Hyperpermeability is the crux of pathogenesis of sudden lung edema in many pulmonary disorders, especially in acute lung injury and acute respiratory distress syndrome (ARDS). Using our modified method for assessment of pulmonary vascular permeability, we observed the effects of xanthine with xanthine oxidase (X-XO) perfused in rat pulmonary artery and the protection of vasoactive intestinal polypeptide (VIP) against the injury of pulmonary vascular permeability. After addition of xanthine oxidase in the perfusate reservoir containing xanthine, 125I-albumin leak index (125I-ALI) was remarkably increased while peak airway pressure (Paw) showed no significant increase, and perfusion pressure of pulmonary artery (Ppa) and lung wet/dry weight ratio (W/D) were only slightly increased. Xanthine plus xanthine oxidase also increased thromboxane B2 (TX B2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in the perfusate. Treatment with VIP obviously reduced or totally prevented all signs of injury. Simultaneously, VIP also diminished or abolished the associated generation of arachidonate products. The results indicated that VIP has potent protective activity against injury of pulmonary vascular permeability and may be a physiological modulator of inflammatory damage to vascular endothelium associated with toxic oxygen metabolites.
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PMID:[Vasoactive intestinal polypeptide prevents injury of pulmonary vascular permeability due to xanthine with xanthine oxidase]. 857 46

Because neutrophils contribute to reperfusion injury associated with acute myocardial infarction (MI), and because tissue plasminogen activator (tPA) is often used in the management of MI, we evaluated the effect of tPA on superoxide (O2.-) production by human neutrophils in vitro. We found that adding increasing amounts of tPA significantly (r = 0.89, P < 0.025) and progressively reduced O2.- generation by neutrophils treated with phorbol myristate acetate (PMA) in vitro. Furthermore, adding tPA that had been previously treated with the protease inhibitor, D-Phe-Pro-Arg-chloromethyl ketone HCl (PPACK), also decreased neutrophil O2.- generation in vitro (P < 0.05). In contrast, adding L-arginine, a component of the tPA preparation and a precursor of nitric oxide (NO), did not inhibit PMA-induced neutrophil O2.- production. Also, adding increasing concentrations of tPA did not reduce (P > 0.05) the concentrations of O2.- produced by xanthine oxidase (XO) in vitro. Our findings suggest that tPA reduces neutrophil O2.- generation by a mechanism that is not related to L-arginine, is not dependent on tPA proteolytic activity, and is not a function of direct scavenging. This property may account for some of the effectiveness of tPA in the treatment of MI and/or make tPA valuable for treating acute respiratory distress syndrome (ARDS) or other inflammatory disorders involving neutrophil O2.- production.
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PMID:Tissue plasminogen activator (tPA) inhibits human neutrophil superoxide anion production in vitro. 917 19

The nuclear regulatory factor (NF)-kappa B is activated in the lungs of patients with acute respiratory distress syndrome (ARDS). In experimental models of acute lung injury, activation of NF-kappa B contributes to the increased expression of immunoregulatory cytokines and other proinflammatory mediators in the lungs. Because of the important role that NF-kappa B activation appears to play in the development of acute lung injury, we examined cytoplasmic and nuclear NF-kappa B counterregulatory mechanisms in lung mononuclear cells, using a murine model in which inflammatory lung injury develops after blood loss. Sustained activation of NF-kappa B was present in lung mononuclear cells over the 4-h period after blood loss. The activation of NF-kappa B after hemorrhage was accompanied by alterations in levels of the NF-kappa B regulatory proteins I kappa B alpha and Bcl-3. Cytoplasmic and nuclear I kappa B alpha were increased and nuclear Bcl-3 was decreased during the first hour after blood loss, but, by 4 h posthemorrhage, cytoplasmic and nuclear I kappa B alpha levels were decreased and nuclear levels of Bcl-3 were increased. Inhibition of xanthine oxidase activity in otherwise unmanipulated unhemorrhaged mice resulted in increased levels of I kappa B alpha and decreased amounts of Bcl-3 in nuclear extracts from lung mononuclear cells. No changes in the levels of nuclear I kappa B alpha or Bcl-3 occurred after hemorrhage when xanthine oxidase activity was inhibited. These results demonstrate that blood loss, at least partly through xanthine oxidase-dependent mechanisms, produces alterations in the levels of both I kappa B alpha and Bcl-3 in lung mononuclear cell populations. The effects of hemorrhage on proteins that regulate activation of NF-kappa B may contribute to the frequent development of inflammatory lung injury in this setting.
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PMID:Systemic blood loss affects NF-kappa B regulatory mechanisms in the lungs. 925 55

