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Ebselen Improves Ischemia-Reperfusion Injury After Rat Lung Transplantation

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Abstract

The heterocyclic organic compound ebselen (2-phenyl-1,2-benizsoselenazol-3(2H)-one) is a glutathione peroxidase mimick with protective properties against oxidative injury. Ebselen also has anti-inflammatory activity, including attenuation of tumor necrosis factor release and increase of interleukin-10, as shown in vivo, in inflammatory and ischemia-reperfusion injuries, including those of the lung. This study was designed to assess its effect on severe ischemia-reperfusion injury in a model of left-sided rat lung isotransplantation. Orthotopic single left-sided lung allotransplantation (Wistar to Wistar) was performed in female rats after a total ischemic time of 18 h. In nine recipients given 500 mg/kg oral ebselen 1 h before transplantation, graft PaO2/FiO2 was improved 24 h after transplantation, as evidenced with a mean (standard deviation) PaO2 of 139 (61) mmHg vs. eight controls with 65 (33) mmHg (p = 0.009). Bronchoalveolar PMN count was reduced to approximately 50% in the ebselen group compared with controls, whereas no difference in the tumor necrosis factor content was found. We conclude that the improvement of lung function in ebselen-treated transplanted rats is mainly the result of the anti-inflammatory activity of the drug during reperfusion.

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References

  1. Parnham MJ, Kindt S (1984) A novel biologically active seleno-organic compound-III. Effects of PZ 51 (Ebselen) on glutathione peroxidase and secretory activities of mouse macrophages. Biochem Pharmacol 33:3247–3250. doi:10.1016/0006-2952(84)90085-6

    Article  PubMed  CAS  Google Scholar 

  2. Wendel A, Fausel M, Safayhi H, Tiegs G, Otter R (1984) A novel biologically active seleno-organic compound-II. Activity of PZ 51 in relation to glutathione peroxidase. Biochem Pharmacol 33:3241–3245. doi:10.1016/0006-2952(84)90084-4

    Article  PubMed  CAS  Google Scholar 

  3. Hattori R, Inoue R, Sase K, Eizawa H, Kosuga K, Aoyama T, Masayasu H, Kawai C, Sasayama S, Yui Y (1994) Preferential inhibition of inducible nitric oxide synthase by ebselen. Eur J Pharmacol 267:R1–R2

    PubMed  CAS  Google Scholar 

  4. Wendel A, Otter R, Tiegs G (1986) Inhibition by ebselen of microsomal NADPH-cytochrome P450-reductase in vitro but not in vivo. Biochem Pharmacol 35:2995–2997. doi:10.1016/0006-2952(86)90376-X

    Article  PubMed  CAS  Google Scholar 

  5. Cotgreave IA, Duddy SK, Kass GE, Thompson D, Moldeus P (1989) Studies on the anti-inflammatory activity of ebselen. Ebselen interferes with granulocyte oxidative burst by dual inhibition of NADPH oxidase and protein kinase C? Biochem Pharmacol 38:649–656. doi:10.1016/0006-2952(89)90211-6

    Article  PubMed  CAS  Google Scholar 

  6. Patrick RA, Peters PA, Issekutz AC (1993) Ebselen is a specific inhibitor of LTB4-mediated migration of human neutrophils. Agents Actions 40:186–190. doi:10.1007/BF01984060

    Article  PubMed  CAS  Google Scholar 

  7. Wendel A, Tiegs G (1986) A novel biologically active seleno-organic compound-VI. Protection by ebselen (PZ 51) against galactosamine/endotoxin-induced hepatitis in mice. Biochem Pharmacol 35:2115–2118. doi:10.1016/0006-2952(86)90578-2

    Article  PubMed  CAS  Google Scholar 

  8. Wendel A, Kuesters S, Tiegs G (1997) Ebselen: an in vivo immune response modifier. Biomed Environ Sci 10:253–259

    PubMed  CAS  Google Scholar 

  9. Tiegs G, Kusters S, Kunstle G, Hentze H, Kiemer AK, Wendel A (1998) Ebselen protects mice against T cell-dependent, TNF-mediated apoptotic liver injury. J Pharmacol Exp Ther 287:1098–1104

