The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지

Effect of Defibrotide on Rat Reflux Esophagitis

  • Kim, Hyoung-Ki (Department of Pharmacology, College of Medicine, Chung-Ang University) ;
  • Choi, Soo-Ran (Department of Pharmacology, College of Medicine, Chung-Ang University) ;
  • Choi, Sang-Jin (Department of Pharmacology, College of Medicine, Chung-Ang University) ;
  • Chio, Myung-Sup (Department of Pharmacology, College of Medicine, Chung-Ang University) ;
  • Shin, Yong-Kyoo (Department of Pharmacology, College of Medicine, Chung-Ang University)
  • Published : 2004.12.21
Download PDF
⟨ Previous Next ⟩

Abstract

This study was aimed at evaluating the effect of defibrotide on the development of the surgically induced reflux esophagitis, on gastric secretion, lipid peroxidation, polymorphonuclear leukocytes (PMNs) accumulation, polymorphonuclear leukocytes adherence, superoxide anion and hydrogen peroxide production in PMNs, scavenge of hydroxyl radical and hydrogen peroxide, cytokine (interleukin-1 ${\beta}$, tumor necrosis $factor-{\alpha}$) production in blood, and intracelluar calcium mobilization in PMNs. Defibrotide did not inhibit the gastric secretion and not change the gastric pH. Treatment of esophagitis rats with defibrotide inhibited lipid peroxidation, and myeloperoxidase (MPO) in the esophagus in comparison with untreated rats. Defibrotide significantly decreased the PMN adherence to superior mesenteric artery endothelium in a dose-dependent manner, Superoxide anion and hydrogen peroxide production in $1{\mu}M$ formylmethionylleucylphenylalanine (fMLP)- or $0.1{\mu}g/ml$ N-phorbol 12-myristate 13-acetate (PMA)-activated PMNs was inhibited by defibrotide in a dose-dependent fashion. Defibrotide effectively scavenged the hydrogen peroxide but did not scavenge the hydroxyl radical. Treatment of esophagitis rats with defibrotide inhibited interleukin-1 ${\beta}$ production in the blood in comparison with untreated rats, but tumor necrosis $factor-{\alpha}$ production was not affected by defibrotide. The fMLP-induced elevation of intracellular calcium in PMNs was inhibited by defibrotide. The results of this study suggest that defibrotide may have partly beneficial protective effects against reflux esophagitis by the inhibition lipid peroxidation, PMNs accumulation, PMNs adherence to endothelium, reactive oxygen species production in PMNs, inflammatory cytokine production(i.e. interleukin-1 ${\beta}$), and intracellular calcium mobilization in PMNs in rats.

