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Post-Transplant Events

Plasma antioxidants in subjects before hematopoietic stem cell transplantation

Abstract

Chemo-irradiation induced oxidative damage to vascular endothelium may contribute to pulmonary complications of hematopoietic stem cell transplantation (HSCT). We measured antioxidants, markers of oxidative stress and plasma antioxidant capacity in plasma or serum from 24 subjects at day 7 before HSCT and 20 control subjects. The plasma concentration of extracellular glutathione peroxidase (GPX-3) was significantly reduced in the HSCT subjects compared with controls (HSCT: 98±42 μg/ml, control: 169±56 μg/ml, P<0.0001). The concentration of γ-tocopherol was significantly higher in the HSCT subjects compared with controls (HSCT: 207±103 μg/dl; Control: 98±52 μg/dl; P=0.0002). The plasma concentrations of protein carbonyl, nitrotyrosine, malondialdehyde, α-tocopherol, vitamin A, homocysteine, cysteine and cysteinylglycine did not differ between HSCT and control subjects. Plasma from HSCT subjects was as effective as control plasma in quenching menadione-induced intracellular reactive oxygen species production in human microvascular endothelial cells. In summary, subjects before HSCT have significantly reduced plasma concentrations of GPX-3, elevated plasma γ-tocopherol yet retains the ability to quench an acute oxidative stress. These changes may play a role in chronic oxidative stress in the HSCT population.

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References

  1. Soubani AO, Miller KB, Hassoun PM . Pulmonary complications of bone marrow transplantation. Chest 1996; 109: 1066–1077.

    Article  CAS  Google Scholar 

  2. Bhalla KS, Folz RJ . Idiopathic pneumonia syndrome after syngeneic bone marrow transplant in mice. Am J Resp Critical Care Med 2002; 166 (12 Part 1): 1579–1589.

    Article  Google Scholar 

  3. Haddad IY, Panoskaltsis-Mortari A, Ingbar DH, Yang S, Milla CE, Blazar BR . High levels of peroxynitrite are generated in the lungs of irradiated mice given cyclophosphamide and allogeneic T cells. A potential mechanism of injury after marrow transplantation. Am J Respir Cell Mol Biol 1999; 20: 1125–1135.

    Article  CAS  Google Scholar 

  4. Evens AM, Mehta J, Gordon LI . Rust and corrosion in hematopoietic stem cell transplantation: the problem of iron and oxidative stress. Bone Marrow Transplant 2004; 34: 561–571.

    Article  CAS  Google Scholar 

  5. Altes A, Remacha AF, Sarda P, Sancho FJ, Sureda A, Martino R et al. Frequent severe liver iron overload after stem cell transplantation and its possible association with invasive aspergillosis. Bone Marrow Transplant 2004; 34: 505–509.

    Article  CAS  Google Scholar 

  6. Sheng-Tanner X, McKerlie C, Spaner D . Characterization of graft-versus-host disease in SCID mice and prevention by physicochemical stressors. Transplantation 2000; 70: 1683–1693.

    Article  CAS  Google Scholar 

  7. Sohal RS, Weindruch R . Oxidative stress, caloric restriction, and aging. Science 1996; 273: 59–63.

    Article  CAS  Google Scholar 

  8. Durken M, Agbenu J, Finckh B, Hubner C, Pichlmeier U, Zeller W et al. Deteriorating free radical-trapping capacity and antioxidant status in plasma during bone marrow transplantation. Bone Marrow Transplant 1995; 15: 757–762.

    CAS  Google Scholar 

  9. High KP, Legault C, Sinclair JA, Cruz J, Hill K, Hurd DD . Low plasma concentrations of retinol and alpha-tocopherol in hematopoietic stem cell transplant recipients: the effect of mucositis and the risk of infection. Am J Clin Nutr 2002; 76: 1358–1366.

    Article  CAS  Google Scholar 

  10. Forsberg L, de Faire U, Morgenstern R . Oxidative stress, human genetic variation, and disease. Arch Biochem Biophys 2001; 389: 84–93.

    Article  CAS  Google Scholar 

  11. White AC, Terrin N, Miller KB, Ryan HF . Impaired respiratory and skeletal muscle strength in patients before hematopoietic stem cell transplantation. Chest 2005; 128: 145–152.

    Article  Google Scholar 

  12. Gibson GJ . Standardised lung function testing. Eur Resp J 1993; 6: 155–157.

    CAS  Google Scholar 

  13. Bieri JG, Tolliver TJ, Catignani GL . Simultaneous determination of alpha-tocopherol and retinol in plasma or red cells by high pressure liquid chromatography. Am J Clin Nutr 1979; 32: 2143–2149.

    Article  CAS  Google Scholar 

  14. Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG et al. Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol 1990; 186: 464–478.

    Article  CAS  Google Scholar 

  15. Hong YL, Yeh SL, Chang CY, Hu ML . Total plasma malondialdehyde levels in 16 Taiwanese college students determined by various thiobarbituric acid tests and an improved high-performance liquid chromatography-based method. Clin Biochem 2000; 33: 619–625.

