Reactive Oxygen Species as Mediators of Organ Dysfunction: Potential Benefits of Resuscitation with Ringer’s Ethyl Pyruvate Solution

  • M. P. Fink


Reactive oxygen species (ROS) are reactive, partially reduced derivatives of molecular oxygen (O2). Important ROS in biological systems include superoxide radical anion (O 2 −• ), hydrogen peroxide (H2O2), hydroxyl radical (OH), and peroxynitrite (ONOO). Other related nitrogen-containing moieties, such as nitroso-peroxocarboxylate (ONOOCO 2 ) and nitrogen dioxide (NO 2 −• ), may also be significant [1, 2]. Most cell types are capable of generating ROS under certain conditions. However, the major sources of these reactive molecules are phagocytic cells, especially macrophages, Kupffer cells, and polymorphonuclear neutrophils (PMN), endothelial cells, and various epithelial cell types, including enterocytes, hepatocytes, alveolar epithelial cells, and renal tubular epithelial cells.


Acute Lung Injury NADPH Oxidase Xanthine Oxidase Hemorrhagic Shock Ethyl Pyruvate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Radi R, Peluffo G, Alvarez MN, Naviliat M, Cayota A (2001) Unraveling peroxynitrite formation in biological systems. Free Rad Biol Med 30: 463–488PubMedCrossRefGoogle Scholar
  2. 2.
    Wink DA, Mitchell JB (1998) Chemical biology of nitric oxide: insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Rad Biol Med 25: 434–456PubMedCrossRefGoogle Scholar
  3. 3.
    Griendling KK, Minieri CA, 011erenshaw JD, Alexander RW (1994) Angiotensin I stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 74: 1141–1148PubMedCrossRefGoogle Scholar
  4. 4.
    Jones SA, O’Donnell VB, Wood JD, Broughton JP, Hughes EJ, Jones OT (1996) Expression of phagocyte NADPH oxidase components in human endothelial cells. Am J Physiol 271: H1626–H1634PubMedGoogle Scholar
  5. 5.
    Souza HP, Laurindo FRM, Ziegelstein RC, Berlowitz CO, Zweier JL (2001) Vascular NAD(P)H oxidase is distinct from the phagocytic enzyme and modulates vascular reactivity control. Am J Physiol 280: H658–H667Google Scholar
  6. 6.
    Meyer JW, Holland JA, Ziegler LM, Chang MM, Beebe G, Schmitt ME (1999) Identification of a functional leukocyte-type NADPH oxidase in human endothelial cells: a potential atherogenic source of reactive oxygen species. Endothelium 7: 11–22PubMedGoogle Scholar
  7. 7.
    Bayraktutan U, Draper N, Lang D, Shah AM (1998) Expression of functional neutrophiltype NADPH oxidase in cultured rat coronary microvascular endothelial cells. Cardiovasc Res 38: 256–262PubMedCrossRefGoogle Scholar
  8. 8.
    Parks DA, Granger DN (1986) Xanthine oxidase: biochemistry, distribution and physiology. Acta Physiol Scand Suppl 548: 87–99PubMedGoogle Scholar
  9. 9.
    Parks DA, Williams TK, Beckman JS (1988) Conversion of xanthine dehydrogenase to oxidase in ischemic rat intestine: a reevaluation. Am J Physiol 254: G768–G774PubMedGoogle Scholar
  10. 10.
    Jaseschke H, Smith CV, Mitchell JR (1988) Reactive oxygen species during ischemia-reflow injury in isolated perfused rat liver. J Clin Invest 81: 1240–1246CrossRefGoogle Scholar
  11. 11.
    Yokoyama Y, Beckman JS, Beckman TK, et al (1990) Circulating xanthine oxidase: potential mediator of ischemic injury. Am J Physiol 258: G564–G570PubMedGoogle Scholar
  12. 12.
    Tan S, Yokoyama Y, Dickens E, Cash TG, Freeman BA, Parks DA (1993) Xanthine oxidase activity in the circulation of rats following hemorrhagic shock. Free Rad Biol Med 15: 407–414PubMedCrossRefGoogle Scholar
  13. 13.
    Terada LS, Dormish JJ, Shanley PF, Leff JA, Anderson B0, Repine JE (1992) Circulating xanthine oxidase mediates lung neutrophil sequestration after intestinal ischemia-reperfusion. Am J Physiol 263: L394–L401PubMedGoogle Scholar
  14. 14.
    Houston M, Estevez A, Chumley P, et al (1999) Binding of xanthine oxidase to vascular endothelium. Kinetic characterization and oxidative impairment of nitric oxide-dependent signaling. J Biol Chem 274: 4985–4994PubMedCrossRefGoogle Scholar
  15. 15.
