The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지

Protective Effect of Defibrotide on Splanchnic Injury following Ischemia and Reperfusion in Rats

  • Choi, Soo-Ran (Department of Pharmacology, College of Medicine, Chung-Ang University) ;
  • Jeong, Ji-Hoon (Department of Pharmacology, College of Medicine, Chung-Ang University) ;
  • Song, Jin-Ho (Department of Pharmacology, College of Medicine, Chung-Ang University) ;
  • Shin, Yong-Kyoo (Department of Pharmacology, College of Medicine, Chung-Ang University)
  • Published : 2006.04.21
Download PDF
⟨ Previous Next ⟩

Abstract

A splanchic artery occlusion for 90 min followed by reperfusion of the mesenteric circulation resulted in a severe form of circulatory shock, characterized by endothelial dysfunction, severe hypotension, marked intestinal tissue injury, and a high mortality rate. The effect of defibrotide, a complex of single-stranded polydeoxyribonucleotides having antithrombotic effect, was investigated in a model of splanchnic artery occlusion (SAO) shock in urethane anesthetized rats. Occlusion of the superior mesenteric artery for 90 min produced a severe shock state, resulting in a fatal outcome within 120 min of reperfusion in many rats. Defibrotide (10 mg/kg body weight) 10 min prior to reperfusion significantly improved mean arterial blood pressure in comparison to vehicle treated rats (p＜0.05). Defibrotide treatment also significantly attenuated in the increase of plasma amino nitrogen concentration, intestinal myeloperoxidase activity, intestinal lipid peroxidation, infiltration of neutrophils in intestine and thrombin induced adherence of neutrophils to superior mesentric artery segments. Superoxide anion and hydrogen peroxide production in $1{\mu}M$ formylmethionylleucylphenylalanine (fMLP)-activated PMNs was inhibited by defibrotide in a dose-dependent fashion. Defibrotide effectively scavenged hydrogen peroxide, but not hydroxyl radical. Treatment of SAO rats with defibrotide inhibited tumor necrosis factor-${\alpha}$, and interleukin-1${\beta}$ productions in blood in comparison with untreated rats. These results suggest that defibrotide partly provides beneficial effects by preserving endothelial function, attenuating neutrophil accumulation, and antioxidant in the ischemic reperfused splanchnic circulation

