Skip to main content
SpringerLink
Log in

Pentoxifylline attenuates ischemia/reperfusion injury to the small intestine in the rat

  • Original Article
  • Published:
Pediatric Surgery International Aims and scope Submit manuscript

Abstract

There is a large body of evidence that neutrophils may play an important role in the mucosal injury that follows ischemia of the intestine. Pentoxifylline (PTF), a methylxanthine derivative, prevents leukocyte adherence to vascular endothelium and restores intestinal blood flow following hemorrhagic shock and sepsis. The purpose of this study was to evaluate the protective properties of PTF in an ischemia-reperfusion model of the intestine and whether its action is mediated through tissue neutrophils as assessed by myeloperoxidase (MPO) determination. Intestinal ischemia of either 1 or 2 h was induced in rats by clamping the superior mesenteric artery, followed by a 17-min reperfusion period. PTF (25 mg/kg) or saline solution was injected IP 10 min prior to ischemia. Multiple bowel samples were harvested at the end of the reperfusion period and evaluated for histology and tissue MPO. PTF significantly changed the resultant histologic damage to the intestinal mucosa exerted by prolonged ischemia of 1 and 2 h duration, although the beneficial effect of PTF in this animal model was independent of the number of tissue neutrophils as assessed by tissue MPO levels. Pretreatment with PTF can thus reduce the histologic damage caused by prolonged ischemia to the intestine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Barroso AJ, Schmid SG (1990) Pentoxifylline pretreatment decreases the pool of circulating activated neutrophils, in-vivo adhesion to endothelium, and improves survival from hemorrhagic shock. Biorheology 27: 401–418

    Google Scholar 

  2. Berens KL, Langston JD, Wasan KM, Luke DR (1991) Influence of pentoxifylline and related analogues in endotoxemic renal failure. Circ Shock 34: 344–348

    PubMed  CAS  Google Scholar 

  3. Bessler H, Gilgal R, Djaldetti M, Zahavi I (1986) Effect of pentoxifylline on the phagocytic activity, cAMP levels, and superoxide anion production by monocytes and polymorphonuclear cells. J Leukoc Biol 40: 747–754

    PubMed  CAS  Google Scholar 

  4. Blume J, Ruhlmann KU, de la Haye R, Rettig K (1992) Treatment of chronic cerebrovascular disease in elderly patients with pentoxifylline. J Med 23: 417–432

    PubMed  CAS  Google Scholar 

  5. Boogaerts MA, Malbrain S, Meeus P, van Hove L, Verhoef GE (1990) In vitro modulation of normal and diseased human neutrophil function by pentoxifylline. Blut 61: 60–65

    Article  PubMed  CAS  Google Scholar 

  6. Bowton DL, Stump DA, Prough DS, Toole JF, Lefkowitz DS, Coker L (1989) Pentoxifylline increases cerebral blood flow in patients with cerebrovascular disease. Stroke 20: 1662–1666

    Article  PubMed  CAS  Google Scholar 

  7. Caplan MS, MacKendrick W (1993) Necrotizing enterocolitis: a review of pathogenetic mechanisms and implications for prevention. Pediatr Pathol 13: 357–369

    Article  PubMed  CAS  Google Scholar 

  8. Ciuffetti G, Mercuri M, Ott C, Lombardini R, Paltriccia R, Lupattelli G, Santambrogio L, Mannarino E (1991) Use of pentoxifylline as an inhibitor of free radical generation in peripheral vascular disease. Results of a double-blind placebo-controlled study. Eur J Clin Pharmacol 41: 511–515

    Article  PubMed  CAS  Google Scholar 

  9. Ciuffetti G, Paltriccia R, Lombardini R, Lupattelli G, Pasqualini L, Mannarino E (1994) Treating peripheral arterial occlusive disease: pentoxifylline vs exercise. Int Angiol 13: 33–39

    PubMed  CAS  Google Scholar 

  10. Dauber IM, Lesnefsky EJ, Ashmore RC, Martel DM, Sheridan FM, Weil JV, Horwitz LD (1992) Coronary vascular injury due to ischemia-reperfusion is reduced by pentoxifylline. J Pharmacol Exp Ther 260: 1250–1256

    PubMed  CAS  Google Scholar 

  11. Dettelbach HR, Aviado DM (1985) Clinical pharmacology of pentoxifylline with special reference to its hemorrheologic effect for the treatment of intermittent claudication. J Clin Pharmacol 25: 8–26

    Article  PubMed  CAS  Google Scholar 

  12. Ernst E, Kollar L, Resch KL (1992) Does pentoxifylline prolong the walking distance in exercised claudicants? A placebo-controlled double-blind trial. Angiology 43: 121–125

    Article  PubMed  CAS  Google Scholar 

  13. Flynn WJ, Cryer HG, Garrison RN (1991) Pentoxifylline but not saralasin restores hepatic blood flow after resuscitation from hemorrhagic shock. J Surg Res 50: 616–621