Decreases in the alveolar O2 tension commonly follow gram-negative bacteremic shock that progresses to the acute respiratory distress syndrome (ARDS). To examine the effects of alveolar hypoxia and reoxygenation (H/R) on postbacteremic pulmonary cytokine expression, lungs from Sprague-Dawley rats (n = 43) were perfused over 180 min after hematogenous infection with 10(9) live Escherichia coli serotype O55:B5 (EC) or infusion of 0.9% NaCl (NS). Compared with normoxic EC and NS controls, EC + H/R and NS + H/R lungs received 90 min of constant-flow hypoxia followed by 60 min of reoxygenation. Perfusates were cultured and analyzed for TNF-alpha, IL-1alpha, IL-1beta, and PGE2 while monitoring pulmonary artery pressure (Ppa). Changes in the filtration coefficient (Kf) were evaluated at 180 min when cytokine mRNA levels were assessed in lung homogenates. Transcripts of the anti-inflammatory cytokine TGF-beta1 and of inducible cyclooxygenase (COX-2) were similarly analyzed. For equivalent EC clearance, Ppa, and Kf as in normoxic EC, postbacteremic H/R increased TNF-alpha gene expression and doubled the export of TNF-alpha from the lungs, an effect not blocked by allopurinol. IL-1alpha transcripts were also increased in EC + H/R versus EC lungs, in contrast to the lack of change in IL-1beta, TGF-beta, or COX-2 mRNA levels, or in cell-associated or circulating IL-1beta and PGE2. Thus, gram-negative bacteremic lung infection and secondary alveolar H/R upregulate the expression of specific inflammatory cytokines compared with pulmonary infection under normoxic conditions, independently of xanthine oxidase-induced O2 radicals. These findings identify the alveolar PO2 as a potent immunomodulatory signal whose reductions early after gram-negative sepsis may enhance lung inflammation in ARDS.
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PMID:Upregulation of postbacteremic TNF-alpha and IL-1alpha gene expression by alveolar hypoxia/reoxygenation in perfused rat lungs. 947 82

Acute lung injury represents a wide spectrum of pathologic processes, the most severe end of the spectrum being the acute respiratory distress syndrome. Reactive oxygen intermediates have been implicated as important in the pathobiochemistry of acute lung injury. The endogenous sources that contribute to the generation of reactive oxygen intermediates in acute lung injury are poorly defined but probably include the molybdenum hydroxylases, NAD(P)H oxidoreductases, the mitochondrial electron transport chain, and arachidonic acid-metabolizing enzymes. Our laboratory has focused, in particular, on the regulation of two of these enzyme systems, xanthine oxidoreductase (XDH/XO) and NAD(P)H oxidase. We observe that gene expression of XDH/XO is regulatory in a cell-specific manner and is markedly affected by inflammatory cytokines, steroids, and physiologic events such as hypoxia. Posttranslational processing is also important in regulating XDH/XO activity. More recently, the laboratory has characterized an NAD(P)H oxidase in vascular cells. The cytochrome components of the oxidase, gp91 and p22, appear similar to the components present in phagocytic cells that contribute to their respiratory burst. In human vascular endothelial and smooth muscle cells, oncostatin M potently induces gp91 expression. We believe that regulation of gp91 is a central controlling factor in expression of the vascular NAD(P)H oxidase. In summary, the studies support the concept that the oxidoreductases of vascular cells are expressed in a highly regulated and self-specific fashion.
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PMID:Lung injury and oxidoreductases. 978 4

Exhaled nitric oxide (NO) is increased in some inflammatory airway disorders but not in others such as cystic fibrosis and acute respiratory distress syndrome. NO can combine with superoxide (O-2) to form peroxynitrite, which can decompose into nitrate. Activated polymorphonuclear neutrophils (PMNs) releasing O-2 could account for a reduction in exhaled NO in disorders such as cystic fibrosis. To test this hypothesis in vitro, we stimulated confluent cultures of LA-4 cells, a murine lung epithelial cell line, to produce NO. Subsequently, human PMNs stimulated to produce O-2 were added to the LA-4 cells. A gradual increase in NO in the headspace above the cultures was observed and was markedly reduced by the addition of PMNs. An increase in nitrate in the culture supernatant fluids was measured, but no increase in nitrite was detected. Superoxide dismutase attenuated the PMN effect, and xanthine/xanthine oxidase reproduced the effect. No changes in epithelial cell inducible NO synthase protein or mRNA were observed. These data demonstrate that O-2 released from PMNs can decrease NO by conversion to nitrate and suggest a potential mechanism for modulation of NO levels in vivo.
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PMID:Superoxide released from neutrophils causes a reduction in nitric oxide gas. 984 49

Iron, through its participation in reactions that generate reactive oxygen species, may contribute to the oxidative lung injury observed in patients with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). A number of investigators have shown that the endogenous iron storage protein ferritin increases in the blood of patients with and at-risk for ALI and ARDS, but the significance of these increases are not known. In the present investigation, we measured lung tissue levels of thiobarbituric acid reactive substances (TBARS) and lung leak in isolated rat lungs perfused with xanthine oxidase (XO) and purine, an enzymatic system which generates reactive oxygen species. We found that adding ferritin (100 ng/mL) or desferrioxamine (DFO, 10 mM), an iron chelator, to the vascular perfusate solution decreased oxidant-induced leak in isolated rat lungs perfused with XO and purine. Addition of ferritin or DFO also decreased TBARS in isolated rat lungs perfused with XO and purine; neither ferritin nor DFO, however, decreased XO activity in vitro. Our results suggest that oxidative lung leak may be altered by the availability of reactive iron and that ferritin may contribute to protection against oxidative lung injury.
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PMID:Ferritin and desferrioxamine attenuate xanthine oxidase-dependent leak in isolated perfused rat lungs. 1218 28


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