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A Study on the Protective Effect of Antioxidants on Damage Induced by Liver Ischemia/Repefusion in a Rat Model

모델 랫드에 간 허혈/재관류로 유발된 손상에 대한 항산화제의 보호 효과에 관한 연구

  • Ahn, Yong Ho (Department of Clinical Laboratory Science, Dongnam Health University) ;
  • Seok, Pu Reum (Department of Biomedical Laboratory Science, Eulji University) ;
  • Oh, Su Jin (Department of Biomedical Laboratory Science, Eulji University) ;
  • Choi, Jin Woo (Department of Biomedical Laboratory Science, Eulji University) ;
  • Shin, Jae-Ho (Department of Biomedical Laboratory Science, Eulji University)
  • 안용호 (동남보건대학교 임상병리과) ;
  • 석푸름 (을지대학교 임상병리학과) ;
  • 오수진 (을지대학교 임상병리학과) ;
  • 최진우 (을지대학교 임상병리학과) ;
  • 신재호 (을지대학교 임상병리학과)
  • Received : 2019.06.26
  • Accepted : 2019.08.04
  • Published : 2019.09.30

Abstract

The hepatic ischemic model has recently been widely used for the epidemiological study of ischemic reperfusion injury. This study was carried out to investigate the protective effect of vanillin, which is known to have antioxidant and anti-inflammatory effects, against hepatic and renal injury using an ischemia-reperfusion rat model, and we also investigated the mechanism related to vanillins' protective effect. The test material was administered at a concentration of 100 mg/kg for 3 days, followed by ligation of the liver for 60 minutes to induce ischemia reperfusion. As control groups, there was a negative control, sham control and ischemia-reperfusion-only ischemia reperfusion control, and the controls groups were compared with the drug administration group. In the vanillin group, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were significantly inhibited compared with the AST and ALT activities of the ischemia-reperfusion group, and histopathological examination showed significant reduction of both inflammation and necrosis. The malondialdehyde (MDA) and superoxide dismutase (SOD) levels were significantly different from the ischemia-reperfusion group. In conclusion, vanillin showed a hepatocyte protective action by alleviating the cellular inflammation and cell necrosis caused by hepatic ischemia-reperfusion, and vanillin mitigated inflammatory changes in the kidney glomeruli and distal tubules. The protective effect is considered to be caused by vanillin's antioxidant function. Further studies such as on cell death and possibly vanillin's same effect on damaged tissue will be necessary for clinical applications such as organ transplantation.

허혈 재관류 손상은 기관 이식, 외과적 혈관 재개통 및 출혈시에 발생하며 조직 및 기관 기능 장애를 유발한다. 최근 허혈 재관류 손상의 기전적 연구를 위해 간장 허혈 모델을 많이 이용하고 있다. 본 연구는 허혈 재관류 랫드 모델을 이용하여 항산화와 항염증 효과를 가진 것으로 알려진 Vanillin에 의한 간장 및 신장 손상에 대한 보호 효과를 알아보고 관련된 기전을 조사하기 위하여 실시하였다. 시험물질은 각각 100 mg/kg의 농도로 3일간 투여한 후, 60분동안 간을 결찰하여 허혈 재관류를 유도하여 관찰하였으며, 음성대조군, sham대조군 및 허혈재관류만 실시한 허혈 재관류대조군을 따로 두어, 약물투여군과 비교하였다. Vanillin 처치군에서는 AST, ALT 활성이 허혈 재관류대조군에 비해 유의하게 억제되었고, 조직병리학적 관찰에서도 염증 부분과 괴사부분이 현저하게 감소하였다. MDA와 SOD는 허혈 재관류군에 비해 유의적인 변화를 보였다. 이상의 결과를 종합하면 Vanillin은 간장 허혈 재관류에 의한 세포염증 및 세포괴사를 완화시켜 간세포 보호작용을 나타내었고, 신장의 사구체 및 원위세뇨관에 염증 변화를 완화 시키고 있어 세포 손상을 방어하는 것으로 생각되며, 이러한 방어효과는 항산화 기능에 의한 영향으로 사료된다.

