Role of Oxidants, Proinflammatory Agents, and Granulocytes in the Post Ischemic Intestine

  • P. Kubes
  • D. N. Granger


In 1981, it was first postulated that xanthine oxidase (XO)-derived oxidants play an integral role in the microvascular injury associated with the reperfusion of ischemic tissue [1]. Since that time much work has been done to substantiate this hypothesis and to further expand on the pathophysiological alterations associated with ischemia-reperfusion (I/R). Figure 1 illustrates that during ischemia, cellular adenosine triphosphate (ATP) is converted to the catabolic substrate hypoxanthine while the enzyme xanthine dehydrogenase (XD) is converted to XO. Following reperfusion, oxygen reacts with hypoxanthine and XO to produce superoxide and hydrogen peroxide. These reactive oxygen metabolites may then be converted to the highly cytotoxic hydroxyl radical by the ironcatalyzed Haber-Weiss reaction. This initiates the process of lipid peroxidation which may stimulate the release of chemoattractants and the subsequent activation and recruitment of granulocytes. The objective of this chapter is to summarize supportive evidence regarding each component of the scheme presented in Fig. 1.


Xanthine Oxidase Platelet Activate Factor Neutrophil Infiltration Ischemic Intestine Microvascular Permeability 
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  1. 1.
    Granger DN, Rutili G, McCord JM (1981) Superoxide radicals in feline intestinal ischemia. Gastroenterology 81:22–29PubMedGoogle Scholar
  2. 2.
    Granger DN, Sennett M, McElearney PM, Taylor AE (1980) Effect of local arterial hypotension on cat intestinal capillary permeability. Gastroenterology 79:474–480PubMedGoogle Scholar
  3. 3.
    Parks DA, Granger DN (1986) Contributions of ischemia and reperfusion to mucosal lesion formation. Am J Physiol 250:G749–G753PubMedGoogle Scholar
  4. 4.
    Crissinger KD, Granger DN (1989) Mucosal injury induced by ischemia and reperfusion in the piglet intestine: influences of age and feeding. Gastroenterology 97:920–926PubMedGoogle Scholar
  5. 5.
    Korthuis RJ, Smith JK, Carden DL (1989) Hypoxic reperfusion attenuates post-ischemic microvascular injury. Am J Physiol 256:H315–H319PubMedGoogle Scholar
  6. 6.
    Morris JB, Bulkley GB, Haglund U, Cardenas E, Sies H (1987) The direct, real-time demonstration of oxygen free radical generation at reperfusion following ischemia in rat small intestine. Gastroenterology 92:1541Google Scholar
  7. 7.
    Krenitsky TA, Tuttle JV, Cattau EL, Wang PA (1974) A comparison of the distribution and electron acceptor specificities of xanthine oxidase and aldehyde oxidase. Comp Biochem Physiol 181:177–182Google Scholar
  8. 8.
    Batelli MG, Dellacorte E, Stirpe F (1972) Xanthine oxidase type D (dehydrogenase) in the intestine and other organs of the rat. Biochem J 126:747–749Google Scholar
  9. 9.
    Parks DA, Granger DN (1986) Xanthine oxidase: biochemistry, distribution and physiology. Acta Physiol Scand [Suppl] 548:87–99Google Scholar
  10. 10.
    Simon RH, Scoggin CH, Patterson D (1981) Hydrogen peroxide causes the fatal injury to human fibroblasts exposed to oxygen radicals. J Biol Chem 256:7181–7186PubMedGoogle Scholar
  11. 11.
    Roy RS, McCord JM (1983) Superoxide and ischemia: conversion of xanthine dehydrogenase to xanthine oxidase. In: Greenwald RA, Cohen RA, Cohen G (ed) Oxy radicals and their scavenger systems, vol II: cellular and medical aspects. Elsevier/North Holland Biomedical, New york, pp 143–153Google Scholar
  12. 12.
    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
  13. 13.
    Gilman AG, Goodman LS, Gilman A (1980) The pharmacological basis of therapeutics, 6th edn. MacMillan, New YorkGoogle Scholar
