Role of Xanthine Oxidase-Derived Oxidants and Granulocytes in Ischemia/Reperfusion

  • Barbara J. Zimmerman
  • D. Neil Granger
Conference paper


There is now a large body of experimental data which suggests that oxygen radicals mediate the microvascular and parenchymal cell damage observed during reperfusion of ischemic tissues. The information derived from several studies performed in our laboratory and by others have led us to construct a biochemical scheme to explain oxygen-dependent reperfusion injury (Fig. 1). The scheme predicts that xanthine oxidase-derived oxidants produced after reoxygenation of ischemic intestine play an important role in recruiting and activating circulating granulocytes, which ultimately mediate reperfusion-induced microvascular injury. Although the proposed mechanism may be applicable to several organ systems, the following discussion is largely confined to the small intestine (Granger, 1988).


Xanthine Oxidase Leukocyte Adherence Intestinal Ischemia Microvascular Permeability Xanthine Oxidase Activity 
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  1. Blum H, Summers JJ, Schnall MD, Barlow C, Leigh JS, Chance B, Buzby GP (1986). Acute intestinal ischemia studies by phosphorous nuclear magnetic resonance spectroscopy. Ann Surg 204: 83–88.PubMedCrossRefGoogle Scholar
  2. Granger DN (1988). Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. Am J Physiol 255: H1269 - H1275.PubMedGoogle Scholar
  3. Granger DN, Hollwarth ME, Parks DA (1986a). Ischemia-reperfusion injury: role of oxygen-derived free radicals. Acta Physiol Scand Suppl 548: 47–64.PubMedGoogle Scholar
  4. Granger DN, McCord JM, Parks DA, Hollwarth ME (1986b). Xanthine oxidase inhibitors attenuate ischemia-induced vascular permeability changes in the cat intestine. Gastroenterology 90: 80–84.PubMedGoogle Scholar
  5. Granger DN, Sennett M, McElearney P, Taylor AE (1980). Effect of local arterial hypotension on cat intestinal capillary permeability. Gastroenterology 79: 474–480, 1980.Google Scholar
  6. Grisham, M.B., L.A. Hernandez, and D.N. Granger (1986). Xanthine oxidase and neutrophil infiltration in intestinal ischemia. Am J Physiol 251:G567–G574.Google Scholar
  7. Haglund UH, Morris JB, Bulkley GB (1988). Hemodynamic characterization of the isolated (denervated) parabiotically perfused rat jejunum. Acta Physiol Scand 132: 151–158.PubMedCrossRefGoogle Scholar
  8. Hernandez LA, Grisham MB, Granger DN (1987a). A role for iron in oxidant-mediated ischemic injury to intestinal microvasculature. Am J Physiol 253: G49 - G53.PubMedGoogle Scholar
  9. Hernandez LA, Grisham MB, Twohig B, Arfors KE, Harlan JM, Granger DN (1987b). Role of neutrophils in ischemia-reperfusion induced microvascular injury. Am J Physiol 253: H699 - H703.PubMedGoogle Scholar
  10. Hernandez LA, Grisham MB, von Ritter C, Granger DN (1987c). Biochemical localization of xanthine oxidase in the cat small intestine. Gastroenterology 92: 1433.Google Scholar
  11. Inauen W, Granger DN, Kvietys PR (1989). Neutrophils enhance anoxia/reoxygenation-induced injury to microvascular. Gastroenterology 96: A684.Google Scholar
  12. Jarasch ED, Bruder G, Heid HW (1986). Significance of xanthine oxidase in capillary endothelial cells. Acta Physiol Scand Suppl 548: 39–46.PubMedGoogle Scholar
  13. Moorhouse PC, Grootveld M, Halliwell B, Quinlan JG, Gutteridge JMC (1987). Allopurinol and oxypurinol are hydroxyl radical scavengers. FEBS Letters 213 (l): 23–28.Google Scholar
  14. Morris JB, Bulkley GB, Haglund U, Cadenas E, Sies H (1987a). The direct, real-time demonstration of oxygen free radical generation at reperfusion following ischemia in rat small intestine. Gastroenterology 92: 1541.Google Scholar
  15. Morris JB, Haglund U, Bulkley GB (1987b). The protection from postischemic injury by xanthine oxidase inhibition: Blockade of free radical generation or purine salvage. Gastroenterology 92: 1542.Google Scholar
  16. Mousson B, Desjacques P, Baltasatt P (1983). Measurement of xanthine oxidase activity in some human tissues. Enzyme 29: 32–43.PubMedGoogle Scholar
  17. Nilsson UA, Lundgren O, Haglind E, Bylund-Fellienius A-C (1988). Radical production during intestinal ischemia and reperfusion in vivo in the cat - An ESR study. In Simic M, Taylor KA, Ward JF, von Sonntag C (eds): “Proceedings of 4th International Congress on Oxygen Radicals” New York: Plenum Press, pp 150–152.Google Scholar
  18. Parks DA, Bulkley GB, Granger DN, Hamilton SR, McCord JM (1982). Ischemic injury in the cat small intestine: Role of superoxide radicals. Gastroenterology 82: 9–15.Google Scholar
  19. Parks DA, Granger DN (1986a). Xanthine oxidase: Biochemistry, distribution and physiology. Acta Physiol Scand Supp 548: 97–100.Google Scholar
