Extended (29 days) use of intravascular gas exchanger.
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Adult↗
Biomedical subjects
R Stocker
Publications and source records attributed to R Stocker.
Simultaneous determination of 3-hydroxyanthranilic and cinnabarinic acid by high-performance liquid chromatography with photometric or electrochemical detection.
A convenient and rapid method for the simultaneous determination by HPLC of 3-hydroxyanthranilic acid and the dimer derived by its oxidation, cinnabarinic acid, is described. Buffers or biological samples containing these two Trp metabolites were acidified to pH 2.0 and extracted with ethyl acetate with recoveries of 96.5 +/- 0.5 and 93.4 +/- 3.7% for 3-hydroxyanthranilic and cinnabarinic acid, respectively. The two compounds were separated on a reversed-phase (C18) column combined with ion-pair chromatography and detected photometrically or electrochemically. The method was applied successfully to biological systems in which formation of either 3-hydroxyanthranilic or cinnabarinic acid had been described previously. Thus, interferon-gamma-treated human peripheral blood mononuclear cells formed and released significant amounts of 3-hydroxyanthranilic acid into the culture medium and mouse liver nuclear fraction possessed high "cinnabarinic acid synthase" activity. In contrast, addition of 3-hydroxyanthranilic acid to human erythrocytes resulted in only marginal formation of cinnabarinic acid. We conclude that the method described is specific, sensitive, and suitable for the detection of the two Trp metabolites in biological systems.
3-Hydroxyanthranilic Acid↗
Transvaginal mobilization and utilization of the anterior bladder wall to repair vesicovaginal fistulas involving the urethra.
Repair of vesicovaginal fistulas resulting from obstetric trauma remains a major challenge to surgeons worldwide. Large defects that result in partial or total urethral loss are especially difficult to repair. Even when closure of such fistulas is accomplished, return of normal urogenital function is often impaired, underscoring the need to improve existing surgical procedures. Transvaginal urethral and bladder neck reconstruction using mobilized anterior bladder wall was helpful in closing 18 of 20 vesicovaginal fistulas with urethral involvement caused by obstetric trauma. This method involves advancement of an anterior bladder wall flap into the vagina, where it is rolled into a neo-urethra or connected to whatever remnant of urethral tissue exists. Complications included stress incontinence requiring further surgery (four), small bladder capacity with detrusor instability (two), urethral stenosis requiring dilatation (two), postoperative hemorrhage (one), and vaginal stenosis (one). Continued modification of this procedure holds promise for many patients considered inoperable in the past.
Birth Injuries↗
Alterations in antioxidant defences in lung and liver of mice infected with influenza A virus.
We investigated the possible involvement of oxidative mechanisms in the pathogenesis of influenza A/PR8/34 virus infection in mice. As a biochemical marker of oxidative stress, we determined the endogenous concentrations of the antioxidants glutathione and vitamins C and E in their reduced and oxidized forms in the lungs, liver and blood plasma of control and infected animals. Following intranasal infection with 8 to 10 LD50, influenza virus was detected in the lungs, but not in the plasma, liver or other organs. Infection resulted in a decrease in the total concentration of glutathione and vitamins C and E, whereas no relevant change in the ratio of oxidized to total concentration of antioxidants was observed. Changes in the concentration of hepatic antioxidants were significant in the early stages of the infection. The results suggest that hepatic alterations may be caused indirectly by mechanisms related to the host response to virus infection. The observed general decrease in the antioxidant buffering capacity may reduce the ability of tissues to protect against potential oxidative stress. Such stress can occur during bacterial superinfections, which are common in influenza, thereby rendering the host more susceptible to the pathogenic effects of such agents. In addition, reactive oxygen species produced in the lung may inactivate protease inhibitors, resulting in increased protease activity. Using an in vitro system consisting of alpha 1-antiprotease, trypsin and HOCl as the oxidant, we have shown that the infectivity of influenza viruses can be increased up to 10,000-fold by proteolytic cleavage of haemagglutinin, leading to activation of the fusogenic properties of this protein.
Animals↗
Oxidative stress in lungs of mice infected with influenza A virus.