  14. 14.
    Moorhouse PC, Grootveld G, Halliwell B, Quinlan JG, Gutteridge JMC (1987) Allopurinol and oxypurinol are hydroxy radical scavengers. FEBS Lett 213:23–28PubMedCrossRefGoogle Scholar
  15. 15.
    Spector, T, Ferone R (1984) Folic acid does not inactivate xanthine oxidase. J Biol Chem 259:10784–10786PubMedGoogle Scholar
  16. 16.
    Granger DN, McCord JM, Parks DA, Hollwarth ME (1986b) Xanthine oxidase inhibitors attenuate ischemia-induced vascular permeability changes in the cat intestine. Gastroenterology 90:80–84PubMedGoogle Scholar
  17. 17.
    Topham RW, Walker MC, Calisch MP, Williams RW (1982) Evidence for the participation of intestinal xanthine oxidase in the mucosal processing of iron. Biochemistry 21:4529–4535PubMedCrossRefGoogle Scholar
  18. 18.
    Parks DA, Henson JL, Granger DN (1986) Effect of xanthine oxidase inactivation on ischemic injury to the small intestine (abstract) Physiologist 29:101Google Scholar
  19. 19.
    Parks DA, Granger DN, Bulkley GB, Shah AK (1985) Soybean trypsin inhibitor attenuates ischemic injury to the feline small intestine. Gastroenterology 89:6–12PubMedGoogle Scholar
  20. 20.
    Hernandez LA, Grisham MB, Granger DN (1987) Effects of Cu-DIPS on ischemia-reperfusion injury. In: Sorenson JRJ (ed) Biology of copper complexes. Humana, Clifton, pp 201–210CrossRefGoogle Scholar
  21. 21.
    Parks DA, Shah AK, Granger DN (1984) Oxygen radicals: effects on intestinal vascular permeability. Am J Physiol 247:G167–G170PubMedGoogle Scholar
  22. 22.
    Granger DN, Hollwarth ME, Parks DA (1986) Ischemia-reperfusion injury: role of oxygenderived free radicals. Acta Physiol Scand [Suppl] 548:47–64Google Scholar
  23. 23.
    Thomas CE, Morehouse LA, Aust SD (1985) Ferritin and superoxide-dependent lipid peroxidation. J Biol Chem 260:3275–3280PubMedGoogle Scholar
  24. 24.
    Weiss SJ (1986) Oxygen, ischemia, and inflamation. Acta Physiol Scand [Suppl] 548:9–38Google Scholar
  25. 25.
    Hernandez LA, Grisham MB, Granger DN (1987) A role for iron in oxidant-mediated ischemic injury to intestinal microvasculature. Am J Physiol 253:G49–G53PubMedGoogle Scholar
  26. 26.
    Bielski BHJ, Shiue GG (1979) Reaction rates of superoxide radicals with the essential amino acids. In: Ciba Found (ed) Oxygen free radicals and tissue damage. Elsevier, New York, pp 43–56Google Scholar
  27. 27.
    Jennings RB, Reimer KA, Hill ML, Mayer SE (1981) Total ischemia in dog hearts in vitro. Circ Res 49:892–899PubMedGoogle Scholar
  28. 28.
    Buege JA, Aust SD (1976) Lactoperoxidase-catalyzed lipid peroxidation of microsomal and artificial membranes. Biochim Biophys Acta 444:192–201PubMedCrossRefGoogle Scholar
  29. 29.
    Freeman BA, Crapo JD (1982) Free radicals and tissue injury. Lab Invest 47:412–426Google Scholar
  30. 30.
    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 (Berl) 187:9–17CrossRefGoogle Scholar
  31. 31.
    Parks DA, Granger DN (1983) Ischemia-induced vascular changes: role of xanthine oxidase and hydroxyl radicals. Am J Physiol 245:G285–G289PubMedGoogle Scholar
  32. 32.
    Granger DN, Benoit JN, Suzuki M, Grisham MB (1989) Leukocyte adherance to venular endothelium during ischemia reperfusion. Am J Physiol 257.G683–G688PubMedGoogle Scholar
  33. 33.
    Grisham MB, Hernandez LA, Granger DN (1986) Xanthine oxidase and neutrophil infiltration in intestinal ischemia. Am J Physiol 25J:G567–G574Google Scholar
  34. 34.
    Romson JL, Hook BG, Kunkel SL, Abrams GD, Schork A, Lucchesi BR (1983) Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Circulation 67:1016–1023PubMedCrossRefGoogle Scholar
  35. 35.
