World Journal of Surgery

, Volume 32, Issue 2, pp 288–295 | Cite as

The Potential Role for Xanthine Oxidase Inhibition in Major Intra-abdominal Surgery

  • Anubhav Mittal
  • Anthony R. J. Phillips
  • Benjamin Loveday
  • John A. Windsor
Article
First Online:

Abstract

Background

Xanthine oxidase (XO) is a cytosolic metalloflavoprotein that has been implicated in the pathogenesis of a wide spectrum of diseases, and is thought to be the most important source of oxygen-free radicals and cell damage during re-oxygenation of hypoxic tissues. Clinical studies have already shown that XO inhibition is safe and effective for the treatment of gout, tumour-lysis syndrome, and to reduce complications such as post-operative arrhythmias, myocardial infarction and mortality in cardiovascular surgery. Here, we review the evidence from two decades of animal studies that have investigated the effects of XO inhibition during intra-abdominal surgery.

Materials and methods

A search of the Ovid MEDLINE database from 1950 through January 2007 was carried out using the following search terms: xanthine oxidase, allopurinol, ischemia, reperfusion, intestine, bowel, and general surgery.

Results

The inhibition of XO has been shown to reduce oxidative stress, neutrophil priming, damage to intestinal mucosa due to ischemia reperfusion injuries, intestinal anastomotic dehiscence, bacterial translocation, adhesion formation, distant organ injury and mortality.

Conclusions

Despite this evidence which very strongly suggests a likely clinically beneficial role for XO inhibition in the elective and acute operative setting, it is surprising that such an approach has not been investigated in general surgery. There is now sufficient evidence to justify dedicated studies to determine the clinical benefits, dosing and duration of XO inhibition before and after gastrointestinal surgery.

Keywords

Xanthine Reperfusion Injury Xanthine Oxidase Allopurinol Bacterial Translocation 
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.
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References