  20. Parks DA, Granger DN (1986b). Contributions of ischemia and reperfusion to mucosal lesion formation. Am J Physiol 250. G749 - G753.PubMedGoogle Scholar
  21. Parks DA, Granger DN (1986c). Role of oxygen radicals in gastrointestinal ischemia. In Rotilio G (ed): “Superoxide and Superoxide Dismutase in Chemistry, Biology and Medicine,” Amsterdam: Elsevier, pp 614–617.Google Scholar
  22. Parks DA, Shah AK, Granger DN (1984). Oxygen radicals: effects on intestinal vascular permeability. Am J Physiol 247: G167 - G170.PubMedGoogle Scholar
  23. Parks DA, Williams TK, Beckman JS (1988). Conversion of xanthine dehydrogenase to oxidase in ischemic rat intestine: A re-evaluation. Am J Physiol 254: G768–G774.PubMedGoogle Scholar
  24. Perry MA, Granger DN (1984). Permeability characteristics of intestinal capillaries. In Shepherd AP, Granger DN (eds):“Physiology of the intestinal circulation,” New York: Raven Press, pp 233–248.Google Scholar
  25. Ratych RE, Chuknyiska RS, Bulkley GB (1987). The primary localization of free radical generation following anoxia/reoxygenation in isolated endothelial cells. Surgery 102: 122–131.PubMedGoogle Scholar
  26. Robinson JWL, Mirkovitch V, Winistorfer B, Saegesser F (1981). Response of the intestinal mucosa to ischemia. Gut 22: 512–527.PubMedCrossRefGoogle Scholar
  27. Roldan EJA, Pinus CR, Turrens JF, Boveris A (1989). Chemiluminescence of ischaemic and reperfused intestine in vivo. Gut 30: 184–187.PubMedCrossRefGoogle Scholar
  28. Roy RS, McCord JM (1983). Superoxide and ischemia: Conversion of xanthine dehydrogenase to xanthine oxidase. In Greenwald RA, Cohen G (eds): “Oxygen Radicals and Their Scavenger Systems: Cellular and Molecular Aspects” New York: Elsevier, pp. 14–153.Google Scholar
  29. Schmid-Schonbein GW, Engler RL (1987). Granulocytes as active participants in acute myocardial ischemia and infarction. Am J Cardiovasc Pathol 1: 15–30.PubMedGoogle Scholar
  30. Schoenberg MH, Fredholm BB, Haglund U, Jung H, Sellin D, Younes M, Schildberg FW (1985). Studies on the oxygen radical mechanism involved in small intestinal reperfusion damage. Acta Physiol Scand 124: 581–589.PubMedCrossRefGoogle Scholar
  31. Schoenberg MH, Muhl E, Sellin D, Younes M, Schildberg FW, Haglund U (1984). Posthypotensive generation of superoxide free radicals - possible role in the pathogenesis of the intestinal mucosal damage. Acta Chir Scand 150: 301–309.PubMedGoogle Scholar
  32. Sekizuka E, Benoit JN, Grisham MB, Granger, DN (1989). Dimethylsulfoxide prevents chemoattractant-induced leukocyte adherence. Am J Physiol 256: H594–H597.PubMedGoogle Scholar
  33. Simon RH, Scoggin CH, Patterson D (1981). Hydrogen peroxide causes the fatal injury to human fibroblasts exposed to oxygen radicals. J Biol Chem 256: 7181–7186.PubMedGoogle Scholar
  34. Suzuki M, Grisham MB, Granger DN (1989). Superoxide plays a role in reperfusion-induced leukocyte adherence to microvascular endothelium. Gastroenterology 96: A497.Google Scholar
  35. Turrens JF, Giulivi C, Pinus C, Roldan E, Boveris A (1988). Low level chemiluminescence from isolated hepatocytes, intact lung and intestine in situ. In Simic M, Taylor KA, Ward JF, von Sonntag C (ed): Proceedings of 4th International Congress on Oxygen Radicals pp: 64–65.Google Scholar
  36. Weiss SJ (1986). Oxygen, ischemia and inflammation. Acta Physiol Scand Suppl 548: 9–37.PubMedGoogle Scholar
  37. Weiss SJ, Peppin G, Oritz X, Ragsdale C, Test ST (1985). Oxidative autoactivation of latent collagenase by human neutrophils. Science 227: 747–749.PubMedCrossRefGoogle Scholar
  38. Younes M, Mohr A, Schoenberg MH, Schildberg FW (1987). Inhibition of lipid peroxidation by superoxide dismutase following regional intestinal ischemia and reperfusion. Res Exp Med 187: 9–17.CrossRefGoogle Scholar
  39. Zimmerman BJ, Granger DN (1988). Role of hydrogen peroxide, iron, and hydroxyl radicals in ischemia/reperfusion-induced neutrophil infiltration. The Physiologist 31: A229.Google Scholar
  40. Zimmerman BJ, Granger DN (1989). Role of leukotriene B4 in ischemia/reperfusion-induced granulocyte infiltration. Gastroenterology 96: A697.Google Scholar
  41. Zimmerman BJ, Grisham MB, Granger DN (1987). Role of superoxide- dependent chemoattractants in ischemia-reperfusion induced neutrophil infiltration. Fed Proc 46: 1124.Google Scholar
  42. Zimmerman BJ, Parks DA, Grisham MB, Granger DN (1988). Allopurinol does not enhance the antioxidant properties of extracelllular fluid. Am J Physiol 255: H202–H206.PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin, Heidelberg 1990

Authors and Affiliations

  • Barbara J. Zimmerman
    • 1
  • D. Neil Granger
    • 1
  1. 1.Department of PhysiologyLouisiana State University Medical CenterShreveportUSA

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