    PubMed  CAS  Google Scholar 

  10. d’Alessio P, Moutet M, Coudrier E, Darquenne S, Chaudiere J (1998) ICAM-1 and VCAM-1 expression induced by TNF-alpha are inhibited by a glutathione peroxidase mimic. Free Radic Biol Med 24:979–987. doi:10.1016/S0891-5849(97)00396-1

    Article  PubMed  Google Scholar 

  11. Briviba K, Roussyn I, Sharov VS, Sies H (1996) Attenuation of oxidation and nitration reactions of peroxynitrite by selenomethionine, selenocystine and ebselen. Biochem J 319(Pt 1):13–15

    PubMed  CAS  Google Scholar 

  12. Daiber A, Zou MH, Bachschmid M, Ullrich V (2000) Ebselen as a peroxynitrite scavenger in vitro and ex vivo. Biochem Pharmacol 59:153–160. doi:10.1016/S0006-2952(99)00309-3

    Article  PubMed  CAS  Google Scholar 

  13. Ishii Y, Hashimoto K, Hirano K, Morishima Y, Mochizuki M, Masuyama K, Nomura A, Sakamoto T, Uchida Y, Sagai M, Sekizawa K (2000) Ebselen decreases ozone-induced pulmonary inflammation in rats. Lung 178:225–234

    PubMed  CAS  Google Scholar 

  14. Brodsky SV, Gealekman O, Chen J, Zhang F, Togashi N, Crabtree M, Gross SS, Nasjletti A, Goligorsky MS (2004) Prevention and reversal of premature endothelial cell senescence and vasculopathy in obesity-induced diabetes by Ebselen. Circ Res 94:377–384. doi:10.1161/01.RES.0000111802.09964.EF

    Article  PubMed  CAS  Google Scholar 

  15. Gao JX, Issekutz AC (1994) The effect of ebselen on T-lymphocyte migration to arthritic joints and dermal inflammatory reactions in the rat. Int J Immunopharmacol 16:279–287. doi:10.1016/0192-0561(94)90002-7

    Article  PubMed  CAS  Google Scholar 

  16. Haraoka M, Matsumoto T, Mizunoe Y, Takahashi K, Kubo S, Koikawa Y, Tanaka M, Sakamoto Y, Sakumoto M, Nagafuji T (1995) Effect of ebselen on renal scarring in rats following renal infection. Chemotherapy 41:208–213

    Article  PubMed  CAS  Google Scholar 

  17. Johshita H, Sasaki T, Matsui T, Hanamura T, Masayasu H, Asano T, Takakura K (1990) Effects of ebselen (PZ51) on ischaemic brain oedema after focal ischaemia in cats. Acta Neurochir Suppl (Wien) 51:239–241

    CAS  Google Scholar 

  18. Kondoh S, Nagasawa S, Kawanishi M, Yamaguchi K, Kajimoto S, Ohta T (1999) Effects of ebselen on cerebral ischemia and reperfusion evaluated by microdialysis. Neurol Res 21:682–686

    PubMed  CAS  Google Scholar 

  19. Sui H, Wang W, Wang PH, Liu LS (2005) Protective effect of antioxidant ebselen (PZ51) on the cerebral cortex of stroke-prone spontaneously hypertensive rats. Hypertens Res 28:249–254. doi:10.1291/hypres.28.249

    Article  PubMed  Google Scholar 

  20. Kalayci M, Coskun O, Cagavi F, Kanter M, Armutcu F, Gul S, Acikgoz B (2005) Neuroprotective effects of ebselen on experimental spinal cord injury in rats. Neurochem Res 30:403–410. doi:10.1007/s11064-005-2615-2

    Article  PubMed  CAS  Google Scholar 

  21. Miorelli ST, Rosa RM, Moura DJ, Rocha JC, Lobo LA, Henriques JA, Saffi J (2008) Antioxidant and anti-mutagenic effects of ebselen in yeast and in cultured mammalian V79 cells. Mutagenesis 23:93–99. doi:10.1093/mutage/gem048

    Article  PubMed  CAS  Google Scholar 

  22. Hoshida S, Kuzuya T, Nishida M, Yamashita N, Hori M, Kamada T, Tada M (1994) Ebselen protects against ischemia-reperfusion injury in a canine model of myocardial infarction. Am J Physiol 267:H2342–H2347