  1. 1.
    Massey V, Harris CM (1997) Milk xanthine dehydrogenase: the first one hundred years. Biochem Soc Trans 25:750–755PubMedGoogle Scholar
  2. 2.
    Blauch M, Koch F, Hanke M (1939) A study of xanthine oxidase of rat blood. J Biol Chem 130:471–486Google Scholar
  3. 3.
    Borges F, Fernandes E, Roleira F (2002) Progress towards the discovery of xanthine oxidase inhibitors. Curr Med Chem 9:195–217PubMedGoogle Scholar
  4. 4.
    Parks DA, Granger DN (1986) Xanthine oxidase: biochemistry, distribution and physiology. Acta Physiol Scand 548(Suppl):87–99Google Scholar
  5. 5.
    Pacher P, Nivorozhkin A, Szabo C (2006) Therapeutic effects of xanthine oxidase inhibition: renaissance half a century after the discovery of allopurinol. Pharmacol Rev 58:87–114PubMedCrossRefGoogle Scholar
  6. 6.
    Meneshian A, Bulkley GB (2002) The physiology of endothelial xanthine oxidase: from urate catabolism to reperfusion injury to inflammatory signal transduction. Microcirculation 9:161–175PubMedCrossRefGoogle Scholar
  7. 7.
    Parks D, Skinner K, Skinner H et al. (1998) Multiple organ dysfunction syndrome: role of xanthine oxidase and nitric oxide. Pathophysiology 5:49–66CrossRefGoogle Scholar
  8. 8.
    Folch E, Gelpi E, Rosello-Catafau J et al. (1998) Free radicals generated by xanthine oxidase mediate pancreatitis-associated organ failure. Dig Dis Sci 43:2405–2410PubMedCrossRefGoogle Scholar
  9. 9.
    Granell S, Bulbena O, Genesca M et al. (2004) Mobilization of xanthine oxidase from the gastrointestinal tract in acute pancreatitis. BMC Gastroenterology 4:1PubMedCrossRefGoogle Scholar
  10. 10.
    Ichida K, Amaya Y, Noda K et al. (1993) Cloning of the cDNA encoding human xanthine dehydrogenase (oxidase): structural analysis of the protein and chromosomal location of the gene. Gene 133:279–284PubMedCrossRefGoogle Scholar
  11. 11.
    Glantzounis GK, Tsimoyiannis EC, Kappas AM et al. (2005) Uric acid and oxidative stress. Curr Pharm Des 11:4145–4151PubMedCrossRefGoogle Scholar
  12. 12.
    Engerson TD, McKelvey TG, Rhyne DB et al. (1987) Conversion of xanthine dehydrogenase to oxidase in ischemic rat tissues. J Clin Invest 79:1564–1570PubMedGoogle Scholar
  13. 13.
    Mallick I, Yang W, Winslet M et al. (2004) Ischemia–reperfusion injury of the intestine and protective strategies against injury. Dig Dis Sci 49:1359–1377PubMedCrossRefGoogle Scholar
  14. 14.
    Chung H, Baek B, Song S et al. (1997) Xanthine dehydrogenase/xanthine oxidase and oxidative stress. Age 20:127–140CrossRefGoogle Scholar
  15. 15.
    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
  16. 16.
    Martin H, Hancock J, Salisbury V et al. (2004) Role of xanthine oxidoreductase as an antimicrobial agent. Infection and immunity 72:4933–4939PubMedCrossRefGoogle Scholar
  17. 17.
    Tan S, Gelman S, Wheat J et al. (1995) Circulating xanthine oxidase in human ischemia reperfusion. South Med J 88:479–482PubMedGoogle Scholar
  18. 18.
    Granell S, Gironella M, Bulbena O et al. (2003) Heparin mobilizes xanthine oxidase and induces lung inflammation in acute pancreatitis. Crit Care Med 31:525–530PubMedCrossRefGoogle Scholar
  19. 19.
    Schimpl G, Pabst MA, Feierl G et al. (1999) A tungsten supplemented diet attenuates bacterial translocation in chronic portal hypertensive and cholestatic rats: role of xanthine dehydrogenase and xanthine oxidase. Gut 45:904–910PubMedGoogle Scholar
  20. 20.
    Thomas S, Pulimood A, Balasubramanian KA (2003) Heat preconditioning prevents oxidative stress-induced damage in the intestine and lung following surgical manipulation. Br J Surg 90:473–481PubMedCrossRefGoogle Scholar
  21. 21.
    Thomas S, Ramachandran A, Ramamoorthy P et al. (2001) Effect of surgical manipulation of the rat intestine on enterocyte populations. Surgery 130:479–488CrossRefGoogle Scholar
  22. 22.
    Anup R, Susama P, Balasubamanian KA (2001) Intestinal mitochondrial dysfunction induced by surgical stress. J Surg Res 99:120–128CrossRefGoogle Scholar
  23. 23.
    Kalff J, Schraut W, Simmons R et al. (1998) Surgical manipulation of the gut elicits an intestinal muscularis inflammatory response resulting in postsurgical ileus. Ann Surg 228:652–663PubMedCrossRefGoogle Scholar
  24. 24.