Keywords

References

  1. Champion HR, Jones RT, Trump BF. A clinicopathologic study of hepatic dysfunction following shock. Surg Gynecol Obstet. 1976;142:657-663.
  2. Kanufman RP, Anner H, Kobzik L, Valeri CR, Shepro D, Hechman HB. Vasodilator prostaglandins prevent renal damage after ischemia. Ann Surg. 1987;205:195-198. https://doi.org/10.1097/00000658-198702000-00015
  3. Stephensen KR, Steinberg SM, Hughes KS, Vetto JT, Sugarbaker PH, Chang AE. Perioperative blood transfusions are associated with decreased time to recurrence and decreased survival after resection of colorectal liver metastasis. Ann Surg. 1988;208:679-687. https://doi.org/10.1097/00000658-198812000-00002
  4. Matsumata T, Kanematsu T, Shirabe K, Sonoda T, Furuta T, Sugimachi K. Decreased morbidity and mortality rates in surgical patients with hepatocellular carcinoma. Br J Surg. 1990;77:677-680. https://doi.org/10.1002/bjs.1800770629
  5. Taniguchi H, Takahashi T. Analysis of 210 elective hepatic resections. Hepatogastroenterology. 1997;44:1624-1631.
  6. Fujimoto J, Okamoto E, Yamanaka N, Tanaka T, Tanaka W. Adverse effect of perioperative blood transfusions on survivial after hepatic resection for epatocellular ciacinoma. Hepatogastroenterology. 1997;44:1390-1396.
  7. Demetrios V, Nikolaos A, Georgia K, Sofia S, Loukas K, Dimitrios D, et al. Deferoxamine attenuates lipid peroxidation, blocks Interleukin-6 production, ameliorates sepsis inflammatory response syndrome, and confers renoprotection after acute hepatic ischemia in pigs. Artif Organs. 2012;36:400-408. https://doi.org/10.1111/j.1525-1594.2011.01385.x
  8. Lee HT, Park SW, Kim M, D'Agati VD. Acute kidney injury after hepatic ischemia and reperfusion injury in mice. Lab Invest. 2009;89:196-208. https://doi.org/10.1038/labinvest.2008.124
  9. Daemen MA, Vreis BD, Buurman WA. Apoptosis and inflammation in renal reperfusion injury. Transplantation. 2002;73:1693-1700. https://doi.org/10.1097/00007890-200206150-00001
  10. Seifi B, Kadkhodaee M, Delavari F, Mikaeili S, Shams S, Ostad SN. Pretreatment with pentoxifylline and N-acetylcysteine in liver ischemia reperfusion-induced renal injury. Ren Fail. 2012;34:610-615. https://doi.org/10.3109/0886022X.2012.660827
  11. Korthuis RJ, Granger DN. Reactive oxygen metabolites, neutrophils, and the pathogenesis of ischemic-tissue/reperfusion. Clin Cardiol. 1993;16(4 Suppl 1):19-26. https://doi.org/10.1002/clc.4960161307
  12. Tsung A, Hiroyuki T, Nakao A, Fink MP, Lotze MT, Yang H, et al. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemiareperfusion. J Exp Me. 2005;201:1135-1143. https://doi.org/10.1084/jem.20042614
  13. Brand K. Aerobic glycolysis by proliferating cells: protection against oxidative stress at the expense of energy yield. J Bioenerg Biomembr. 1997;29:355-364. https://doi.org/10.1023/A:1022498714522
  14. Lirdprapamongkol K, Sakurai H, Kawasaki N, Choo MK, Saitoh Y, Aozuka Y, et al. Vanillin suppresses in vitro invasion and in vivo metastasis of mouse breast cancer cells. Eur J Pharm Sci. 2005:25:57-65. https://doi.org/10.1016/j.ejps.2005.01.015
  15. Cheng WY, Wu SL, Hsiang CY, Li CC, Lai TY, Lo HY, et al. Relationship between San-Huang-Xie-Xin-Tang and its herbal components on the gene expression profiles in HepG2 cells. Am J Chin Med. 2008;36:783-797. https://doi.org/10.1142/S0192415X08006235
  16. Liang JA, Wu SL, Lo HY, Hsiang CY, and Ho TY. Vanillin inhibits matrix metalloproteinase-9 expression through down-regulation of nuclear factor-B signaling pathway in human hepatocellular carcinoma cells. Mol Pharmacol. 2009:75:151-157. https://doi.org/10.1124/mol.108.049502
  17. Durant. S. and Kaman. P. Vanillins- a novel family of DNA-PK inhinitors. Nucleiic Acids Res. 2003;31:5501-5512. https://doi.org/10.1093/nar/gkg753
  18. Fitzgerald DJ, Stratford M, Gasson MJ, Ueckert J, Bos A, Narbad A. Mode of antimicrobial action of vanillin against Escherichia coli, Lactobacillus plantarum and Listeria innocua. J Appl Microbiol. 2004:97:104-113. https://doi.org/10.1111/j.1365-2672.2004.02275.x
  19. Santosh Kumar SS, Priyadarsini KI, Sainis KB. Inhibition of peroxynitrite-mediated reactions by vanillin. J Agric Food Chem. 2004:52:139-145. https://doi.org/10.1021/jf030319d
  20. Roumen RM, Hendriks T, van der Ven-Jongekrig J, Nieuwenhuijzen GA, Sauerwein RW, van der Meer JW, et al. Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma, Relation with subsequent adult respiratory distress syndrome and multiple organ failure. Ann Surg. 1993;218:769-776. https://doi.org/10.1097/00000658-199312000-00011