Keywords

References

  1. Allen AO, Hochanadel CJ, Ghormley JA, Davis TW. Decomposition of water and aqueous solutions under mixed fast neutron and gamma radiation. J Phys Chem 56: 575-586, 1952 https://doi.org/10.1021/j150497a007
  2. Ambrosio G, Flaherty JT. Effects of the superoxide radical scavenger superoxide dismutase, and of the hydroxyl radical scavenger mannitol, on reperfusion injury in isolated rabbit hearts. Cardiovasc Drugs Ther 6: 623-632, 1992 https://doi.org/10.1007/BF00052564
  3. Armstead VE, Minchenko AG, Schuhl RA, Hayward R, Nossuli TO, Lefer AM. Regulation of P-selectin expression in human endothelial cells by nitric oxide. Am J Physiol 42: H740-H746, 1997
  4. Aruoma OI. Deoxyribose assay for detecting hydroxyl radicals, In: Packer L ed, Methods Enzymol 233. p 57-66, 1994 https://doi.org/10.1016/S0076-6879(94)33008-5
  5. Bianchi G, Barone D, Lanzarotti E, Tettamanti R, Porta R, Moltrasio D, Cedro A, Salvetti L, Mantovani M, Prino G. Defibrotide, a single-stranded polydeoxyribonucleotides acting as an adenosine receptor agonist. Eur J Pharmacol 238: 327-334, 1993 https://doi.org/10.1016/0014-2999(93)90864-E
  6. Crow JP, Beckman JS. The role of peroxynitrite in nitric oxidemediated toxicity. Current Top Microbiol Immunol 1996: 57-73, 1995
  7. Bittermann H, Aoki N, Lefer AM. Anti-shock effects of human superoxide dismutase in splanchnic occlusion shock. Proc Soc Exp Biol Med 188: 256-271, 1988
  8. Bradly PP, Priebaat DA, Christensen RD, Rohstein GR. Measurement ofcutaneous inflammation: Estimation of the neutrophil content with an enzyme marker. J Invest Dermatol 78: 206-209, 1985
  9. Buerke M, Weyrich AS, Zheng Z, Gaeta FCA, Forrest MJ, Lefer AM. Sialyl Lewisx- containing oligosaccharide attenuates myocardial reperfusioninjury in cats. J Clin Invest 93: 1140-1148, 1994 https://doi.org/10.1172/JCI117066
  10. Butcher EC. Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell 67: 1033-1036, 1991 https://doi.org/10.1016/0092-8674(91)90279-8
  11. Butcher EC. Leukocyte-endothelial cell adhesion as an active, multi-step process: a combinatorial mechanism for specificity and diversity in leukocyte targeting. Adv Exp Med Biol 323: 181 -194, 1992
  12. Butcher EC. Specificity of leukocyte-endothelial interaction and diapedesis: physiologic and therapeutic implications of an active decision process. Res Immunol 144: 695-698, 1993 https://doi.org/10.1016/S0923-2494(93)80053-2
  13. Carey C, Siegfried MR, Ma XL, Weyrich AS, Lefer AM. Antishock and endothelial protective actions of a NO donor in mesenteric ischemia and reperfusion. Circ Shock 38: 209-216, 1992
  14. De Caaterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone Jr. MA, Shin WS, Liao JK. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 96: 60-68, 1995 https://doi.org/10.1172/JCI118074
  15. Deitch EA, Bridges W, Berg R, Specian RD, Granger N. Hemorrhagic shock-induced bacterial translocation: The role of neutrophils and hydroxyl radicals. J Trauma 30: 942-951, 1990 https://doi.org/10.1097/00005373-199008000-00002
  16. Dix TA, Hess KM, Medina MA, Sullivan RW, Tilly SL, Webb TLL. Mechanism of site-selective DNA nicking by the hydrodioxyl (perhydroxy) radical. Biochemistry 35: 4578-4583, 1996 https://doi.org/10.1021/bi952010w
  17. Grill HP, Zweier JL, Kuppusamy P, Weisfeldt ML, Flaherty JT. Direct measurement of myocardial free radical generation in an in vivo model: Effects of postischemic reperfusion and treatment with human recombinant superoxide dismutase. J Am Coll Cardilo 20: 1604-1611, 1992 https://doi.org/10.1016/0735-1097(92)90457-X
  18. Goossens DP, Rao VK, Harms BA, Starling JR. Superoxide dismutase and catalase in skin flaps during venous occlusion and reperfusion. Ann Plast Surg 1: 21-25, 1990
  19. Granger DN. Cel adhesion and migration. II. Leukocyte-endothelial cell adhesion in the digestive system. Am J Physiol 273: G982- G986, 1977
  20. Grisham MB, Hernandez LA, Granger DN. Xanthin oxidase and neutrophil infiltration in intestinal ischemia. Am J Physiol 251: G456-G462, 1986
  21. Gutteridge JMC. Thiobarbituric acid-reactivity following iron- dependent free radical damage to amino acids and carbohydrates. FEBS Lett 128: 343-346, 1981 https://doi.org/10.1016/0014-5793(81)80113-5
