Abstract
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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REFERENCES
Chabot, F., J. A. Mitchell, J. M. C. Gutteridge, and T. W. Evans. 1998. Reactive oxygen species in acute lung injury. Eur. Respir. J. 11:745–757.
Repine, J. E. 1992. Scientific perspectives on adult respiratory distress syndrome. Lancet. 339:466–469.
Cochrane, C. G., R. G. Spragg, and S. D. Revak. 1983. Pathogenesis of the adult respiratory distress syndrome: evidence of oxidant activity in bronchoalveolar lavage fluid. J. Clin. Invest. 71:754–758.
Louie, S., B. Halliwell, and C. E. Cross. 1997. Adult respiratory distress syndrome: a radical perspective. Adv. Pharmacol. 38:457–490.
Richard, C., F. Lemonnier, M. Thibault, M. Couturier, and P. Auzepy. 1990. Vitamin E deficiency and lipoperoxidation during adult respiratory distress syndrome. Crit. Care Med. 18:4–9.
Quinlan, G. J., N. J. Lamb, T. W. Evans, and J. M. Gutteridge. 1996. Plasma fatty acid changes and increased lipid peroxidation in patients with adult respiratory distress syndrome. Crit. Care Med. 24:241–246.
Baldwin, S. R., C. M. Grum, L. A. Boxer, R. H. Simon, L. H. Ketai, and D. J. Devall. 1986. Oxidant activity in expired breath of patients with adult respiratory distress syndrome. Lancet. 1:11–14.
Kietzmann, D., R. Kahl, M. Muller, H. Burchardi, and D. Kettler. 1993. Hydrogen peroxide in expired breath condensate of patients with acute respiratory failure and with ARDS.Int. Care Med. 19:78–81.
Quinlan, G. J., T. W. Evans, and J. M. Gutteridge. 1994. Oxidative damage to plasma proteins in adult respiratory distress syndrome. Free Radic. Res. 20:289–298.
Seeger, W., F. Grimminger, M. Barden, G. Becker, J. Lohmeyer, D. Heinrich, and H. G. Lasch. 1991. Omega-oxidized leukotriene B4 detected in the broncho-alveolar lavage fluid of patients with noncardiogenic pulmonary edema, but not in those with cardiogenic edema. Int. Care Med. 17:1–6.
Bertrand, Y., J. Pincemail, G. Hanique, B. Denis, L. Leenaerts, L. Vankeerberghen, and C. Deby. 1989. Differences in tocopherollipid ratios in ARDS and non-ARDS patients. Int. Care Med. 15:87–93.
Pacht, E. R., A. P. Timerman, M. G. Lykens, and A. J. Merola. 1991. Deficiency of alveolar fluid glutathione in patients with sepsis and the adult respiratory distress syndrome. Chest. 100:1397–1403.
Balla, G., H. S. Jacob, J. Balla, M. Rosenberg, K. Nath, F. Apple, J. W. Eaton, and G. M. Vercellotti. 1992. Ferritin: a cytoprotective antioxidant strategem of endothelium.J. Biol. Chem. 267:18148–18153.
Biemond, P., H. G. van Eijk, A. J. Swaak, and J. F. Koster. 1984. Iron mobilization from ferritin by superoxide derived from stimulated polymorphonuclear leukocytes. Possible mechanism in inflammation diseases. J. Clin. Invest. 73:1576–1579.
Biemond, P., A. J. Swaak, H. G. van Eijk, and J. F. Koster. 1988.Superoxide dependent iron release from ferritin in inflammatory diseases. Free Radic. Biol. Med. 4:185–198.
Morris, C. J., J. R. Earl, C. W. Trenam, and D. R. Blake. 1995.Reactive oxygen species and iron-a dangerous partnership in inflammation. Int. J. Biochem. Cell Biol. 27:109–122.
Herbert, V., S. Shaw, E. Jayatilleke, and T. Stopler-Kasdan. 1994.Most free-radical injury is iron-related: it is promoted by iron, hemin, holoferritin and vitamin C, and inhibited by desferoxamine and apoferritin.Stem. Cells (Dayt.) 12:289–303.
Connelly, K. G., and J. E. Repine. 1997. Markers for predicting the development of acute respiratory distress syndrome. Annu. Rev.Med. 48:429–445.
Connelly, K. G., M. Moss, P. E. Parsons, E. E. Moore, F. A. Moore, P. C. Giclas, P. A. Seligman, and J. E. Repine. 1997. Serum ferritin as a predictor of the acute respiratory distress syndrome.Am. J. Respir. Crit. Care Med. 155:21–25.
Sharkey, R. A., S. C. Donnelly, K. G. Connelly, C. E. Robertson, C. Haslett, and J. E. Repine. 1999. Initial serum ferritin levels in patients with multiple trauma and the subsequent development of acute respiratory distress syndrome.Am. J. Respir. Crit. Care Med. 159:1506–1509.
Johnson, K. J., P. A. Ward, R. G. Kunkel, and B. S. Wilson. 1986. Mediation of IgA induced lung injury in the rat.Role of macrophages and reactive oxygen products. Lab. Invest. 54:499–506.
Okayama, N., M. B. Grisham, C. G. Kevil, L. A. Eppihimer, D.A. Wink, and J. S. Alexander. 1999. Effect of reactive oxygen metabolites on endothelial permeability: role of nitric oxide and iron. Microcirculation. 6:107–116.
Fridovich, I. 1970. Quantitative aspects of the production of superoxide anion radical by milk xanthine oxidase.J. Biol. Chem. 245:4053–4057.
Hybertson, B. M., R. P. Kitlowski, E. K. Jepson, and J. E. Repine. 1998. Supercritical fluid-aerosolized vitamin E pretreatment decreases leak in isolated oxidant-perfused rat lungs.J. Appl. Physiol. 84:263–268.