    PubMed  CAS  Google Scholar 

  23. Maulik N, Yoshida T (2000) Oxidative stress developed during open heart surgery induces apoptosis: reduction of apoptotic cell death by ebselen, a glutathione peroxidase mimic. J Cardiovasc Pharmacol 36:601–608. doi:10.1097/00005344-200011000-00009

    Article  PubMed  CAS  Google Scholar 

  24. Baljinnyam E, Hasebe N, Morihira M, Sumitomo K, Matsusaka T, Fujino T, Fukuzawa J, Ushikubi F, Kikuchi K (2006) Oral pretreatment with ebselen enhances heat shock protein 72 expression and reduces myocardial infarct size. Hypertens Res 29:905–913. doi:10.1291/hypres.29.905

    Article  PubMed  CAS  Google Scholar 

  25. Ozaki M, Nakamura M, Teraoka S, Ota K (1997) Ebselen, a novel anti-oxidant compound, protects the rat liver from ischemia-reperfusion injury. Transpl Int 10:96–102

    Article  PubMed  CAS  Google Scholar 

  26. Noiri E, Nakao A, Uchida K, Tsukahara H, Ohno M, Fujita T, Brodsky S, Goligorsky MS (2001) Oxidative and nitrosative stress in acute renal ischemia. Am J Physiol Renal Physiol 281:F948–F957

    PubMed  CAS  Google Scholar 

  27. Dhanarajan R, Abraham P, Isaac B (2006) Protective effect of ebselen, a selenoorganic drug, against gentamicin-induced renal damage in rats. Basic Clin Pharmacol Toxicol 99:267–272. doi:10.1111/j.1742-7843.2006.pto_474.x

    Article  PubMed  CAS  Google Scholar 

  28. Yamasoba T, Pourbakht A, Sakamoto T, Suzuki M (2005) Ebselen prevents noise-induced excitotoxicity and temporary threshold shift. Neurosci Lett 380:234–238. doi:10.1016/j.neulet.2005.01.047

    Article  PubMed  CAS  Google Scholar 

  29. Kil J, Pierce C, Tran H, Gu R, Lynch ED (2007) Ebselen treatment reduces noise induced hearing loss via the mimicry and induction of glutathione peroxidase. Hear Res 226:44–51. doi:10.1016/j.heares.2006.08.006

    Article  PubMed  CAS  Google Scholar 

  30. Cotgreave IA, Johansson U, Westergren G, Moldeus PW, Brattsand R (1988) The anti-inflammatory activity of Ebselen but not thiols in experimental alveolitis and bronchiolitis. Agents Actions 24:313–319. doi:10.1007/BF02028288

    Article  PubMed  CAS  Google Scholar 

  31. Belvisi MG, Haddad EB, Battram C, Birrell M, Foster M, Webber S (2000) Anti-inflammatory properties of ebselen in a model of sephadex-induced lung inflammation. Eur Respir J 15:579–581. doi:10.1034/j.1399-3003.2000.15.25.x

    Article  PubMed  CAS  Google Scholar 

  32. Haddad el-B, McCluskie K, Birrell MA, Dabrowski D, Pecoraro M, Underwood S, Chen B, De Sanctis GT, Webber SE, Foster ML, Belvisi MG (2002) Differential effects of ebselen on neutrophil recruitment, chemokine, and inflammatory mediator expression in a rat model of lipopolysaccharide-induced pulmonary inflammation. J Immunol 169:974–982

    CAS  Google Scholar 

  33. Bouhafs RK, Jarstrand C (2002) Effects of antioxidants on surfactant peroxidation by stimulated human polymorphonuclear leukocytes. Free Radic Res 36:727–734. doi:10.1080/10715760290032593

    Article  PubMed  CAS  Google Scholar 

  34. Ogawa A, Yoshimoto T, Kikuchi H, Sano K, Saito I, Yamaguchi T, Yasuhara H (1999) Ebselen in acute middle cerebral artery occlusion: a placebo-controlled, double-blind clinical trial. Cerebrovasc Dis 9:112–118. doi:10.1159/000015908