  21. Klebanoff SJ, Vadas MA, Harian JM, Sparks LH, Gamble JR, Agosti JM, et al. Stimulation of neutrophils by tumor necrosis factor. J Immunol. 1986;136:4220-4225.
  22. Gomez-Cambronero LG, Sabater L, Pereda J, Cassinello N, Camps B, Vina J, et al. Role of cytokines and oxidative stress in the pathophysiology of acute pancreatitis: therapeutical implications. Current Drug Targets Inflamm Allergy. 2002;1:393-403. https://doi.org/10.2174/1568010023344544
  23. Zingarelli B, Sheehan M, Wong HR. Nuclear factor-kappa B as a therapeutic target in critical care medicine. Critical Care Medicine. 2003;31(1 Suppl):105-111. https://doi.org/10.1097/00003246-200301001-00015
  24. Sasaki H, Matsuno T, Tanaka N, Orita K. Activation of apoptosis during the reperfusion phase after rat liver ischemia. Transplant Proc. 1996;28:1908-1909.
  25. Nankivell BJ, Chapman JR. Chronic allograft nephropathy: current concepts and future directions. Transplantation. 2006;81:643-654. https://doi.org/10.1097/01.tp.0000190423.82154.01
  26. Wald R, Waikar SS, Liangos O, Pereira BI, Chertow GM, Laber BL. Acute renal failure after endovascular vs open repair of abdominal aortic aneurysm. J Vasc Surg. 2006;43:460-466. https://doi.org/10.1016/j.jvs.2005.11.053
  27. Matas AJ, Payne WD, Simmons RL, Buselmeier TJ, Kjellstrand CM. Acute renal failure following blunt civilian trauma. Ann Surg. 1977;185:301-306. https://doi.org/10.1097/00000658-197703000-00009
  28. Dame JB, Juul SE. The distribution of receptors for the pro-inflammatory cytokines interleukin (IL)-6 and IL-8 in the developing human fetus. Early Hum Dev. 2000;58:25-39. https://doi.org/10.1016/S0378-3782(00)00064-5
  29. Horii Y, Muraguchi A, Iwano M, Matsuda T, HirayamamT, Yamada H, et al. Involvement of IL-6 in measangial proliferative glomerulonephritis. J Immunol. 1989:143:3949-3955.
  30. Taniguchi Y, Yorioka N, Kumagai J, Katsutani M, Kuratsune M, Amimoto D, et al. Interleukin-6 localization and the prognosis of Ig A nephropathy. Nephron. 1999:81:94-98. https://doi.org/10.1159/000045254
  31. Homis E, Ribeiro-Alves MA, Lopes de Faria JB, Dias EP. Interleukin-6 stimulates tubular regeneration in rats with glycerol-induced acute renal failure. Nephron. 2002;92:192-199. https://doi.org/10.1159/000064478
  32. Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S, et al. Angioyrndion II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kid Int suppul. 2002:82:12-22.
  33. Ahn EK, Jeon HJ, Lim EJ, Jung HJ, Park EH. Anti-inflammatoryand anti-angiogenic activities of Gastrodia elata Blume. J Ethnophamacol. 2007;110:476-482. https://doi.org/10.1016/j.jep.2006.10.006
  34. Lirdprapamongkol K, Sakurai H, Kawasaki N, Choo MK, Saitoh Y, Aozuka Y, et al. Vanillin suppresses in vitro invasion and in vivo metastasis of mouse breast cancer cells. Eur J Pharm Sci. 2005;25:57-65. https://doi.org/10.1016/j.ejps.2005.01.015
  35. Akagi K, Hirose M, Hoshiya T, Mizoguchi Y, Ito N, Shirai T. Modulating effects of ellagic acid, vanillin and quercetin in a rat medium term multi-organ carcinogenesis model. Cancer Lett. 1995;94:113-121. https://doi.org/10.1016/0304-3835(95)03833-I
  36. Kaynar K, Gul S, Ersoz S, Ozdemir F, Ulusoy H, Ulusoy S. Amikacin-induced nephropathy: Is there any protective way? Ren Fail. 2007;29:23-27. https://doi.org/10.1080/08860220601039072
  37. Nam JH, Park HS. Effect of quality and quantity of dietary fat on status of tocopherol and lipid peroxidation of plasma tissue in rats. Korean J Nutr. 1993;26:566-577.
  38. Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. 3rd ed. New York, USA: Oxford University Press; 1999.
  39. Kang YH, Park YK, Ha TY, Moon KD. Effects of pine needle extract on enzyme activities of serum and liver and liver morphology in rats fed high fat diet. J Korean Soc Food Nutr. 1996;25:374-378.
  40. Zaitone S, Hassan N, El-Orabi N, El-Awady S. Pentoxifylline and melatonin in combination with pioglitazone ameliorate experimental non-alcoholic fatty liver disease. Eur J Pharmacol. 2011;662:70-77. https://doi.org/10.1016/j.ejphar.2011.04.049
  41. Da Silveira M, Yoshida WB. Trimetazidine and Nacetylcysteine in attenuating hind-limb ischemia and reperfusion injuries: Experimental study in rats. Int Angiol. 2009;28:412-417.

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