Terada, L. S., J. J. Dormish, P. F. Shanley, J. A. Leff, B. O. Anderson, and J. E. Repine. 1992. Circulating xanthine oxidase mediates lung neutrophil sequestration after intestinal ischemia-reperfusion.Am. J. Physiol. 263:L394–L401.
Yokoyama, Y., J. S. Beckman, T. K. Beckman, J. K. Wheat, T. G. Cash, B. A. Freeman, and D. A. Parks. 1990. Circulating xanthine oxidase: potential mediator of ischemic injury. Am. J. Physiol. 258:G564–G570.
Fox, R. B., R. B. Parad, R. H. Demling, and M. Merrigan. 1986.Permeability of isolated rat lungs perfused with purine and xanthine oxidase under constant perfusing pressure. In: Physiology of Oxygen Radicals, A. E. Taylor, S. Matalon and P. Ward, eds: American Physiological Society, Bethesda, MD, p. 163–168.
Weinbroum, A., V. G. Nielsen, S. Tan, S. Gelman, S. Matalon, K.A. Skinner, E. Bradley, Jr., and D. A. Parks. 1995. Liver ischemiareperfusion increases pulmonary permeability in rat: role of circulating xanthine oxidase.Am. J. Physiol. 268:G988–G996.
Grum, C. M., R. A. Ragsdale, L. H. Ketai, and R. H. Simon. 1987.Plasma xanthine oxidase activity in patients with ARDS. J. Crit. Care. 2:22–26.
Friedl, H. P., D. J. Smith, G. O. Till, P. D. Thomson, D. S. Louis, and P. A. Ward. 1990. Ischemia-reperfusion in humans: appearance of xanthine oxidase activity. Am. J. Pathol. 136:491–495.
Tan, S., S. Gelman, J. K. Wheat, and D. A. Parks. 1995. Circulating xanthine oxidase in human ischemia reperfusion. South Med. J. 88:479–482.
Morse, E. 1947. Anthrone in estimating low concentrations of sucrose. Anal. Chem. 19:1012–1013.
Rinaldo, J. E., and M. Gorry. 1990. Protection by deferoxamine from endothelial injury: a possible link with inhibition of intracellular xanthine oxidase. Am. J. Respir. Cell Mol. Biol. 3:525–533.
Cozzi, A., P. Santambrogio, S. Levi, and P. Arosio. 1990. Iron detoxifying activity of ferritin. Effects of H and L human apoferritins on lipid peroxidation in vitro. FEBS Lett. 277:119–122.
Ohkawa, H., N. Ohishi, and K. Yagi. 1979. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 95:351–358.
Quinlan, G. J., N. J. Lamb, R. Tilley, T. W. Evans, and J. M. C. Gutteridge. 1997. Plasma hypoxanthine levels in ARDS: Implications for oxidative stress, morbidity, and mortality.Am. J. Respir.Crit. Care Med. 155:479–484.
Kavanagh, B. P., A. Mouchawar, J. Goldsmith, and R. G. Pearl. 1994. Effects of inhaled NO and inhibition of endogenous NO synthesis in oxidant-induced acute lung injury. J. Appl. Physiol. 76:1324–1329.
Berisha, H., H. Foda, H. Sakakibara, M. Trotz, H. Pakbaz, and S. I. Said. 1990. Vasoactive intestinal peptide prevents lung injury due to xanthine /xanthine oxidase. Am. J. Physiol. 259:L151–L155.
Seibert, A. F., A. E. Taylor, J. B. Bass, and J. Haynes, Jr. 1991.Hemoglobin potentiates oxidant injury in isolated rat lungs. Am.J. Physiol. 260:H1980–H1984.
Sullivan, J. L., G. O. Till, P. A. Ward, and R. B. Newton. 1989.Nutritional iron restriction diminishes acute complement-dependent lung injury. Nutr. Res. 9:625–634.
Sappey, C., J. R. Boelaert, S. Legrand-Poels, C. Forceille, A. Favier, and J. Piette. 1995. Iron chelation decreases NF-kappa B and HIV type 1 activation due to oxidative stress. AIDS Res. Hum. Retroviruses 11:1049–1061.
Schreck, R., B. Meier, D. N. Mannel, W. Droge, and P.A. Baeuerle. 1992. Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J. Exp. Med. 175:1181–1194.
Lin, M., R. A. Rippe, O. Niemela, G. Brittenham, and H. Tsukamoto. 1997. Role of iron in NF-kappa B activation and cytokine gene expression by rat hepatic macrophages.Am. J. Physiol. 272:G1355–G1364.
Sullivan, J. L. 1981. Iron and the sex difference in heart disease risk. Lancet. June 13:1293–1294.
Gutteridge, J. M., G. J. Quinlan, S. Mumby, A. Heath, and T.W. Evans. 1994. Primary plasma antioxidants in adult respiratory distress syndrome patients: changes in iron-oxidizing, ironbinding, and free radical-scavenging proteins. J. Lab. Clin. Med. 124:263–273.
Marx, J. J., and B. S. van Asbeck. 1996. Use of iron chelators in preventing hydroxyl radical damage: adult respiratory distress syndrome as an experimental model for the pathophysiology and treatment of oxygen-radical-mediated tissue damage. Acta. Haematol. 95:49–62.
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Hybertson, B.M., Connelly, K.G., Buser, R.T. et al. Ferritin and Desferrioxamine Attenuate Xanthine Oxidase-Dependent Leak in Isolated Perfused Rat Lungs. Inflammation 26, 153–159 (2002). https://doi.org/10.1023/A:1016511611435
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DOI: https://doi.org/10.1023/A:1016511611435