    Hernandez LA, Grisham MB, Twohig B, Arfors KE, Harlan JM, Granger DN (1987) Role of neutrophils in ischemia-reperfusion induced microvascular injury. Am J Physiol 253:H699–H703PubMedGoogle Scholar
  36. 36.
    Kubes PK, Hunter JA, Granger ND (1991) Chronic but not acute treatment with a CD-18 specific antibody protects the intestine against ischemia/reperfusion (I/R)-induced mucosal dysfunction (abstract). Gastroenterology (in press)Google Scholar
  37. 37.
    Zimmerman BJ, Grisham MB, Granger DN (1990) Role of oxidants in ischemia/reperfusion-induced granulocyte infiltration. Am J Physiol 258:G185PubMedGoogle Scholar
  38. 38.
    Petrone WF, English DK, Wong K, McCord JM (1980) Free radicals and inflammation: Superoxide dependent activation of a neutrophil chemotactic factor in plasma. Proc Natl Acad Sci USA 77:1159PubMedCrossRefGoogle Scholar
  39. 39.
    Perez HD, Weksler BB, Goldstein IM (1980) Generation of a chemotactic lipid from arachidonic acid by exposure to a superoxide-generating system. Inflammation 4:313PubMedCrossRefGoogle Scholar
  40. 40.
    Dreyling KW, Hoppe U, Peskar BA, Morgenroth K, Kozuschek W, Peskar BM (1986) Leukotriene synthesis by human gastrointestinal tissues. Biochim Biophys Acta 878:184PubMedGoogle Scholar
  41. 41.
    Boughton-Smith NK, Hawkey CJ, Whittle BJR (1983) Biosynthesis of lipoxygenase and cyclooxygenase products from [14C]-arachidonic acid by human colonic mucosa. Gut 4:1176CrossRefGoogle Scholar
  42. 42.
    Lauritsen K, Laursen LS, Bukhave K, Rask-Madsen J (1988) In vivo profiles of eicosanoids in ulcerative colitis, Crohn’s colitis, and Clostridium difficile colitis. Gastroenterology 95:11PubMedGoogle Scholar
  43. 43.
    Mullane K, Read N, Salmon JA, Moncada S (1984) Role of leukocytes in acute myocardial infarction in anesthetized dogs: relationship to myocardial salvage by anti-inflammatory drugs. J Pharm Exp Ther 228:510 (1984)Google Scholar
  44. 44.
    Sharon P, Stenson WF (1984) Enhanced synthesis of leukotriene B4 by colonic mucosa in inflammatory bowel disease. Gastroenterology 86:453PubMedGoogle Scholar
  45. 45.
    Mangino MJ, Anderson CB, Murphy MK, Brunt E, Turk J (1989) Mucosal arachidonate metabolism and intestinal ischemia-reperfusion injury. Am J Physiol 257:G299PubMedGoogle Scholar
  46. 46.
    Zimmerman BJ, Granger DN (1990) Role of leukotriene B in ischemia/reperfusion-induced granulocyte infiltration. Gastroenterology (1990) 99:1358–1363PubMedGoogle Scholar
  47. 47.
    Lewis MS, Whatley RE, Cain P, McIntyre TM, Prescot SM, Zimmerman GA (1988) Hydrogen peroxide stimulates the synthesis of platelet-activating factor by endothelium and induces endothelial cell-dependent neutrophil adhesion, J Clin Invest 82:2045PubMedCrossRefGoogle Scholar
  48. 48.
    Otamiri T, Lindmark D, Franzen L, Tagesson C (1988) Increased phospholipase A2 and decreased lysophospholipase activity in the small intestinal mucosa after ischaemia and revascularisation. Gut 28:1445CrossRefGoogle Scholar
  49. 49.
    Otamiri T, Lindahl M, Tagesson C (1988) Phospholipase A2 inhibition prevents mucosal damage associated with small intestinal ischaemia in rats. Gut 29:489.PubMedCrossRefGoogle Scholar
  50. 50.
    Filep J, Herman F, Braquet P, Mozes T (1989) Increased levels of platelet activating factor in blood following intestinal ischemia in the dog. Biochem Biophys Res Commun 158:353–359PubMedCrossRefGoogle Scholar
  51. 51.
    Tagesson C, Lindahl M, Otamiri T (1988) BN 52021 ameliorates mucosal damage associated with small intestinal ischaemia in rats. In: Braquet P (ed) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives. Prous, Barcelona, pp 553–561 (1990)Google Scholar
  52. 52.