As oxidative stress has been implicated in the pathogenesis of certain viral diseases we determined antioxidant and prooxidant parameters in lungs and bronchoalveolar lavage fluid (BALF) of mice infected with a lethal dose of influenza A/PR8/34 virus. Viral infection was characterized by massive infiltration of leukocytes, mainly polymorphonuclear leukocytes, into the alveolar space. The total number of BALF cells increased up to 8-fold (day 3 post-infection) and these cells appeared activated as judged by their increased rates of superoxide anion radical (O2-.) generation upon stimulation. Maximal rates of radical generation by BALF cells during the early stages of infection were 15- or 70-fold higher than those of cells from control animals when expressed per cell or total BALF cells, respectively. At the terminal stages of infection the total capacity of BALF cells to release O2-. declined to approximately 35-fold the control values. Infection also resulted in increased in vivo formation of hydrogen peroxide (H2O2) within the lungs at a time that coincided with the maximal capacity of BALF cells to release O2-.. Whereas pulmonary activities of glutathione peroxidase and reductase remained unaltered, levels of ascorbate in the cell-free BALF decreased significantly during the early stages of the infection and then returned to normal levels and above, late in infection. The oxidation state of the dehydroascorbic acid/ascorbate couple increased concomitantly with the decrease in ascorbate concentrations early in infection and remained elevated throughout the infection. As assessed by the prevention of peroxyl radical-induced loss of phycoerythrin fluorescence, the total antioxidant capacity present in lung tissue homogenate from terminally ill animals was not diminished when compared to that prepared from lungs of control mice. We conclude that although early stages of influenza infection are associated with the presence of oxidative stress in the lung tissue and alveolar fluid lining the epithelial cells, this stress does not appear to overwhelm local antioxidant defenses. The results therefore do not support a direct causative role of oxidative tissue damage in the pathogenesis of influenza virus infection.
Animals↗
Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does alpha-tocopherol.
The temporal disappearance of natural antioxidants associated with human low density lipoprotein (LDL) in relation to the appearance of various classes of lipid hydroperoxides was investigated under three types of oxidizing conditions. Freshly isolated LDL from plasma of healthy subjects was free of detectable amounts of lipid hydroperoxides as measured by HPLC postcolumn chemiluminescence detection. Exposure of such LDL to a mild, constant flux of aqueous peroxyl radicals led to rapid and complete oxidation of ubiquinol-10, followed by slower partial depletion of lycopene, beta-carotene, and alpha-tocopherol. After an initial lag period of complete inhibition of detectable lipid peroxidation, formation of hydroperoxides of cholesterol esters, triglycerides, and phospholipids was observed. The onset of detectable lipid peroxidation corresponded closely with the completion of ubiquinol-10 consumption. However, small amounts of ascorbate, present as a contaminant in the LDL preparation, rather than ubiquinol-10 itself were responsible for the initial lag period. Thus, complete consumption of ubiquinol-10 was preceded by that of ascorbate, and exposure of ascorbate-free LDL to aqueous peroxyl radicals resulted in immediate formation of detectable amounts of lipid hydroperoxides. The rate of radical-mediated formation of lipid hydroperoxides in ascorbate-free LDL was low as long as ubiquinol-10 was present, but increased rapidly after its consumption, even though more than 80% and 95% of endogenous carotenoids and alpha-tocopherol, respectively, were still present. Qualitatively similar results were obtained when peroxyl radicals were generated within LDL or when the lipoprotein was exposed to oxidants produced by activated human polymorphonuclear leukocytes. LDL oxidation was reduced significantly by supplementing the lipoprotein preparation with physiological amounts of either ascorbate or ubiquinol-10. Our data show that ubiquinol-10 is much more efficient in inhibiting LDL oxidation than either lycopene, beta-carotene, or alpha-tocopherol.
Adult↗
Ascorbate: the most effective antioxidant in human blood plasma.
Ascorbate is the only endogenous antioxidant in plasma that can completely protect the lipoproteins from detectable peroxidative damage induced by aqueous peroxyl radicals and the oxidants released from activated PMNs. In contrast to aqueous oxidants, lipid-soluble peroxyl radicals unsparingly induce detectable peroxidative damage to plasma lipids. However, under these conditions, too, ascorbate appears to belong to the first line of antioxidant defense. Our findings strongly suggest that pathologically relevant lipid hydroperoxide formation consequent to acute or chronic leukocyte activation can be prevented by ascorbate supplementation, provided no free metal catalysts are present. Ascorbate should prove very helpful in the treatment and prevention of diseases and degenerative processes caused by oxidative stress.