    Thomas S, Ramamoorthy P, Balasubamanian KA (2005) Surgical manipulation of the intestine and distant organ damage—protection by oral glutamine supplementation. Surgery 137:48–55PubMedCrossRefGoogle Scholar
  25. 25.
    Anup R, Susama P, Balasubamanian KA (2000) Role of xanthine oxidase in small bowel mucosal dysfunction after surgical stress. Br J Surg 87:1094–1101PubMedCrossRefGoogle Scholar
  26. 26.
    Ramachandran A, Susama P, Balasubamanian KA (2001) Intestinal mitochondrial dysfunction induced by surgical stress. J Surg Res 99:120–128PubMedCrossRefGoogle Scholar
  27. 27.
    Galley H, Davies M, Webster N (1996) Xanthine oxidase activity and free radical generation in patients with sepsis syndrome. Crit Care Med 24:1649–1653PubMedCrossRefGoogle Scholar
  28. 28.
    Reilly PM, Wilkins KB, Fuh KC et al. (2001) The mesenteric hemodynamic response to circulatory shock: an overview. Shock 15:329–343PubMedGoogle Scholar
  29. 29.
    Ceppa EP, Fuh KC, Bulkley GB (2003) Mesenteric hemodynamic response to circulatory shock. Curr Opin Crit Care 9:127–132PubMedCrossRefGoogle Scholar
  30. 30.
    Oldenburg W, Lau L, Rodenberg T et al. (2004) Acute mesenteric ischemia. Arch Intern Med 164:1054–1062PubMedCrossRefGoogle Scholar
  31. 31.
    Lundberg J, Lundberg D, Norgren L et al. (1990) Intestinal hemodynamics during laparotomy: effects of thoracic epidural anesthesia and dopamine in humans. Anesth Analg 72:9–15Google Scholar
  32. 32.
    Holland J, Carey M, Hughes N et al. (2005) Intraoperative splanchnic hypoperfusion, increased intestinal permeability, down-regulation of monocyte class II major histocompatibility complex expression, exaggerated acute phase response, and sepsis. Am J Surg 190:393–400PubMedCrossRefGoogle Scholar
  33. 33.
    Stollman N, Metz D (2005) Pathophysiology and prophylaxis of stress ulcer in intensive care unit patients. J Crit Care 20:35–45PubMedCrossRefGoogle Scholar
  34. 34.
    Yilmaz S, Koken T, Tokyol C et al. (2003) Can preconditioning reduce laparoscopy-induced tissue injury. Surg Endosc 17:819–824PubMedCrossRefGoogle Scholar
  35. 35.
    Emir H, Akman M, Belce A et al. (2001) Is intestinal ischaemia a risk of laparoscopy? An experimental study in rabbits. Eur J Paediatr Surg 11:158–162CrossRefGoogle Scholar
  36. 36.
    Hasson H, Galanopoulos C, Langerman A (2004) Ischemic necrosis of small bowel following laparoscopic surgery. JSLS 8:159–163PubMedGoogle Scholar
  37. 37.
    Xian-Ping L, Ya-Xiong S, Cheng-Ren S et al. (1995) Changes in body fluid markers in intestinal ischemia. J Pediatr Surg 30:1412–1415CrossRefGoogle Scholar
  38. 38.
    Prichard M, Norm G, Ducharme P et al. (1991) Xanthine oxidase formation during experimental ischemia of the equine small intestine. Can J Vet Res 55:310–314PubMedGoogle Scholar
  39. 39.
    Cizova H, Papezikova I, Kubala L et al. (2006) Increased antioxidant capacity of serum did not prevent lipid peroxidation in the intermittent ischemia–reperfusion of rat small intestine. Dig Dis Sci 51:657–661PubMedCrossRefGoogle Scholar
  40. 40.
    Wilkins EG, Rees RS, Smith D (1993) Identification of xanthine oxidase activity following reperfusion in human tissue. Ann Plast Surg 31:60–65PubMedGoogle Scholar
  41. 41.
    Lammers K, Innocenti G, Venturi A (2003) The effect of transient intestinal ischemia on inflammatory parameters. Int J Colorectal Dis 18:78–85PubMedCrossRefGoogle Scholar
  42. 42.
    Flynn W, Pilati D, Hoover E (1997) Xanthine oxidase inhibition after resuscitated hemorrhagic shock restores mesenteric blood flow without vasodilation. Shock 8:300–304PubMedGoogle Scholar
  43. 43.
    Flynn W, Pilati D, Hoover E (1997) Xanthine oxidase inhibition prevents mesenteric blood flow deficits after resuscitated shock by preserving endothelial function. J Surg Res 68:175–180PubMedCrossRefGoogle Scholar
  44. 44.
    Flynn W, Pilati D, Hoover E (1999) Effect of allopurinol on venous endothelial dysfunction after resuscitated hemorrhagic shock. Int J Surg Invest 1:11–18Google Scholar
  45. 45.
    Flynn W, Hoover E (1994) Allopurinol plus standard resuscitation preserves hepatic blood flow and function following hemorrhagic shock. J Trauma 37:956–961PubMedGoogle Scholar
  46. 46.