    Higson FK, Kohen R, Chevion M (1988) Iron enhancement of ascorbate toxicity. Free Rad Res Commun 5: 107–115CrossRefGoogle Scholar
  16. 16.
    Xia Y, Roman LJ, Masters BS, Zweier JL (1998) Inducible nitric-oxide synthase generates superoxide from the reductase domain. J Biol Chem 273: 22635–22639PubMedCrossRefGoogle Scholar
  17. 17.
    Pou S, Pou WS, Bredt DS, Snyder SH, Rosen GM (1992) Generation of superoxide by purified brain nitric oxide synthase. J Biol Chem 267: 24173–24176PubMedGoogle Scholar
  18. 18.
    Xia Y, Tsai AL, Berka V, Zweier JL (1998) Superoxide generation from endothelial nitric-oxide synthase. A Cat+/calmodulin-dependent and tetrahydrobiopterin regulatory process. J Biol Chem 273: 25804–25808Google Scholar
  19. 19.
    Dawson TL, Gores GJ, Nieminen AL, Herman B, Lemasters JJ (1993) Mitochondria as a source of reactive oxygen species during reductive stress in rat hepatocytes. Am J Physiol 264: C961–C967PubMedGoogle Scholar
  20. 20.
    Du G, Mouithys-Mickalad A, Sluse FE (1988) Generation of superoxide anion by mitochondria and impairment of their functions during anoxia and reoxygenation in vitro. Free Rad Biol Med 25: 1066–1074CrossRefGoogle Scholar
  21. 21.
    Du XL, Edelstein D, Rossetti L, et al (2000) Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA 97: 12222–12226PubMedCrossRefGoogle Scholar
  22. 22.
    Janero DR, Hreniuk D, Sharif HM (1994) Hydroperoxide-induced oxidative stress impairs heart muscle cell carbohydrate metabolism. Am J Physiol 266: C179–C188PubMedGoogle Scholar
  23. 23.
    Mohr S, Stamler JS, Brune B (1996) Posttranslational modification of glyceraldehyde-3phosphate dehydrogenase by S-nitrosylation and subsequent NADH attachment. J Biol Chem 271: 4209–4214PubMedCrossRefGoogle Scholar
  24. 24.
    Mahadev K, Zilbering A, Zhu L, Goldstein BJ (2001) Insulin-stimulated hydrogen peroxide reversibly inhibits protein-tyrosine phosphatase lb in vivo and enhances the early insulin action cascade. J Biol Chem 276: 21938–21942PubMedCrossRefGoogle Scholar
  25. 25.
    Fink MP (2001) Cytopathic hypoxia: mitochondria) dysfunction as a mechanism contributing to organ dysfunction in sepsis. Crit Care Clin North Am 17: 219–237CrossRefGoogle Scholar
  26. 26.
    Dalledonne I, Milzani A, Colombo R (1995) H202-treated actin: assembly and polymer interactions with cross-linking proteins. Biophys J 69: 2710–2719PubMedCrossRefGoogle Scholar
  27. 27.
    Verhasselt V, Berghe WV, Vanderheyde N, Willems F, Haegeman G, Goldman M (1999) Nacetyl-L-cysteine inhibits primary human T cell responses at the dendritic cell level: association with NF-KB inhibition. J Immunol 162: 2569–2574PubMedGoogle Scholar
  28. 28.
    Schoonbroodt S, Ferreira V, Best-Belpomme M, et al (2000) Crucial role of the amino-terminal tyrosine residue 42 and the carboxyl-terminal PEST domain of IK KB in NF-B activation by oxidative stress. J Immunol 164: 4292–4300PubMedGoogle Scholar
  29. 29.
    Livolsi A, Busuttil V, Imbert V, Abraham RT, Peyron J-F (2001) Tyrosine phosphorylationdependent activation of NF-KB: Requirement for p56 LCK and ZAP-70 protein tyrosine kinases. Eur J Biochem 268: 1508–1515PubMedCrossRefGoogle Scholar
  30. 30.
    Bowie AG, Moynagh PN, O’Neill LAJ (1997) Lipid peroxidation is involved in the activation of NF-KB by tumor necrosis factor but not interleukin-1 in the human endothelial cell line ECV304. J Biol Chem 272: 25941–25950PubMedCrossRefGoogle Scholar
  31. 31.
    Jaspers I, Zhang W, Fraser A, Samet JM, Reed W (2001) Hydrogen peroxide has opposing effects on IKK activity and IK Bu breakdown in airway epithelial cells. Am J Respir Cell Mol Biol 24: 769–777CrossRefGoogle Scholar
  32. 32.