Antioxidants↗
Antioxidant activities of bile pigments: biliverdin and bilirubin.
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Antioxidants↗
Antioxidant activities of some tryptophan metabolites: possible implication for inflammatory diseases.
The antioxidant properties of tryptophan and some of its oxidative metabolites were examined by measuring how efficiently they inhibited peroxyl radical-mediated oxidation of phosphatidylcholine liposomes and B-phycoerythrin. Low micromolar concentrations of 5-hydroxytryptophan, 3-hydroxykynurenine, xanthurenic acid, or 3-hydroxyanthranilic acid, but not their corresponding nonhydroxylated metabolic precursors, scavenged peroxyl radicals with high efficiency. In particular, 3-hydroxykynurenine and 3-hydroxyanthranilic acid protected B-phycoerythrin from peroxyl radical-mediated oxidative damage more effectively than equimolar amounts of either ascorbate or Trolox (a water-soluble analog of vitamin E). Enzyme activities involved or related to oxidative tryptophan metabolism, as well as endogenous concentrations of tryptophan and its metabolites, were determined within tissues of mice suffering from acute viral pneumonia. Infection resulted in a 100-fold induction of pulmonary indoleamine 2,3-dioxygenase (EC 1.13.11.17) as reported [Yoshida, R., Urade, Y., Tokuda, M. & Hayaishi, O. (1979) Proc. Natl. Acad. Sci. USA 76, 4084-4086]. This was accompanied by a 16- and 3-fold increase in the levels of lung kynurenine and 3-hydroxykynurenine, respectively. In contrast, endogenous concentrations of tryptophan and xanthurenic acid did not increase and 3-hydroxyanthranilic acid could not be detected. The activity of the superoxide anion (O2-.)-producing enzyme xanthine oxidase increased 3.5-fold during infection while that of the O2-.-removing superoxide dismutase decreased to 50% of control levels. These results plus the known requirement of indoleamine 2,3-dioxygenase for superoxide anion for catalytic activity suggest that viral pneumonia is accompanied by oxidative stress and that induction of indoleamine 2,3-dioxygenase may represent a local antioxidant defence against this and possibly other types of inflammatory diseases.
Animals↗
Selective degeneration of oligodendrocytes mediated by reactive oxygen species.
The mechanism underlying demyelination in inflammatory canine distemper encephalitis is uncertain. Macrophages and their secretory products are thought to play an important effector role in this lesion. Recently, we have shown that anti-canine distemper virus antibodies, known to occur in chronic inflammatory lesions, stimulate macrophages leading to the secretion of reactive oxygen species (ROS). To investigate whether ROS could be involved in demyelination, dog glial cell cultures were exposed to xanthine/xanthine oxidase (X/XO), a system capable of generating O2-. This treatment resulted in a specific time-dependent degeneration and loss of oligodendrocytes, the myelin producing cells of the central nervous system. Initial degeneration was not associated with a decrease in viability of oligodendrocytes as judged by trypan blue and propidium iodide exclusion. Astrocytes and brain macrophages were not affected morphologically by this treatment. Further, an evaluation of the effect of several ROS scavengers, transition metal chelators and inhibitors of poly (ADP-ribose) polymerase suggests that a metal dependent formation of .OH or a similar highly oxidizing species could be responsible for the observed selective damage to oligodendrocytes.
Animals↗
Induction of haem oxygenase as a defence against oxidative stress.
Cells respond to metabolic perturbations by producing specific stress proteins. Exposure of mammalian cells to various forms of oxidative stress induces haem oxygenase, the rate-limiting enzyme in haem degradation. This response is proposed to represent an antioxidant defence operating at two different stages simultaneously. It (i) decreases the levels of the potential pro-oxidants haem and haem proteins such as cytochrome P-450 and protoporphyrinogen oxidase, and (ii) increases the tissue concentrations of antioxidatively active bile pigments.
Animals↗
Oxidative stress and the redox status of malaria-infected erythrocytes.
The chief focus of this article is the relationship between the redox status of the host erythrocyte and that of the malaria parasite. Roles for oxidative processes in the reduced growth of malaria parasites in abnormal erythrocytes, in the host response against the parasite, and in the action of certain anti-malarial drugs are widely accepted as being established. We believe the evidence underpinning these ideas to be unacceptably deficient in a number of areas and suggest some ways in which the questions could be re-examined experimentally.