  22. Haglind HP, Xia G, Rylander R. Effects of antioxidants and PAF receptor antagonist in intestinal shock in the rat. Circ Shock 42: 83-91, 1994
  23. Halliwell B, Gutteridge JMC. The role of iron in free radical reactions. Medical biochemical and chemical aspects of free radicals. In: Hayaishi O, Niki E, Kondo M, Yoshikawa T ed, Elsevier Science. Publishers BV, Amsterdam, p 21-32, 1989
  24. Huie RE, Padmaja S. The reaction of NO with superoxide. Free Radic Res Commun 18: 195-199, 1993 https://doi.org/10.3109/10715769309145868
  25. Johnston B, Kanwar S, Kubes P. Hydrogen peroxide induces leukocyte rolling: modulation by endogenous antioxidant mechanism including NO. Am J Physiol 271: H614-H621, 1996
  26. Karasawa A, Guo JP, Ma XL, Tsao PS, Lefer AM. Protective actions of a leukotriene B4 antagonist in splanchnic ischemia and reperfusion in rats. Am J Physiol 261: G191-G198, 1991
  27. Kim KJ, Shin YK, Song JH, Oh BK, Choi MS, Sohn UD. Effects of defibrotide, a novel oligodeoxyribonucleotide, on ischaemia and reperfusion injury of the rat liver. Auton Autac Pharmacol 22: 37-46, 2002 https://doi.org/10.1046/j.1474-8673.2002.00240.x
  28. Klcking HP. Acute t-PA release by defibrotide. Thromb Res 66: 779- 785, 1992 https://doi.org/10.1016/0049-3848(92)90054-E
  29. Lafrado LJ, Olsen. Demonstration of depressed polymorphonuclear leukocyte function in non-viremic FeLV-infected cats. Cancer Invest 4: 297-300, 1986 https://doi.org/10.3109/07357908609017509
  30. Lanzarototti E, Porta R, Mantovani M, Cedro A, Prino G, Moltrasio D. New oligodeoxynucleotides having anti-ischemic activity and methods or preparation thereof. Eur Patent Publication number 0 558 833 A2, 1993
  31. Lawrence MB, Springer TA. Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins. Cell 65: 859-873, 1991 https://doi.org/10.1016/0092-8674(91)90393-D
  32. Lefer AM, Barenholz Y. Pancreatic hydrolases and the formation of a myocardial depressant factor in shock. Am J Physiol 223: 1103-1109, 1972
  33. Lefer AM, Lefer DJ. Pharmacology of the endothelium in ischemiareperfusion and circulatory shock. Annu Rev Pharmacol Toxicol 33: 71-90, 1993 https://doi.org/10.1146/annurev.pa.33.040193.000443
  34. Lefer AM, Nakanishi K, Johnston WE, Vinten-Johansen J. Antineutrophil and myocardial protecting actions of a novel nitric oxide donor after acute myocardial ischemia and reperfusion in dogs. Circulation 88: 2337-2350, 1993 https://doi.org/10.1161/01.CIR.88.5.2337
  35. Lefer AM, Tsao PS, Lefer DJ, Ma XL. Role of endothelial dysfunction in the pathogenesis of reperfusion injury after myocardial ischemia. FASEB J 5: 2029-2034, 1991 https://doi.org/10.1096/fasebj.5.7.2010056
  36. Ma X, Tsao PS, Lefer AM. Antibody to CD-18 exerts endothelial and cardiac protective effects in myocardial ischemia and reperfusion. J Clin Invest 88: 1237-1243, 1991 https://doi.org/10.1172/JCI115427
  37. Markert M, Andrews PC, Babior BM. Measurement of O-2 production by human neutrophils, the preparation and assay of NADPH oxidase-containing particles from human neutrophils. In: Packer L ed, Methods Enzymol 105. Academic Press, Orlando, FL, p. 358-365, 1984
  38. Misko TP, Highkin MK, Veenhuizen AW, Manning PT, Stern MK, Currie MG, Salvemini D. Characterization of the cytoprotective action of peroxynitrite decomposition catalysts. J Buik Chem 273: 15646-15653, 1998 https://doi.org/10.1074/jbc.273.25.15646
  39. Morpurgo E, Cadrobbi R, Morpugo M, Rigotti P, Schiavon F, Schiavon O, Caliceti P, Ancona E, Veronese FM. Protective effect of superoxide dismutase and polyethylene glycol-linked superoxide dismutase against renal warm ischemia/reperfusion injury. Transplantation 62: 1221-1223, 1996 https://doi.org/10.1097/00007890-199611150-00006
  40. Mullane KM, Kraemer R, Smith B. Myeloperoxidase activity as a quantitative assessment of neutrophil infiltration into ischemic myocardium. J Pharmacol Methods 14: 157-167, 1985 https://doi.org/10.1016/0160-5402(85)90029-4
  41. Mullane KM, Westlin W, Kraemer R. Activated neutrophils release mediators that may contribute to myocardial injury and dysfunction associated with ischemia and reperfusion. Ann NY Acad Sci 524: 103-121, 1988 https://doi.org/10.1111/j.1749-6632.1988.tb38534.x