    Rahman I, Mulier B, Gilmour PS, et al (2001) Oxidant-mediated lung epithelial cell tolerance: the role of intracellular glutathione and nuclear factor-kappaB. Biochem Pharmacol 62: 787–794PubMedCrossRefGoogle Scholar
  33. 33.
    Schreck R, Meier B, Mannel DN, Droge W, Baeuerle PA (1992) Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J Exp Med 175: 1181–1194PubMedCrossRefGoogle Scholar
  34. 34.
    Oka S, Kamata H, Kamata K, Yagisawa H, Hirata H (2000) N-acetylcysteine suppresses TNF-induced NF-kappaB activation through inhibition of IkappaB kinases. FEBS Lett 472: 196–202PubMedCrossRefGoogle Scholar
  35. 35.
    Sprong RC, Aarsman CJ, van Oirschot JF, van Asbeck BS (1997) Dimethylthiourea protects rats against gram-negative sepsis and decreases tumor necrosis factor and nuclear factor kappaB activity. J Lab Clin Med 129: 470–481PubMedCrossRefGoogle Scholar
  36. 36.
    Liu SF, Ye X, Malik AB (1999) Inhibition of NF-kappaB activation by pyrrolidine dithiocarbamate prevents in vivo expression of proinflammatory genes. Circulation 100: 1330–1337PubMedCrossRefGoogle Scholar
  37. 37.
    Sen CK, Khanna S, Reznick AZ, Roy S, Packer L (1997) Glutathione regulation of tumor necrosis factor-alpha-induced NF-kappa B activation in skeletal muscle-derived L6 cells. Biochem Biophys Res Comm 237: 645–649PubMedCrossRefGoogle Scholar
  38. 38.
    Keffer J, Rahman A, Anwar KN, Malik AB (2001) Decreased oxidant buffering impairs NFkappaB activation and ICAM-1 transcription in endothelial cells. Shock 15: 11–15CrossRefGoogle Scholar
  39. 39.
    Brennan P, O’Neill LAJ (1996) 2-mercaptoethanol restores the ability of nuclear factor B (NF-B) to bind DNA in nuclear extracts from interleukin 1-treated cells incubated with pyrollidine dithiocarbamate ( PDTC ). Biochem J 320: 975–981Google Scholar
  40. 40.
    Moellering D, McAndrew J, Jo H, Darley-Usmar VM (1999) Effects of pyrrolidine dithiocarbamate on endothelial cells: protection against oxidative stress. Free Rad Biol Med 26: 1138–1145PubMedCrossRefGoogle Scholar
  41. 41.
    Ranganathan AC, Nelson KK, Rodriguez AM, et al (2001) Manganese superoxide dismutase signals matrix metalloproteinase expression via H2O2-dependent ERK1/2 activation. J Biol Chem 276: 14264–14270PubMedGoogle Scholar
  42. 42.
    Lakshminarayanan V, Drab-Weiss EA, Roebuck KA (1998) H2O2 and tumor necrosis factor-alpha induce differential binding of the redox-responsive transcription factors AP-1 and NF-kappaB to the interleukin-8 promoter in endothelial and epithelial cells. J Biol Chem 273: 32670–32678PubMedCrossRefGoogle Scholar
  43. 43.
    Ramana CV, Boldogh I, Izumi T, Mitra S (2001) Activation of apurinic/apyrmidinic endonuclease in human cells by reactive oxygen species and its correlation with their adaptive response to genotoxicity of free radicals. Proc Natl Acad Sci USA 95: 5061–5066CrossRefGoogle Scholar
  44. 44.
    Bernard GR, Lucht WD, Niedermeyer ME, Snapper JR, Ogletree ML, Brigham KL (1984) Effect of N-acetylcysteine on the pulmonary response to endotoxin in the awake sheep and upon in vitro granulocyte function. J Clin Invest 73: 1772–1784PubMedCrossRefGoogle Scholar
  45. 45.
    Seekamp A, Lalonde C, Deguang Z, Demling R (1988) Catalase prevents prostanoid release and lung lipid peroxidation after endotoxemia in sheep. J Appl Physiol 65: 1210–1216PubMedGoogle Scholar
  46. 46.
    Milligan SA, Hoeffel JM, Goldstein IM, Flick MR (1988) Effect of catalase on endotoxin-induced acute lung injury in unanesthetized sheep. Am Rev Respir Dis 137: 420–428PubMedCrossRefGoogle Scholar
  47. 47.