    Article  PubMed  CAS  Google Scholar 

  14. Flynn WJ, Cryer HG, Garrison RN (1991) Pentoxifylline restores intestinal microvascular blood flow during resuscitated hemorrhagic shock. Surgery 110: 350–356

    PubMed  CAS  Google Scholar 

  15. Granger DN, Kvietys PR, Perry MA (1993) Leukocyte-endothelial cell adhesion induced by ischemia and reperfusion. Can J Physiol Pharmacol 71: 67–75

    Article  PubMed  CAS  Google Scholar 

  16. Grisham MB, Benoit JN, Granger DN (1990) Assessment of leukocyte involvement during ischemia and reperfusion of intestine. Methods Enzymol 186: 729–742

    Article  PubMed  CAS  Google Scholar 

  17. Hadjiminas DJ, McMasters KM, Robertson SE, Cheadle WG (1994) Enhanced survival from cecal ligation and puncture with pentoxifylline is associated with altered neutrophil trafficking and reduced interleukin-1 beta expression but not inhibition of tumor necrosis factor synthesis. Surgery 116: 348–355

    PubMed  CAS  Google Scholar 

  18. Hakim TS, Petrella J (1988) Attenuation of pulmonary and systematic vasoconstriction with pentoxifylline and aminophylline. Can J Physiol Pharmacol 66: 396–401

    Article  PubMed  CAS  Google Scholar 

  19. Hewett JA, Jean PA, Kunkel SL, Roth RA (1993) Relationship between tumor necrosis factor-alpha and neutrophils in endotoxin-induced liver injury. Am J Physiol 265: G1011-G1015

    PubMed  CAS  Google Scholar 

  20. Ishizaka A, Hatherill JR, Harada H, Yonemaru M, Hoffman H, Zheng H, O'Hanley PT, Raffin TA (1989) Prevention of interleukin 2-induced acute lung injury in guinea pigs by pentoxifylline. J Appl Physiol 67: 2432–2437

    PubMed  CAS  Google Scholar 

  21. Jewett A, Bonavida B (1994) Pentoxifylline suppresses interleukin-2-mediated activation of immature human natural killer cells by inhibiting endogenous tumor necrosis factor-alpha secretion. J Clin Immunol 14: 31–38

    Article  PubMed  CAS  Google Scholar 

  22. Korthuis RJ, Granger DN (1993) Reactive oxygen metabolites, neutrophils, and the pathogenesis of ischemic-tissue/reperfusion. Clin Cardiol 16: 119–126

    Article  Google Scholar 

  23. Kremsner PG, Neifer S, Chaves MF, Rudolph R, Bienzle U (1992) Interferon-gamma induced lethality in the late phase of Plasmodium vinckei malaria despite effective parasite clearance by chloroquine. Eur J Immunol 22: 2873–2878

    Article  PubMed  CAS  Google Scholar 

  24. Langer JC, Sohal SS, Mumford DA (1993) Mucosal permeability in the immature rat intestine: effects of ischemia-reperfusion, cold stress, hypoxia, and drugs. J Pediatr Surg 28: 1380–1383

    Article  PubMed  CAS  Google Scholar 

  25. Mavrelis PG, Doumanian H (1987) Pentoxifylline for mesenteric ischemia. Am J Gastroenterol 82: 175

    PubMed  CAS  Google Scholar 

  26. Megison SM, Horton JW, Chao H, Walker PB (1990) A new model for intestinal ischemia in the rat. J Surg Res 49: 168–173

    Article  PubMed  CAS  Google Scholar 

  27. Michal M, Giessinger N, Schroer R (1989) Reduced thrombus formation in vivo after administration of pentoxifylline (Trental). Thromb Res 56: 359–368

    Article  PubMed  CAS  Google Scholar 

  28. Mitsudo S, Brandt LJ (1992) Pathology of intestinal ischemia. Surg Clin North Am 72: 43–63

    PubMed  CAS  Google Scholar 

  29. Mollitt DL, Poulos ND (1991) The role of pentoxifylline in endotoxin-induced alterations of red cell deformability and whole blood viscosity in the neonate. J Pediatr Surg 26: 572–574

    Article  PubMed  CAS  Google Scholar 

  30. Musemeche CA, Pizzini RP, Andrassy RJ (1993) Intestinal ischemia in the newborn: the role of intestinal maturation. J Surg Res 55: 595–598

    Article  PubMed  CAS  Google Scholar 

  31. Prada J, Prager C, Neifer S, Bienzle U, Kremsner PG (1993) Production of interleukin-6 by human and murine mononuclear leukocytes stimulated with Plasmodium antigens and tumor necrosis factor secretion is reduced. Infect Immun 61: 2737–2740

    PubMed  CAS  Google Scholar 

  32. Raj JU, Kaapa P, Anderson J (1992) Age-related differences in vascular effects of pentoxifylline in isolated perfused ferret lungs. Dev Pharmacol Ther 18: 1–8