    Article  PubMed  CAS  Google Scholar 

  35. de Perrot M, Liu M, Waddell TK, Keshavjee S (2003) Ischemia-reperfusion-induced lung injury. Am J Respir Crit Care Med 167:490–511. doi:10.1164/rccm.200207-670SO

    Article  PubMed  Google Scholar 

  36. Stammberger U, Hamacher J, Hillinger S, Schmid RA (2000) sCR1sLeX ameliorates ischemia/reperfusion injury in experimental lung transplantation. J Thorac Cardiovasc Surg 120:1078–1084. doi:10.1067/mtc.2000.111175

    Article  PubMed  CAS  Google Scholar 

  37. Sekido N, Mukaida N, Harada A, Nakanishi I, Watanabe Y, Matsushima K (1993) Prevention of lung reperfusion injury in rabbits by a monoclonal antibody against interleukin-8. Nature 365:654–657. doi:10.1038/365654a0

    Article  PubMed  CAS  Google Scholar 

  38. DeMeester SR, Rolfe MW, Kunkel SL, Swiderski DL, Lincoln PM, Deeb GM, Strieter RM (1993) The bimodal expression of tumor necrosis factor-alpha in association with rat lung reimplantation and allograft rejection. J Immunol 150:2494–2505

    PubMed  CAS  Google Scholar 

  39. Jassem W, Roake J (1998) The molecular and cellular basis of reperfusion injury following organ transplantation. Transplant Rev 12:14–33. doi:10.1016/S0955-470X(98)80037-2

    Article  Google Scholar 

  40. Gater PR, Wasserman MA, Paciorek PM, Renzetti LM (1996) Inhibition of Sephadex-induced lung injury in the rat by Ro 45-2081, a tumor necrosis factor receptor fusion protein. Am J Respir Cell Mol Biol 14:454–460

    PubMed  CAS  Google Scholar 

  41. Renzetti LM, Paciorek PM, Tannu SA, Rinaldi NC, Tocker JE, Wasserman MA, Gater PR (1996) Pharmacological evidence for tumor necrosis factor as a mediator of allergic inflammation in the airways. J Pharmacol Exp Ther 278:847–853

    PubMed  CAS  Google Scholar 

  42. Ochs M (2006) Stereological analysis of acute lung injury. Eur Respir Rev 15:115–121. doi:10.1183/09059180.00010102

    Article  Google Scholar 

  43. Waypa GB, Schandel NS, Schumacker PT (2001) Model for hypoxic pulmonary vasoconstriction involving mitochondrial oxygen sensing. Circ Res 88:1259–1266. doi:10.1161/hh1201.091960

    Article  PubMed  CAS  Google Scholar 

  44. Stammberger U, Carboni GL, Hillinger S, Schneiter D, Weder W, Schmid RA (1999) Combined treatment with endothelin- and PAF-antagonists reduces posttransplant lung ischemia/reperfusion injury. J Heart Lung Transplant 18:862–868. doi:10.1016/S1053-2498(99)00039-X

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Biochemical Pharmacology, University of Konstanz, Konstanz, Germany

    Jürg Hamacher, Elvira Weber, Rudolf Lucas & Albrecht Wendel

  2. Pulmonary Division, University Hospital Inselspital, CH-3010, Bern, Switzerland

    Jürg Hamacher

  3. Division of General Thoracic Surgery, University Hospital Inselspital, Bern, Switzerland

    Uz Stammberger

  4. Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA

    Rudolf Lucas

Authors
  1. Jürg Hamacher
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  2. Uz Stammberger
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  3. Elvira Weber
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  4. Rudolf Lucas
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  5. Albrecht Wendel
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Corresponding author

Correspondence to Jürg Hamacher.

Additional information

This work was supported by the Deutsche Forschungsgemeinschaft (FOR 321/2-1; research group “Endogenous tissue injury: Mechanisms of autodestruction”).

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Hamacher, J., Stammberger, U., Weber, E. et al. Ebselen Improves Ischemia-Reperfusion Injury After Rat Lung Transplantation. Lung 187, 98–103 (2009). https://doi.org/10.1007/s00408-009-9134-x

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  • DOI: https://doi.org/10.1007/s00408-009-9134-x

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