Keywords

References

  1. Akira S, Hirano T, Toga T, Kishimoto T. Biology of multifunctional cytokines: IL-6 and related molecules (IL-1 and TNF). FASEB J 4: 2860－2867, 1990 https://doi.org/10.1096/fasebj.4.11.2199284
  2. 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
  3. Aruoma OI. Deoxyribose assay for detecting hydroxyl radicals, in: Methods Enzymol 233 (Ed. Packer L), pp 57－66, 1994
  4. Bell NJV, Burget D, Howden CW, Wilkinson J, Hunt RH. Appropriate acid suppression for the management of gastroesophageal reflux disease. Digestion 51: 59－67, 1992 https://doi.org/10.1159/000200917
  5. Berridge MJ. Inositol triphosphate and calcium signaling. Nature 361: 315－325, 1993 https://doi.org/10.1038/361315a0
  6. 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
  7. Biancani P, Sohn UD, Rich HG, Harnett KM, Behar J. Signal transduction pathways in esophageal and lower esophageal sphincter circular muscle. Am J Med 103(5A): 23S－28S, 1997 https://doi.org/10.1016/S0002-9343(97)00316-1
  8. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Annal Biochem 72: 248－254, 1976 https://doi.org/10.1016/0003-2697(76)90527-3
  9. Bradly PP, Priebaat DA, Christensen RD, Rohstein GR. Measurement of cutaneous inflammation: Estimation of the neutrophil content with an enzyme marker. J Invest Dermatol 78: 206－209, 1985 https://doi.org/10.1111/1523-1747.ep12506462
  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. Davies GR, Simmonds NJ, Stevens TRJ, Sheaff MT, Banatvala N, Laurenson IF, Blake DR, Rampton DS. Helicobacter pylori stimulates antral mucosal reactive oxygen metabolite production in vivo. Gut 35: 179－185, 1994 https://doi.org/10.1136/gut.35.2.179
  12. Dinarello CA. The pro-inflammatory cytokines interleukin- 1 and tumour necrosis factor and treatment of the septic shock syndrome. J Infect Dis 163: 1177－1184, 1991 https://doi.org/10.1093/infdis/163.6.1177
  13. Goldstein IM, Hoffstein ST, Weissmann G. Influence of divalent cations upon complement-mediated enzyme release from human polymorphonuclear leukocytes. J Immunol 115: 665－670, 1975
  14. 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
  15. Haegele AD, Briggs SP, Thompson HJ. Antioxidant status and dietary lipid unstruration modulate oxidant DNA damage. Free Radic Biol Med 16: 111－115, 1994 https://doi.org/10.1016/0891-5849(94)90247-X
  16. Halliwell B, Gutteridge JMC. The role of iron in free radical reactions. Medical biochemical and chemical aspects of free radicals. (Ed. Hayaishi O, Niki E, Kondo M, Yoshikawa T). pp 21－32, Elsevier Science Publishers BV, Amsterdam, 1989
  17. Hohlfeld T, Strobach H, Schror K. Stimulation of endogenous prostacyclin protects the reperfused pig myocardium from ischemic injury. J Pharmacol Exp Ther 264: 397－405, 1993
  18. Ito M, Suzuki Y, Ishihara M, Suzuki Y. Anti-ulcer effects of anti-oxidants: effect of probucol. Eur J Pharmacol 354: 189－ 196, 1998 https://doi.org/10.1016/S0014-2999(98)00448-8
  19. Kil BJ, Kim IW, Shin CY, Jeoung JH, Jun CH, Lee SM, Kim DY, Huh IH, Sohn UD. The comparison of IY81149 with omerazole in rat reflux esophagitis. J Auton Pharmacol 20: 291－296, 2000 https://doi.org/10.1046/j.1365-2680.2000.00192.x
  20. Klcking HP. Acute t-PA release by defibrotide. Thromb Res 66: 779 －785, 1992 https://doi.org/10.1016/0049-3848(92)90054-E
  21. 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
  22. Lefer DJ, Scalia R, Campbell B, Nossuli T, Salamon M, Grayson J, Lefer AM. Peroxynitrite inhibits leukocyte- endothelial cell interactions and protects against ischemia-reperfusion injury in rats. J Clin Invest 799: 684－691, 1997
  23. Lorant DE, Patel KD, McIntyre TM, McEver RP, Presscott SA, Zimmermann GA. Coexpression of GMP-140 and PAF by endothelium stimulated by histamine or thrombin: A juxtracrine system for adhesion and activation of neutrophils. J Cell Biol 115: 223－234, 1991 https://doi.org/10.1083/jcb.115.1.223
  24. Luscinskas FW, Nicolaou KC, Webber SE, Veale CA, Gimbrone MA Jr, Serhan CN. Ca2+ mobilization with leukotriene A4 and epoxytetraences in human neutrophils. Biochem Pharmacol 39: 355－365, 1990 https://doi.org/10.1016/0006-2952(90)90035-J
  25. 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
  26. Malech HL, Gallin JI. Neutrophils in human diseases. New Engl J Med 317: 687－694, 1987 https://doi.org/10.1056/NEJM198709103171107
  27. 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
  28. Minotti G, Aust SD. The requirement for iron (III) in the initiation of lipid peroxidation by iron (II) and hydrogen peroxide. J Biol Chem 262: 1098－1104, 1987
  29. 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
  30. Naya MJ, Pereboom D, Ortego J, Alda JO, Lanas A. Superoxide anions produced by inflammatory cells play an important part in the pathogenesis of acid and pepsin induced esophagitis in rabbbits. Gut 40: 175－181, 1997 https://doi.org/10.1136/gut.40.2.175
  31. 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
  32. Oppenheim JJ, Matsushima K, Yoshimura T, Leonard EJ, Neta R. Relationship between interleukin-1 (IL-1), tumor necrois factor (TNF), and a neutrophil attracting peptide (NAP-1). Agent Actions 16: 134－140, 1989
  33. Palmer KJ, Goa KL. Defibrotide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders. Drugs 45: 259－294, 1993
  34. 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
  35. Pihan G, Regillo C, Szabo S. Free radical and lipid peroxidaion in ethanol- or aspirin-induced gastric mucosal injury. Dig Dis Sci 32: 1395－1401, 1987 https://doi.org/10.1007/BF01296666
  36. 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
  37. Selye H. The experimental production of peptic haemorrhagic oesophagitis. Canad Med Ass J 39: 447－448, 1938
  38. Shay H, Komarov SA, Fels SS, Meranze D, Gruenstein M, Siplet H. A simple method for the uniform production of gastric ulceration in the rat. Gastroenterology 5: 43－61, 1945
  39. Stein HJ, Hinder RA, Oosthuizen MMJ. Gastric mucosal injury caused by hemorrhage shock and reperfusion: protective role of the antioxidant glutathione. Surgery 108: 467－474, 1990
  40. Westwick J, Poll C. Mechanisms of calcium homeostasis in the polymorphonuclear leukocyte. Agents and Actions 19: 80－86, 1986 https://doi.org/10.1007/BF01977262
  41. Wetscher GJ, Hinder RA, Bagchi D, Hinder PR, Bagchi M, Perdikis G, McGinn T. Reflux esophagitis in humans is mediated by oxygen-derived free radicals. Am J Surg 170(6): 552－526, 1995 https://doi.org/10.1016/S0002-9610(99)80014-2
  42. Weyrich AS, Ma X, 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
  43. Yuan Y, Fleming BP. A method for isolation and fluorescent labeling of rat neutrophils for intravital microvascular studies. Microvasc Res 40; 218－229, 1990 https://doi.org/10.1016/0026-2862(90)90021-I
  44. Zhang BX, Zhao H, Muallem S. Ca$^{2+}$-dependent kinase and phosphate control 1,4,5-triphosphate mediated Ca$^{2+}$ release. J Biol Chem 268: 10997-11001, 1993