    PubMed  CAS  Google Scholar 

  33. Refsum SE, Norwood W, Rowlands BJ, Boston VE (1993) Pentoxifylline improves resting membrane potential in sepsis. J Pediatr Surg 28: 1144–1146

    Article  PubMed  CAS  Google Scholar 

  34. Reignier J, Mazmanian M, Detruit H, Chapelier A, Weiss M, Libert JM, Herve P (1994) Reduction of ischemia-reperfusion injury by pentoxifylline in the isolated rat lung. Paris-Sud University Lung Transplantation Group. Am J Respir Crit Care Med 150: 342–347

    Article  PubMed  CAS  Google Scholar 

  35. Schade UF (1990) Pentoxifylline increases survival in murine endotoxin shock and decreases formation of tumor necrosis factor. Circ Shock 31: 171–181

    PubMed  CAS  Google Scholar 

  36. Schroer RH (1985) Antithrombotic potential of pentoxifylline. A hemorrheologically active drug. Angiology 36: 387–398

    Article  PubMed  CAS  Google Scholar 

  37. Sigurdsson GH, Youssef H (1993) Effects of pentoxifylline on hemodynamics, gas exchange and multiple organ platelet sequestration in experimental endotoxic shock. Acta Anaesthesiol Scand 37: 396–403

    Article  PubMed  CAS  Google Scholar 

  38. Suzuki K, Ota H, Sasagawa S, Sakatani T, Fujikura T (1983) Assay method for myeloperoxidase in human polymorphonuclear leukocytes. Anal Biochem 132: 345–352

    Article  PubMed  CAS  Google Scholar 

  39. Tighe D, Moss R, Hynd J, Boghossian S, Saady N, Heath MF, Bennett ED (1990) Pretreatment with pentoxifylline improves the hemodynamic and histologic changes and decreases neutrophil adhesiveness in a pig fecal peritonitis model. Crit Care Med 18: 184–189

    Article  PubMed  CAS  Google Scholar 

  40. Toung TJ, Kirsch JR, Maruki Y, Traystman RJ (1994) Effects of pentoxifylline on cerebral blood flow, metabolism, and evoked response after total cerebral ischemia in dogs. Crit Care Med 22: 273–281

    Article  PubMed  CAS  Google Scholar 

  41. Udassin R, Ariel I, Haskel Y, Kitrossky N, Chevion M (1991) Salicylate as an in vivo free radical trap: studies on ischemic insult to the rat intestine. Free Radic Biol Med 10: 1–6

    Article  PubMed  CAS  Google Scholar 

  42. Udassin R, Vromen A, Haskel Y (1994) The time sequence of injury and recovery following transient reversible intestinal ischemia. J Surg Res 56: 221–225

    Article  PubMed  CAS  Google Scholar 

  43. van Leenen D, van der Poll T, Levi M, ten Cate H, van Deventer S, Hack CE, Aarden LA, ten Cate J (1993) Pentoxifylline attenuates neutrophil activation in experimental endotoxemia in chimpanzees. J Immunol 151: 2318–2325

    PubMed  Google Scholar 

  44. Wang P, Ba ZF, Zhou M, Tait SM, Chaundry IH (1993) Pentoxifylline restores cardiac output and tissue perfusion after traumahemorrhage and decreases susceptibility to sepsis. Surgery 114: 352–358

    PubMed  CAS  Google Scholar 

  45. Waxman K, Eloi L, Dinh L, Scannell G, Tominaga GT (1993) Pentoxifylline alone versus pentoxifylline combined with superoxide dismutase prolongs survival in a rat hemorrhagic shock model. Resuscitation 26: 237–242

    Article  PubMed  CAS  Google Scholar 

  46. Yonemaru M, Hatherill JR, Hoffman H, Zheng H, Ishii K, Raffin TA (1991) Pentoxifylline does not attenuate acute lung injury in the absence of granulocytes. J Appl Physiol 71: 342–351

    PubMed  CAS  Google Scholar 

  47. Zabel P, Schade FU, Schlaak M (1993) Inhibition of endogenous TNF formation by pentoxifylline. Immunobiology 187: 447–463

    Article  PubMed  CAS  Google Scholar 

  48. Zheng H, Crowley JJ, Chan JC, Raffin TA (1991) Attenuation of LPS-induced neutrophil thromboxane b2 release and chemiluminescence. J Cell Physiol 146: 264–269

    Article  PubMed  CAS  Google Scholar 

  49. Zimmerman BJ, Granger DN (1992) Reperfusion injury. Surg Clin North Am 72: 65–83

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatric Surgery, Hadassah University Hospital Mount Scopus, IL-91240, Jerusalem, Israel

    R. Udassin, A. Vromen, D. Seror & Y. Haskel

Authors
  1. R. Udassin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Vromen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Seror
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y. Haskel
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Udassin, R., Vromen, A., Seror, D. et al. Pentoxifylline attenuates ischemia/reperfusion injury to the small intestine in the rat. Pediatr Surg Int 11, 329–333 (1996). https://doi.org/10.1007/BF00497805

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00497805

Key words

Search

Navigation