Oxidative stress in Systemic Sclerosis

  • Gabriele Simonini
  • Marco Matucci Cerinic
  • Sergio Generini
  • Massimo Zoppi
  • Mario Anichini
  • C. Cesaretti
  • Alberto Pignone
  • Fernanda Falcini
  • Torello Lotti
  • Mario Cagnoni
Part of the Molecular and Cellular Biochemistry book series (DMCB, volume 32)


In 63 patients affected by Systemic Sclerosis (SSc) (limited subset., 40; diffuse subset: 23; early: 30; advanced: 33) the peroxidation product diene-conjugates (DC) and antibodies against oxidised low density lipoproteins (Ab oxLDL) were tested in serum by a spectrophotometer (absorbance 234 mn) and by a standard ELISA respectively. The data were compared with those obtained by 21 healthy subjects. DC was significantly higher in patients (73.3 ± 37.2 μM/1; p < 0.0001) than in controls (48.4 ± 16.7) as well as in the limited (80 ± 48.8; p < 0.05) than in the diffuse subset (64.5 ± 36.4); and in early (84.1 ±31.4; p < 0.05) than in advanced stage of the disease (67.9 ± 42.5). The levels of Ab oxLDL were significantly higher in SSc patients (309.5 ± 367.2 mU/ml; p < 0.0001) in all its subsets (limited: 351.9 ± 351.1, p < 0.0001; diffuse: 207.7 ± 316. 1, p < 0.05; early: 428.9 ± 417.1, p < 0.001; advanced: 302.7 ± 89.9, p < 0.0001) than in controls (89.3 ± 29.1). These antibodies levels were higher in limited subset than in diffuse (p < 0.05) and in early SSc than in advanced SSc (p < 0.05). The highest values of parameters of oxidative stress are found in the early stages, when the episodes of reperfusion after ischemic episodes (Raynaud’s phenomenon) are very ferequent. Moreover, the damage is higher in the early stages of SSc, with intact microvessels, than in late stages, when microvessels are very reduced in number, destroyed by the worsening of the disease. These data show that the respiratory burst deduced by the lipoperoxidation is higher in SSc than in controls, and may be an important pathogenetic factors involved in tissue changes in SSc. ((Mol Cell Biochem 196: 85-91, 1999)

Key words

oxidative stress Systemic Sclerosis diene-conjugates antibodies against oxidised low density lipoproteins reperfusion injury 