    Pitt RM, McKelvey TG, Saenger JS et al. (1991) A tungsten-supplemented diet delivered by transplacental and breast-feeding routes lowers intestinal xanthine oxidase activity and affords cytoprotection in ischemia–reperfusion injury to the small intestine. J Pediatr Surg 26:930–935PubMedCrossRefGoogle Scholar
  47. 47.
    Megison SM, Horton JW, Chao H et al. (1990) Prolonged survival and decreased mucosal injury after low-dose enteral allopurinol prophylaxis in mesenteric ischemia. J Pediatr Surg 25:917–921PubMedCrossRefGoogle Scholar
  48. 48.
    Krasna I, Lee R (1993) Allopurinol protects the bowel from necrosis caused by indomethacin and temporary intestinal ischemia in mice. J Pediatr Surg 28:1175–1177PubMedCrossRefGoogle Scholar
  49. 49.
    Van Hoorn D, Nijveldt R, Boelens P et al. (2006) Effects of preoperative flavonoid supplementation on different organ function in rats. J Parental Enteral Nutr 30:302–308CrossRefGoogle Scholar
  50. 50.
    Hakguder G, Akgur FM, Ates O et al. (2002) Short-term intestinal ischemia–reperfusion alters intestinal motility that can be preserved by xanthine oxidase inhibition. Dig Dis Sci 47:1279–1283PubMedCrossRefGoogle Scholar
  51. 51.
    Megison SM, Horton JW, Chao H et al. (1990) High dose versus low dose enteral allopurinol for prophylaxis in mesenteric ischemia. Circ Shock 30:323–329PubMedGoogle Scholar
  52. 52.
    Terzi C, Kuzu A, Aslar AK et al. (2001) Prevention of deleterious effects of reperfusion injury using one-week high-dose allopurinol. Dig Dis Sci 46:430–437PubMedCrossRefGoogle Scholar
  53. 53.
    Grisham MB, Hernandez LA, Granger DN (1986) Xanthine oxidase and neutrophil infiltration in intestinal ischemia. Am J Physiol 251(4 Pt 1):G567–G574PubMedGoogle Scholar
  54. 54.
    Koike K, Moore FA, Moore EE et al. (1993) Gut ischemia mediates lung injury by a xanthine oxidase-dependent neutrophil mechanism. J Surg Res 54:469–473PubMedCrossRefGoogle Scholar
  55. 55.
    Nalini S, Mathan MM, Balasubramanian KA (1993) Oxygen free radical induced damage during intestinal ischemia/reperfusion in normal and xanthine oxidase deficient rats. Mol Cell Biochem 124:59–66PubMedCrossRefGoogle Scholar
  56. 56.
    Vaughan WG, Horton JW, Walker PB (1992) Allopurinol prevents intestinal permeability changes after ischemia–reperfusion injury. J Pediatr Surg 27:968–972; discussion 972–963PubMedCrossRefGoogle Scholar
  57. 57.
    Ferrer JV, Ariceta J, Guerrero D et al. (1998) Allopurinol and n-acetylcysteine avoid 60% of intestinal necrosis in an ischemia–reperfusion experimental model. Transplant Proc 30:2672PubMedCrossRefGoogle Scholar
  58. 58.
    Sola A, Hotter G, Parts N et al. (2000) Modification of oxidative stress in response to intestinal preconditioning. Transplantation 69:767–772PubMedCrossRefGoogle Scholar
  59. 59.
    Sola A, Alfaro V, Hotter G (2004) Intestinal ischemic preconditioning: less xanthine accumulation relates with less apoptosis. Apoptosis 9:353–361PubMedCrossRefGoogle Scholar
  60. 60.
    Sandrasegaran K, Maglinte D, Lappas J (2004) Small-bowel complications of major gastrointestinal tract surgery. AJR Am J Roentgenol 185:671–681Google Scholar
  61. 61.
    Slim K, Vicaut E, Panis Y et al. (2004) Meta-analysis of randomized clinical trials of colorectal surgery with or without mechanical bowel preparation. Br J Surg 91:1125–1130PubMedCrossRefGoogle Scholar
  62. 62.
    Calicis B, Parc Y, Caplin S et al. (2002) Treatment of postoperative peritonitis of small-bowel origin with continuous enteral nutrition and succus entericus reinfusion. Arch Surg 137:296–300PubMedCrossRefGoogle Scholar
  63. 63.
    Baker J, Deitch EA, Li M et al. (1988) Hemorrhagic shock induces bacterial translocation from the gut. J Trauma 28:896–906PubMedCrossRefGoogle Scholar
  64. 64.
    Rush B, Fedan J, Flanagan J et al. (1989) Does the bacteremia observed in hemorrhagic shock have clinical significance? Ann Surg 210:342–345PubMedCrossRefGoogle Scholar
  65. 65.
    Celik A, Aydemir S, Alkanat M et al. (2005) Hemorrhagic shock and bacterial translocation. J Appl Res 5:196–205Google Scholar
  66. 66.
    Sedman P, MacFie J, Sagar P et al. (1994) The prevalence of gut translocation in humans. Gastroenterology 107:643–649PubMedGoogle Scholar