    Article  CAS  Google Scholar 

  16. Fukunaga K, Yoshida M, Nakazono N . A simple, rapid, highly sensitive and reproducible quantification method for plasma malondialdehyde by high-performance liquid chromatography. Biomed Chromatogr 1998; 12: 300–303.

    Article  CAS  Google Scholar 

  17. Behrens WA, Madere R . Malonaldehyde determination in tissues and biological fluids by ion-pairing high-performance liquid chromatography. Lipids 1991; 26: 232–236.

    Article  CAS  Google Scholar 

  18. Araki A, Sako Y . Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr A 1987; 422: 43–52.

    Article  CAS  Google Scholar 

  19. Thannickal VJ, Day RM, Klinz SG, Bastien MC, Larios JM, Fanburg BL . Ras-dependent and -independent regulation of reactive oxygen species by mitogenic growth factors and TGF-beta1. FASEB J 2000; 14: 1741–1748.

    Article  CAS  Google Scholar 

  20. Irani K, Xia Y, Zweier JL, Sollott SJ, Der CJ, Fearon ER et al. Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science 1997; 275: 1649–1652.

    Article  CAS  Google Scholar 

  21. Kossenjans W, Rymaszewski Z, Barankiewicz J, Bobst A, Ashraf M . Menadione-induced oxidative stress in bovine heart microvascular endothelial cells. Microcirculation 1996; 3: 39–47.

    Article  CAS  Google Scholar 

  22. Jonas CR, Puckett AB, Jones DP, Griffith DP, Szeszycki EE, Bergman GF et al. Plasma antioxidant status after high-dose chemotherapy: a randomized trial of parenteral nutrition in bone marrow transplantation patients. Am J Clin Nutr 2000; 72: 181–189.

    Article  CAS  Google Scholar 

  23. Look MP, Musch E . Lipid peroxides in the polychemotherapy of cancer patients. Chemotherapy 1994; 40: 8–15.

    Article  CAS  Google Scholar 

  24. Altes A, Remacha AF, Sureda A, Martino R, Briones J, Canals C et al. Iron overload might increase transplant-related mortality in haematopoietic stem cell transplantation. Bone Marrow Transplant 2002; 29: 987–989.

    Article  CAS  Google Scholar 

  25. Cetin T, Arpaci F, Yilmaz MI, Saglam K, Ozturk B, Komurcu S et al. Oxidative stress in patients undergoing high-dose chemotherapy plus peripheral blood stem cell transplantation. Biol Trace Element Res 2004; 97: 237–247.

    Article  CAS  Google Scholar 

  26. Gordon LI, Brown SG, Tallman MS, Rademaker AW, Weitzman SA, Lazarus HM et al. Sequential changes in serum iron and ferritin in patients undergoing high-dose chemotherapy and radiation with autologous bone marrow transplantation: possible implications for treatment related toxicity. Free Radical Biol Med 1995; 18: 383–389.

    Article  CAS  Google Scholar 

  27. Ursini F, Maiorino M, Brigelius-Flohe R, Aumann KD, Roveri A, Schomburg D et al. Diversity of glutathione peroxidases. Methods Enzymol 1995; 252: 38–53.

    Article  CAS  Google Scholar 

  28. Arthur JR . The glutathione peroxidases. Cell Mol Life Sci 2000; 57: 1825–1835.

    Article  CAS  Google Scholar 

  29. Blankenberg S, Rupprecht HJ, Bickel C, Torzewski M, Hafner G, Tiret L et al. Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease. New Engl J Med 2003; 349: 1605–1613.

    Article  CAS  Google Scholar 

  30. Yoshimura S, Suemizu H, Taniguchi Y, Arimori K, Kawabe N, Moriuchi T . The human plasma glutathione peroxidase-encoding gene: organization, sequence and localization to chromosome 5q32. Gene 1994; 145: 293–297.

    Article  CAS  Google Scholar 

  31. Chen N, Liu Y, Greiner CD, Holtzman JL . Physiologic concentrations of homocysteine inhibit the human plasma GSH peroxidase that reduces organic hydroperoxides. J Lab Clin Med 2000; 136: 58–65.

    Article  CAS  Google Scholar 

  32. Bierl C, Voetsch B, Jin RC, Handy DE, Loscalzo J . Determinants of human plasma glutathione peroxidase (GPx-3) expression. J Biol Chem 2004; 279: 26839–26845.

    Article  CAS  Google Scholar 

  33. Avissar N, Ornt DB, Yagil Y, Horowitz S, Watkins RH, Kerl EA et al. Human kidney proximal tubules are the main source of plasma glutathione peroxidase. Am J Physiol 1994; 266 (2 Pt 1): C367–C375.

    Article  CAS  Google Scholar 

  34. Avissar N, Eisenmann C, Breen JG, Horowitz S, Miller RK, Cohen HJ . Human placenta makes extracellular glutathione peroxidase and secretes it into maternal circulation. Am J Physiol 1994; 267 (1 Pt 1): E68–E76.