Animals↗
Oxidative stress and abnormal cholesterol metabolism in patients with adult respiratory distress syndrome.
Oxidative stress has been implicated in the adult respiratory distress syndrome (ARDS). In this study, we determined the levels of selected antioxidants in the plasma of 25 patients with ongoing ARDS and 16 healthy control subjects. We also examined these plasmas and pulmonary edema fluid of ARDS patients for lipid hydroperoxides. Both ascorbate and ubiquinol-10 concentrations in ARDS plasma were significantly lower than in normal plasma. alpha-Tocopherol concentrations, when standardized to total plasma cholesterol, were not lower in ARDS patients than in normal subjects. A pattern of antioxidant levels virtually identical to that observed in ARDS plasma was obtained after in vitro incubation of healthy plasma with stimulated polymorphonuclear leukocytes: very low ascorbate, decreased ubiquinol-10, and unchanged alpha-tocopherol concentrations. Nanomolar concentrations of lipid hydroperoxides were found in pulmonary edema fluid of ARDS patients, but not in plasma, nor in the plasma of healthy individuals, when a sensitive and selective chemiluminescence assay for hydroperoxides was used. ARDS patients also showed significant decreases in plasma levels of cholesterol esters in conjunction with discoidal high-density lipoprotein profiles, indicating a decrease in lecithin-cholesterol acyltransferase activity. We conclude that ARDS is associated with oxidative stress, possibly exerted by oxidants released from activated phagocytic leukocytes, and major changes in plasma cholesterol metabolism.
Adult↗
Synergistic interaction between vitamin E and the bile pigments bilirubin and biliverdin.
The oxidation of soybean phosphatidylcholine (PC) liposomes initiated with a lipid-soluble azo compound within the liposomal membranes has been studied in the absence and presence of membrane-bound vitamin E and water-soluble bile pigments. In the absence of vitamin E, lipid peroxidation proceeded linearly and without delay. Low micromolar amounts of bilirubin ditaurine (BR-DT, a model compound of conjugated bilirubin) or biliverdin (BV) inhibited the oxidation of PC significantly and in a concentration-dependent way. In contrast, neither taurine, ascorbic acid nor reduced glutathione inhibited significantly under these conditions. Both bile pigments were consumed during their protective action. Vitamin E incorporated into the liposomal membranes suppressed the oxidation initially almost completely, thereby producing an induction period. In the combined presence of vitamin E and either of the two bile pigments at 10 microM each, this induction period was increased by at least 200%. In contrast, when 10 microM vitamin E was combined with an equimolar concentration of reduced glutathione, the induction period increased by only about 30%. BR-DT and BV both spared the consumption of vitamin E during the oxidation of PC liposomes. These results demonstrate that conjugated bilirubin and BV located in the aqueous phase can directly scavenge lipid radicals to some extent. Furthermore, both bile pigments can act synergistically with membrane-bound vitamin E to prevent lipid peroxidation initiated in the lipid phase, most likely through regeneration of the vitamin from its chromanoxyl radical.
Ascorbic Acid↗
Antioxidant properties of conjugated bilirubin and biliverdin: biologically relevant scavenging of hypochlorous acid.
Conjugated bilirubin at low micromolar concentrations strongly inhibits the luminol-enhanced chemiluminescence response of stimulated human polymorphonuclear leukocytes. In contrast, it does not inhibit either reduction of ferricytochrome c or lucigenin-mediated chemiluminescence of stimulated cells. Also, conjugated bilirubin and its metabolic precursor, biliverdin, do not inhibit the enzyme myeloperoxidase (MPO) since (i) the MPO-dependent oxidation of guaiacol is not affected by biliverdin and (ii) the spectral changes observed when conjugated bilirubin is oxidized by a MPO-H2O2-Cl(-)-system are very similar to those obtained with reagent HOCl. As judged from these spectroscopic studies, each molecule of conjugated bilirubin can scavenge one molecule of HOCl giving rise to an oxidation product that itself is capable of scavenging further molecules of HOCl. Importantly, at physiological pH, both bile pigments can efficiently protect the elastase-inhibitory capacity of alpha 1-antiprotease against inactivation by reagent HOCl.