    Kubes P, Ibbotson G, Russell J, Wallace JL, Granger DN (1990) Role of platelet-activating factor in reperfusion-induced leukocyte adherence. Am J Physiol 259:G300–G305PubMedGoogle Scholar
  53. 53.
    Weiss SJ, Curnutte JT, Regiani S (1986) Neutrophil-mediated solubilization of the subendothelial matrix: oxidative and nonoxidative mechanisms of proteolysis used by normal and chronic granulomatous disease phagocytes. J Immunol 136:636PubMedGoogle Scholar
  54. 54.
    Pipoly DJ, Crouch EC (1987) Degradation of native type IV procollagen by human neutrophil elastase. Implications for leukocyte-mediated degradation of basement membranes. Biochemistry 26:5748PubMedCrossRefGoogle Scholar
  55. 55.
    Droy-Lefaix M, Drouet Y, Geraud G, Braquet P (1988) Involvement of platelet-activating factor in rat ischemia reperfusion gastric damage. In: Braquet P (ed) Ginkgolides: chemistry, biology, pharmacology and clinical perspectives. Prous, Barcelona, pp 563–574Google Scholar
  56. 56.
    Berkaw RL, Wang D, Larrich JW, Howard TH (1986) Recombinant necrosis factor augments human neutrophil superoxide production (abstract). Blood 68:80Google Scholar
  57. 57.
    Braquet P, Paubert-Braquet M, Koltai M, Bourgain R, Bussolino F, Hosford D (1989) Is there a case for PAF antagonists in the treatment of ischemic states TIPS 10:23–30Google Scholar
  58. 58.
    Paubert-Braquet M, Longchampt MO, Koltz P, Guilbaud J (1988) Tumor necrosis factor (TNF) primes human neutrophils (PMN) platelet activating factor (PAF)-induced superoxide generation. Consequences in promoting PMN-mediated endothelial cell (EC) damages (abstract). Prostaglandins 35:803CrossRefGoogle Scholar
  59. 59.
    Braquet P, Hosford D, Braquet M, Bourgain R, Bussolino F (1989) Role of cytokines and platelet-activating factor in microvascular immune injury. Int Arch Allergy Appl Immunol 88:88–100PubMedCrossRefGoogle Scholar
  60. 60.
    Kobold EE, Thal AP (1963) Quantitation and identification of vasoactive substances liberated during various types of experimental and clinical intestinal ischemia. Surg Gynecol Obstet 117:315–322PubMedGoogle Scholar
  61. 61.
    Haglund U, Lundholm K, Lundgren O, Shersten T (1977) Intestinal lysosomal enzyme activity in regional simulated shock: influence of methylprednisolone and albumin. Circ Shook 4:27–34Google Scholar
  62. 62.
    Ballin HM, Meyer MW (1960) Intestinal lymph flow in dogs after endotoxin. Proc Soc Exp Biol Med 103:93–95PubMedGoogle Scholar
  63. 63.
    Weiss SJ, Regiani S (1984) Neutrophils degrade subendothelial matrices in the presence of alpha-1-proteinase inhibitor. J Clin Invest 73:1297PubMedCrossRefGoogle Scholar
  64. 64.
    Weitz JI, Huang AJ, Landman SL, Nicholson SC, Silverstein SC (1987) Elastase-mediated fibrinogenolysis by chemoattractant-stimulated neutrophils occurs in the presence of physiologic concentrations of antiproteinases. J Exp Med 166:1836PubMedCrossRefGoogle Scholar
  65. 65.
    Zimmerman BJ, Granger DN (1990) Reperfusion-induced leukocyte infiltration: role of elastase. Am J Physiol 259:H390–H394PubMedGoogle Scholar
  66. 66.
    Rossi F (1986) The superoxide forming NADPH oxidase of phagocytes: nature, mechanisms of activation and function. Biochim Biophys Acta 853:65–89PubMedGoogle Scholar
  67. 67.
    Cross AR, Jones ATG (1987) The inhibition by diphenyleneiodonium and its analogues of superoxide generation by macrophages. Bioch J 242:103–107Google Scholar

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© Springer-Verlag, Berlin Heidelberg 1993

Authors and Affiliations

  • P. Kubes
  • D. N. Granger

There are no affiliations available

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