    CAS  PubMed  Google Scholar 

  35. Kim KK, Whitin JC, Sukhova NM, Cohen HJ . Increase in extracellular glutatione peroxidase in plasma and lungs of mice exposed to hyperoxia. Pediatric Res 1999; 46: 715–721.

    Article  CAS  Google Scholar 

  36. Avissar N, Finkelstein JN, Horowitz S, Willey JC, Coy E, Frampton MW et al. Extracellular glutathione peroxidase in human lung epithelial lining fluid and in lung cells. Am J Physiol 1996; 270 (2 Pt 1): L173–L182.

    CAS  PubMed  Google Scholar 

  37. Rush JW, Sandiford SD . Plasma glutathione peroxidase in healthy young adults: influence of gender and physical activity. Clin Biochem 2003; 36: 345–351.

    Article  CAS  Google Scholar 

  38. Jones DP, Mody Jr VC, Carlson JL, Lynn MJ, Sternberg Jr P . Redox analysis of human plasma allows separation of pro-oxidant events of aging from decline in antioxidant defenses. Free Radical Biol Med 2002; 33: 1290–1300.

    Article  CAS  Google Scholar 

  39. Jozwik M, Szczypka M, Gajewska J, Laskowska-Klita T . Antioxidant defense of red blood cells and plasma in stored human blood. Clin Chim Acta 1997; 267: 129–142.

    Article  CAS  Google Scholar 

  40. Dayal S, Brown KL, Weydert CJ, Oberley LW, Arning E, Bottiglieri T et al. Deficiency of glutathione peroxidase-1 sensitizes hyperhomocysteinemic mice to endothelial dysfunction. Arterioscl, Thromb Vasc Biol 1996; 22: 1996–2002.

    Article  Google Scholar 

  41. Yoshida T, Maulik N, Engelman RM, Ho YS, Magnenat JL, Rousou JA et al. Glutathione peroxidase knockout mice are susceptible to myocardial ischemia reperfusion injury. Circulation 1997; 96 (9 Suppl): 216–220.

    CAS  Google Scholar 

  42. Forgione MA, Weiss N, Heydrick S, Cap A, Klings ES, Bierl C et al. Cellular glutathione peroxidase deficiency and endothelial dysfunction. Am J Physiol Heart Circ Physiol 2002; 282: H1255–H1261.

    Article  CAS  Google Scholar 

  43. Loscalzo J . The oxidant stress of hyperhomocyst (e) inemia. J Clin Invest 1996; 98: 5–7.

    Article  CAS  Google Scholar 

  44. Eberhardt RT, Forgione MA, Cap A, Leopold JA, Rudd MA, Trolliet M et al. Endothelial dysfunction in a murine model of mild hyperhomocyst (e) inemia. J Clin Invest 2000; 106: 483–491.

    Article  CAS  Google Scholar 

  45. Jiang Q, Christen S, Shigenaga MK, Ames BN . gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr 2001; 74: 714–722.

    Article  CAS  Google Scholar 

  46. Gysin R, Azzi A, Visarius T . Gamma-tocopherol inhibits human cancer cell cycle progression and cell proliferation by down-regulation of cyclins. FASEB J 2002; 16: 1952–1954.

    Article  CAS  Google Scholar 

  47. Parmentier JH, Schohn H, Bronner M, Ferrari L, Batt AM, Dauca M et al. Regulation of CYP4A1 and peroxisome proliferator-activated receptor alpha expression by interleukin-1beta, interleukin-6, and dexamethasone in cultured fetal rat hepatocytes. Biochem Pharmacol 1997; 54: 889–898.

    Article  CAS  Google Scholar 

  48. Ferrari L, Herber R, Batt AM, Siest G . Differential effects of human recombinant interleukin-1 beta and dexamethasone on hepatic drug-metabolizing enzymes in male and female rats. Biochem Pharmacol 1993; 45: 2269–2277.

    Article  CAS  Google Scholar 

  49. van der Loo B, Labugger R, Aebischer CP, Skepper JN, Bachschmid M, Spitzer V et al. Cardiovascular aging is associated with vitamin E increase. Circulation 2002; 105: 1635–1638.

    Article  CAS  Google Scholar 

  50. Hak AE, Stampfer MJ, Campos H, Sesso HD, Gaziano JM, Willett W et al. Plasma carotenoids and tocopherols and risk of myocardial infarction in a low-risk population of US male physicians. Circulation 2003; 108: 802–807.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank all the subjects who enrolled in the study, the staff of the BMT unit at Tufts-New England Medical Center and the T-NEMC IRB for their help in getting this project completed.

This work was supported by: NIH K23HL04411 and USDA ARS Cooperative Agreement No 58-1950-4-401.

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Correspondence to A C White.

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White, A., Sousa, A., Blumberg, J. et al. Plasma antioxidants in subjects before hematopoietic stem cell transplantation. Bone Marrow Transplant 38, 513–520 (2006). https://doi.org/10.1038/sj.bmt.1705475

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