Animals↗
Antioxidant defenses and lipid peroxidation in human blood plasma.
The temporal disappearance in human blood plasma of endogenous antioxidants in relation to the appearance of various classes of lipid hydroperoxides measured by HPLC postcolumn chemiluminescence detection has been investigated under two types of oxidizing conditions. Exposure of plasma to aqueous peroxyl radicals generated at a constant rate leads immediately to oxidation of endogenous ascorbate and sulfhydryl groups, followed by sequential depletion of bilirubin, urate, and alpha-tocopherol. Stimulating polymorphonuclear leukocytes in plasma initiates very rapid oxidation of ascorbate, followed by partial depletion of urate. Once ascorbate is consumed completely, micromolar concentrations of hydroperoxides of plasma phospholipids, triglycerides, and cholesterol esters appear simultaneously, even though sulfhydryl groups, bilirubin, urate, and alpha-tocopherol are still present at high concentrations. Nonesterified fatty acids, the only lipid class in plasma not transported in lipoproteins but bound to albumin, are preserved from peroxidative damage even after complete oxidation of ascorbate, most likely due to site-specific antioxidant protection by albumin-bound bilirubin and possibly by albumin itself. Thus, in plasma ascorbate and, in a site-specific manner, bilirubin appear to be much more effective in protecting lipids from peroxidative damage by aqueous oxidants than all the other endogenous antioxidants. Hydroperoxides of linoleic acid, phosphatidylcholine, and cholesterol added to plasma in the absence of added reducing substrates are degraded, in contrast to hydroperoxides of trilinolein and cholesterol linoleate. These findings indicate the presence of a selective peroxidase activity operative under physiological conditions. Our data suggest that in states of leukocyte activation and other types of acute or chronic oxidative stress such a simple regimen as controlled ascorbate supplementation could prove helpful in preventing formation of lipid hydroperoxides, some of which cannot be detoxified by endogenous plasma activities and thus might cause damage to critical targets.
Adult↗
Bilirubin is an antioxidant of possible physiological importance.
Bilirubin, the end product of heme catabolism in mammals, is generally regarded as a potentially cytotoxic, lipid-soluble waste product that needs to be excreted. However, it is here that bilirubin, at micromolar concentrations in vitro, efficiently scavenges peroxyl radicals generated chemically in either homogeneous solution or multilamellar liposomes. The antioxidant activity of bilirubin increases as the experimental concentration of oxygen is decreased from 20% (that of normal air) to 2% (physiologically relevant concentration). Furthermore, under 2% oxygen, in liposomes, bilirubin suppresses the oxidation more than alpha-tocopherol, which is regarded as the best antioxidant of lipid peroxidation. The data support the idea of a "beneficial" role for bilirubin as a physiological, chain-breaking antioxidant.
Animals↗
Lipids from Plasmodium vinckei-infected erythrocytes and their susceptibility to oxidative damage.
The constituent lipids of plasma and red blood cells (RBC) from mice late in infection with the malarial parasite Plasmodium vinckei were analyzed and compared with those obtained from uninfected animals. On a dry weight basis, the total extractable lipids of RBC increased threefold during infection, while those of the plasma did not change significantly. In general, changes in individual plasma lipid constituents paralleled those found in RBC of infected mice but were of smaller magnitude. While the increase in the total lipids of parasitized RBC was largely attributable to an increase of more than fourfold in total phospholipids, a significant increase in neutral lipids was also observed. Phosphatidylcholine and phosphatidylethanolamine were the major phospholipids present within RBC, and their total and relative concentrations increased as a result of the infection. A parallel increase occurred in the ratio of unsaturated to saturated fatty acids in the parasitized RBC phospholipids. Infection was also associated with decreases in the relative amount of cholesterol present in RBC and in the ratio of cholesterol to phospholipid. Consistent with this, the fluorescence polarization of 1[4-(trimethylamino)phenyl]-6-phenylhexa-1,3,5-triene within parasitized RBC plasma membranes was decreased in comparison with its value in noninfected RBC, indicating that malarial infection decreases the "order" of membrane lipids. These modifications, in conjunction with the increased levels of vitamin E and malonyldialdehyde reported elsewhere, are important determinants of the susceptibility of the different membrane compartments within infected RBC to peroxidative damage.
Animals↗