    Amari T, Kubo K, Kobayashi T, Sekiguchi M (1993) Effects of recombinant human superoxide dismutase on tumor necrosis factor-induced lung injury in awake sheep. J Appl Physiol 74: 2641–2648PubMedGoogle Scholar
  48. 48.
    Gonzalez PK, Zhuang J, Doctorow SR, et al (1995) EUK-8, a synthetic superoxide dismutase and catalase mimetic, ameliorates acute lung injury in endotoxemic swine. J Pharmacol Exp Ther 275: 798–806PubMedGoogle Scholar
  49. 49.
    Gonzalez PK, Zhuang J, Doctorow SR, et al (1995) Delayed treatment with EUK-8, a novel synthetic superoxide dismutase (SOD) and catalase ( CAT) mimetic, ameliorates acute lung injury in endotoxemic pigs. Surg Forum 46: 72–73Google Scholar
  50. 50.
    Olson NC, Anderson DL, Grizzle MK (1987) Dimethylthiourea attenuates endotoxin-induced acute respiratory failure in pigs. J Appl Physiol 63: 2426–2432PubMedGoogle Scholar
  51. 51.
    Olson NC, Grizzle MK, Anderson DL (1987) Effect of polyethylene glycol-superoxide dismutase and catalase on endotoxemia in pigs. J Appl Physiol 63: 1526–1532PubMedGoogle Scholar
  52. 52.
    Leach M, Frank S, Olbrich A, Pfeilschifter J, Thiemermann C (1998) Decline in the expression of copper/zinc superoxide dismutase in the kidney of rats with endotoxic shock: effects of the superoxide anion radical scavenger, tempol, on organ injury. Br J Pharmacol 125: 817–825PubMedCrossRefGoogle Scholar
  53. 53.
    Zacharowski K, Olbrich A, Cuzzocrea S, Foster SJ, Thiemermann C (2000) Membrane-permeable radical scavenger, tempol, reduces multiple organ injury in a rodent model of Gram-positive shock. Crit Care Med 28: 1953–1961PubMedCrossRefGoogle Scholar
  54. 54.
    Essani NA, Fisher MA, Jaeschke H (1997) Inhibition of NF-KB activation by dimethyl sulfoxide correlates with suppression of TNF-a formation, reduced ICAM-1 gene transcription, and protection against endotoxin-induced liver injury. Shock 7: 90–96PubMedCrossRefGoogle Scholar
  55. 55.
    Pogrebniak HW, Merino MJ, Hahn MJ, Mitchell JB, Pass HI (1992) Spin trap salvage from endotoxemia: the role of cytokine down regulation. Surgery 112: 130–139PubMedGoogle Scholar
  56. 56.
    Holleman MAF (1904) Notice sur l’action de l’eau oxygénée sur les acétoniques et sur le dicétones 1.2. Red Tray Chim Pays-bas Belg 23: 169–171CrossRefGoogle Scholar
  57. 57.
    Bunton CA (1949) Oxidation of a-diketones and a-keto-acids by hydrogen peroxide. Nature 163: 144CrossRefGoogle Scholar
  58. 58.
    Melzer E, Schmidt H (1988) Carbon isotope effects on the decarboxylation of carboxylic acids. Biochem J 252: 913–915PubMedGoogle Scholar
  59. 59.
    Dobsak P, Courdertot-Masuyer C, Zeller M, et al (1999) Antioxidative properties of pyruvate and protection of the ischemic rat heart during cardioplegia. J Cardiovasc Pharmacol 34: 651–659PubMedCrossRefGoogle Scholar
  60. 60.
    Neuman RE, McCoy TA (1958) Growth-promoting properties of pyruvate, oxalacetate, and a-ketoglutarate for isolated Walker carcinosarcoma 256 cells. Proc Soc Exp Biol Med 98: 303–307PubMedGoogle Scholar
  61. 61.
    O’Donnell-Tormey J, Nathan CF, Lanks K, DeBois CJ, de la Harpe J (1987) Secretion of pyruvate. An antioxidant defense of mammalian cells. J Exp Med 165: 500–514Google Scholar
  62. 62.
    Andrae U, Singh J, Ziegler-Skylakakis K (1985) Pyruvate and related a-ketoacids protect mammalian cells in culture against hydrogen peroxide-induced cytotoxicity. Toxicol Lett 28: 93–98PubMedCrossRefGoogle Scholar
  63. 63.
    Salahudeen AK, Clark EC, Nath KA (1991) Hydrogen peroxide-induced renal injury. A protective role for pyruvate in vitro and in vivo. J Clin Invest 88: 1886–1893Google Scholar
  64. 64.