  67. 67.
    Deitch EA, Bridges W, Baker J et al. (1998) Hemorrhagic shock-induced bacterial translocation is reduced by xanthine oxidase inhibition or inactivation. Surgery 104:191–198Google Scholar
  68. 68.
    Senthilkumar MP, Dreyer JS (2006) Peritoneal adhesions: pathogenesis, assessment and effects. Trop Gastroenterol 27:11–18PubMedGoogle Scholar
  69. 69.
    Ellis H (1962) The aetiology of postoperative abdominal adhesions. Br J Surg 50:10–16PubMedCrossRefGoogle Scholar
  70. 70.
    Rijhwani A, Sen S, Gunasekaran S et al. (1995) Allopurinol reduces the severity of peritoneal adhesions in mice. J Pediatr Surg 30:533–537PubMedCrossRefGoogle Scholar
  71. 71.
    Hall JC, Tarala RA, Hall JL et al. (1991) A multivariate analysis of the risk of pulmonary complications after laparotomy. Chest 99:923–927PubMedCrossRefGoogle Scholar
  72. 72.
    Lawrence V, Hilsenbeck S, Mulrow C et al. (1995) Incidence and hospital stay for cardiac and pulmonary complications after abdominal surgery. J Gen Intern Med 10:671–678PubMedCrossRefGoogle Scholar
  73. 73.
    Terada LS, Dormish JJ, Shanley PF et al. (1992) Circulating xanthine oxidase mediates lung neutrophil sequestration after intestinal ischemia–reperfusion. Am J Physiol 263(3 Pt 1):L394–L401PubMedGoogle Scholar
  74. 74.
    Thomas S, Karnik S, Balasubamanian KA (2002) Surgical manipulation of the small intestine and its effect on the lung. J Surg Res 106:145–156PubMedCrossRefGoogle Scholar
  75. 75.
    Nakamura M, Motoyama S, Saito S et al. (2004) Hydrogen peroxide derived from the intestine through mesenteric lymph induces lung edema after surgical stress. Shock 21:160–164PubMedCrossRefGoogle Scholar
  76. 76.
    Nielsen VG, Tan S, Baird MS et al. (1997) Xanthine oxidase mediates myocardial injury after hepatoenteric ischemia–reperfusion. Crit Care Med 25:1044–1050PubMedCrossRefGoogle Scholar
  77. 77.
    Lai I, Ma M, Chen C et al. (2003) The effect of an intestinal ischemia–reperfusion injury on renal nerve activity among rats. Shock 19:480–485PubMedCrossRefGoogle Scholar
  78. 78.
    Ramachandran A, Balasubamanian KA (2000) Protease activation during surgical stress in the rat small intestine. J Surg Res 92:283–290PubMedCrossRefGoogle Scholar
  79. 79.
    Smalley R, Guaspari A, Hasse-Statz S et al. (2000) Allopurinol: intravenous use for prevention and treatment of hyperuricemia. J Clin Oncol 18:1758–1763PubMedGoogle Scholar
  80. 80.
    Nijveldt R, van Nood E, van Hoorn D et al. (2001) Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr 74:418–425PubMedGoogle Scholar
  81. 81.
    Cohen DB, Magnotti LJ, Lu Q et al. (2004) Pancreatic duct ligation reduces lung injury following trauma and hemorrhagic shock. Ann Surg 240:885–891PubMedCrossRefGoogle Scholar
  82. 82.
    Deitch EA, Shi HP, Lu Q et al. (2003) Serine proteases are involved in the pathogenesis of trauma-hemorrhagic shock-induced gut and lung injury. Shock 19:452–456PubMedCrossRefGoogle Scholar
  83. 83.
    Ishimaru K, Mitsuoka H, Unno N et al. (2004) Pancreatic proteases and inflammatory mediators in peritoneal fluid during splanchnic arterial occlusion and reperfusion. Shock 22:467–471PubMedCrossRefGoogle Scholar
  84. 84.
    Fitzal F, DeLano FA, Young C et al. (2004) Improvement in early symptoms of shock by delayed intestinal protease inhibition. Arch Surg 139:1008–1016PubMedCrossRefGoogle Scholar
  85. 85.
    Fitzal F, DeLano FA, Young C et al. (2002) Pancreatic protease inhibition during shock attenuates cell activation and peripheral inflammation. Journal of Vascular Research 39:320–329PubMedCrossRefGoogle Scholar
  86. 86.
    Mitsuoka H, Kistler EB, Schmid-Schonbein GW (2002) Protease inhibition in the intestinal lumen: attenuation of systemic inflammation and early indicators of multiple organ failure in shock. Shock 17:205–209PubMedCrossRefGoogle Scholar

Copyright information

© Société Internationale de Chirurgie 2007

Authors and Affiliations

  • Anubhav Mittal
    • 1
  • Anthony R. J. Phillips
    • 1
  • Benjamin Loveday
    • 1
  • John A. Windsor
    • 1
  1. 1.Department of Surgery, Faculty of Medicine and Health SciencesUniversity of AucklandGraftonNew Zealand

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