  42. Niada R, Porta R, Pescador R, Mantovani M, Prino G. Protective activity of defibrotide against lethal acute myocardial ischemia in the cat. Thromb Res 42: 363-374, 1986 https://doi.org/10.1016/0049-3848(86)90265-3
  43. Palmer KJ, Goa KL. Defibrotide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders. Drugs 45: 259-294, 1993
  44. Pick E, Mizell D. Rapid microassays for the measurement of superoxide and hydrogen peroxide production by macrophages in culture using an automatic immunoassay reader. J Immunol Methods 46: 211-226, 1981 https://doi.org/10.1016/0022-1759(81)90138-1
  45. Placer ZA, Cushman LL and Johnson BC; Estimation of product of lipid peroxidation (malonyl dialdehyde) in biological systems. Anal Biochem 16: 359-364, 1966 https://doi.org/10.1016/0003-2697(66)90167-9
  46. Ratych RE, Chuknyska RS, Burkley GB. The primary localisation of free radical gereation after anoxia/reoxygenation in isolated endothelial cells. Surgery 102: 122-131, 1987
  47. Rubanyi GM, Ho EH, Canto EH, Lumma WC, Parker-Botelho LH. Cytoprotective function of nitric oxide; Inactivation of superoxide radicals produced by human leukocytes. Biochem Biophys Res Commun 181: 1392-1397, 1991 https://doi.org/10.1016/0006-291X(91)92093-Y
  48. Rubin H, Plotnick M, Wang Z, Liu X, Zhong Q, Schechter NM, Cooperman BS. Conversion of 1-antichymotrypsin into a human neutrophil elastase inhibitor: Demonstration of variants with different association rate constants, stoichiometries of inhibition, and complex stabilities. Biochemistry 33: 7627-7633, 1994 https://doi.org/10.1021/bi00190a016
  49. Salvemini D, Currie MG, Mollace V. Nitric oxide-mediated cyclooxygenase activation. A key event in the antiplatelet effects of nitrovasodilators. J Clin Invest 97: 2562-2568, 1996 https://doi.org/10.1172/JCI118704
  50. Salvemini D, Riley DP, Lennon PJ, Wang ZQ, Currie MG, MacArthur H, Misko TP. Protective effects of a superoxide dismutase mimetic and peroxynitrite decomposition catalysts in endotoxininduced intestinal damage. Br J Pharmacol 127: 685-692, 1999a https://doi.org/10.1038/sj.bjp.0702604
  51. Salvemini D, Wang ZQ, Zweier JL, Samouilov A, MacArthur H, Misko TP, Currie MG, Cuzzocrea S, Sikorski JA, Riley DP. A nonpeptidyl mimetic of superoxide dismutase with therapeutic activity in rats. Science 286: 304-306, 1999b https://doi.org/10.1126/science.286.5438.304
  52. Shutenko Z, Henry Y, Pinard E, Seylaz J, Potier P, Berthet F, Girard P, Sercombe R. Influence of the antioxidant quercetin in vivo on the level ofnitric oxide determined by electron paramagnetic resonance in rat brain during global ischemia and reperfusion. Biochem Pharmacol 57: 199-208, 1999 https://doi.org/10.1016/S0006-2952(98)00296-2
  53. Suzuki M, Inauen W, Kvietys PR, Grisham MB, Meininger C, Schelling ME, Granger HJ, Granger DN. Superoxide mediates reperfusion-induced leukocyte-endothelial cell interactions. Am J Physiol 257: H1740-H1745, 1989
  54. Takada M, Nadeau KC, Shaw GD, Marquette KA, Tilney NL. The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand. J Clin Invest 99: 2682-2690, 1997 https://doi.org/10.1172/JCI119457
  55. Weyrich AS, Ma XL, Lefer DJ, Albertine KH, Lefer AM. In vivo neutralization of P-selectin protects feline heart and endothelium in myocardial ischemia and reperfusion injury. J Clin Invest 91: 2620-2629, 1993 https://doi.org/10.1172/JCI116501
  56. Xia ZF, Hollyoak M, Barrow RE, He F, Muller MJ, Herndon DN. Superoxide dismutase and leupeptin prevent delayed reperfusion injury in the rat small intestine during burn shock. J Burn Care Rehab 16: 111-117, 1995 https://doi.org/10.1097/00004630-199503000-00004
  57. Yoshikawa T, Naito Y, Ueda S, Takahashi S, Oyamada H, Yoneta T, Sugino S, Kondo M. Ischemia-reperfusion injury and free radical involvement in gastric mucosal disorders. Adv Exp Med Biol 264: 401-410, 1990
  58. Yuan Y, Fleming BP. A method for isolation and fuorescent labeling of rat neutrophils for intravital microvascular studies. Microvasc Res 40: 218-229, 1990 https://doi.org/10.1016/0026-2862(90)90021-I
  59. Zimmermann BJ, Arndt H, Kubes P, Kurtel H, Granger DN. Reperfusion injury in the small intestine. In: Schlag G, Redl H ed, Pathophysiology of Shock. Sepsis and Organ Failure, Springer- Verlag, Berlin, p 322-335, 1993