    Bunger R, Mallet RT, Hartman DA (1989) Pyruvate-enhanced phosphorylation potential and inotropism in normoxic and postischemic isolated working heart. Near-complete prevention of reperfusion contractile failure. Eur J Biochem 180: 221–233Google Scholar
  65. 65.
    Deboer LWV, Bekx PA, Han L, Steinke L (1993) Pyruvate enhances recovery of hearts after ischemia and reperfusion by preventing free radical generation. Am J Physiol 265: H1571–H1576PubMedGoogle Scholar
  66. 66.
    Park TW, Chun YS, Kim MS, Park YC, Kwak SJ, Park SC (1998) Metabolic modulation of cellular redox potential can improve cardiac recovery from ischemia-reperfusion injury. Int J Cardiol 65: 139–147PubMedCrossRefGoogle Scholar
  67. 67.
    Crestanello JA, Lingle DM, Millili J, Whitman GJ (2001) Pyruvate improves myocardial tolerance to reperfusion injury by acting as an antioxidant: a chemiluminescence study. Surgery 124: 92–99CrossRefGoogle Scholar
  68. 68.
    Cicalese L, Lee K, Schraut W, Watkins S, Borle A, Stanko R (1999) Pyruvate prevents ischemia-reperfusion mucosal injury of rat small intestine. Am J Surg 171: 97–100CrossRefGoogle Scholar
  69. 69.
    Mongan PD, Fontana JL, Chen R, Bunger R (1999) Intravenous pyruvate prolongs survival during hemorrhagic shock in swine. Am J Physiol 277: H2253–H2263PubMedGoogle Scholar
  70. 70.
    von Korff RW (1964) Pyruvate-C14, purity and stability. Anal Biochem 8: 171–178CrossRefGoogle Scholar
  71. 71.
    Montgomery CM, Webb JL (1956) Metabolic studies on heart mitochondria. II. The inhibitory action of parapyruvate on the tricarboxylic acid cycle. J Biol Chem 221: 359–368Google Scholar
  72. 72.
    Margolis SA, Coxon B (1986) Identification and quantitation of the impurities in sodium pyruvate. Anal Biochem 58: 2504–2510Google Scholar
  73. 73.
    Willems JL, de Kort AFM, Vree TB, Trijbels JMF, Veerkamp JH, Monnens LAH (1978) Non-enzymatic conversion of pyruvate in aqueous solution to 2,4-dihydroxy-2-methylglutaric acid. FEBS Lett 86: 42–44PubMedCrossRefGoogle Scholar
  74. 74.
    Halestrap AP, Price NT (1999) The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 343: 281–299PubMedCrossRefGoogle Scholar
  75. 75.
    Halestrap AP (1975) The mitochondrial pyruvate carrier. Kinetics and specificity for substrates and inhibitors. Biochem J 148: 85–96PubMedGoogle Scholar
  76. 76.
    Brooks GA, Brown MA, Butz CE, Sicurello JP, Dubouchaud H (1999) Cardiac and skeletal muscle mitochondria have a monocarboxylate transporter MCT1. J Appl Physiol 87: 1713–1718PubMedGoogle Scholar
  77. 77.
    Mertz RJ, Worley JFI, Spencer B, Johnson JJ, Dukes ID (1996) Activation of stimulus-secretion coupling in pancreatic /3-cells by specific products of glucose metabolism. J Biol Chem 271: 4838–4845PubMedCrossRefGoogle Scholar
  78. 78.
    Lembert N, loos HC, Idahl L-Â, Ammon HPT, Wahl MA (2001) Methyl pyruvate initiates membrane depolarization and insulin release by metabolic factors other than ATP. Biochem J 354: 345–350PubMedCrossRefGoogle Scholar
  79. 79.
    Varma SD, Devamanoharan PS, Ali AH (1998) Prevention of intracellular oxidative stress to lens by pyruvate and its ester. Free Rad Res 28: 131–135CrossRefGoogle Scholar
  80. 80.
    Sims CA, Wattanasirichaigoon S, Menconi MJ, Ajami AM, Fink MP (2001) Ringer’s ethyl pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in rats. Crit Care Med 29: 1513–1518PubMedCrossRefGoogle Scholar
  81. 81.
    Tawadrous ZS, Delude RL, Fink MP (2002) Resuscitation from hemorrhagic shock with Ringer’s ethyl pyruvate solution improves survival and ameliorates intestinal mucosal hyperpermeability in rats. Shock (in press)Google Scholar
  82. 82.
    Ulloa L, Ochani M, Fink MP, Tracey KJ (2001) Ethyl pyruvate prevents endotoxin lethality. Shock 15: 118CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • M. P. Fink

There are no affiliations available

Personalised recommendations