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  1. 1.
    Matucci Cerinic M, Kahaleh BM, LeRoy EC: The vascular involvement in systemic sclerosis. In: P.J. Clements, D.E. Furst (eds). Systemic Sclerosis. Baltimore, 1996, pp 153–174Google Scholar
  2. 2.
    Murrel DF: A radical proposal for the pathogenesis of scleroderma. J Am Acad Dermatol 28: 78–85, 1993CrossRefGoogle Scholar
  3. 3.
    Mapp PI, Grootveld MC, Blake DR: Hypoxia, oxidative stress and rheumatoid arthritis. Br Med Bull 51: 419–436, 1995PubMedGoogle Scholar
  4. 4.
    Halliwell B, Gutteridge JMC: Free radicals in biology and medicine. Clarendon Press, Oxford, 1989Google Scholar
  5. 5.
    Rowley D, Gutteridge JMC, Blake D, Farr M, Halliwell B: Lipid peroxidation in rheumatoid arthritis: Thiobarbituric acid-reactive material and catalytic iron salts in synovial fluid from rheumatoid patients. Clin Sci 66: 691–695, 1984PubMedGoogle Scholar
  6. 6.
    Biemond P, Swaak AJG, Koster JF: Protective factors against oxygen free radicals and hydrogen peroxide in rheumatoid arthritis synovial fluid. Arth Rheum 27: 760–765, 1984CrossRefGoogle Scholar
  7. 7.
    Candeias LP: Free hydroxyl radicals are formed on reaction between oxygen free radicals and hydrogen peroxide in rheumatoid arthritis synovial fluid. Arth Rheum 27: 760–765, 1984CrossRefGoogle Scholar
  8. 8.
    Rathakrishnan C, Tiku K, Raghavan A, Tiku ML: Release of oxygen radicals by articular chondrocytes. J Bone Miner Res 7: 1139–1148, 1992PubMedCrossRefGoogle Scholar
  9. 9.
    Key LL Jr, Ries WL, Glassocock H, Rodriguiz R, Jaffe H: Osteoclastic superoxide generation. Int J Tissue React 14: 295–298, 1992PubMedGoogle Scholar
  10. 10.
    Jarasch ED, Grund C, Bruder G: Localization of xanthine oxidase in mammary gland epithelium and capillary endothelium. Cell 25: 67–82,1981PubMedCrossRefGoogle Scholar
  11. 11.
    Delia Corte E, Stirpe F: The regulation of rat liver xanthine oxidase. Involvement of thiol groups in the conversion of the enzyme activity from dehydrogenase (type D) into oxidase (type)) and purification of the enzyme. Biochem J 126: 739–745, 1972Google Scholar
  12. 12.
    McCord JM, Roy RS, Schaffer SW: Free radicals and myocardial ischemia: The role of xanthine oxidase. Adv Myocardiol 5: 183–189, 1985PubMedGoogle Scholar
  13. 13.
    Granger DN, Holloworth ME, Parks DA: Ischaemia-reperfusion injury: Role of oxygen derived free radicals. Acta Physiol Scand 548: 47–63, 1986Google Scholar
  14. 14.
    Merry P, Grootveld M, Lunec J, Blake DR: Oxidative damage to lipids within the inflamed human joint provides evidence of radical-mediated hypoxic-reperfusion injury. Am J Clin Nutr 53: 362S–369S, 1991PubMedGoogle Scholar
  15. 15.
    Henderson E, Winyard M, Grootveld MC, Blake DR: Pathophysiology of reperfusion injury in human joints. In: D.K. Das (ed). Pathophysiology of Reperfusion Injury. CRC Press, Boca Raton, FL, 1995, pp 429–470Google Scholar
  16. 16.
    Hovdens J, Hovdens AB, Egeland T: A study of the effect of rheumatoid synovial fluid on proliferation and IL-2 production by total mononuclear cells and purified CD4+ cells of synovial fluid and peripheral blood. Scand J Rheumatol 19: 398–406, 1990CrossRefGoogle Scholar
  17. 17.
    Shingu M, Yoshioka K, Nobunaga M: Human vascular smooth muscle cells and endothelial cells lack catalase activity and are susceptible to hydrogen peroxide. Inflammation 9: 309–320, 1985PubMedCrossRefGoogle Scholar
  18. 18.
    Mead JF: In W.A.J. Pryor (ed). Free Radicals in Biology, Vol. 1. Academic Press, New York, 1976, pp 51–68CrossRefGoogle Scholar
  19. 19.
    Winyard PG, Tatzeber F, Esterbauer H, Kus ML, Morris CJ, Blake DR: Presence of foam cells containing oxidised low density lipoprotein in rheumatoid synovial membrane. Ann Rheum Dis 52: 677–680, 1993PubMedCrossRefGoogle Scholar
  20. 20.
    Esterbauer H, Dieber-Rotheneder M, Waeg G, Striegl G, Jurges G: Biochemical structural and functional properties of oxidised low-density lipoprotein. Chem Res Toxicol 3: 77–92, 1990PubMedCrossRefGoogle Scholar
  21. 21.
    Kalant N, McCornick S, Parniak MA: Effects of copper and histidine on oxidative modification of low density lipoprotein and its subsequent binding to collagen. Arterioscler Thromb 11: 1322–1329, 1991PubMedCrossRefGoogle Scholar
  22. 22.
    Morris CJ, Bradby GVH, Walton KW: Fibrous longspacing collagen in human atherosclerosis. Atherosclerosis 31: 345–354, 1978PubMedCrossRefGoogle Scholar
  23. 23.
    Berliner JA, Territo MC, Sevanian A: Minimally modified low density lipoprotein stimulates monocyte endothelial cell interactions. J Clin Invest 85: 1260–1266, 1990PubMedCrossRefGoogle Scholar
  24. 24.
    lauen W, Payne DK, Kvietys PR: Hyposica/reoxygenation increases the permeability of endothelial cell monolayers: Role of oxygen radicals. J Clin Invest 9: 219–233, 1990Google Scholar
  25. 25.
    Parks DA, Granger DN: Ischemia-induced vascular changes. Role of xanthine oxidase and hydroxyl radicals. Am J Physiol 245: 285–289, 1983Google Scholar
  26. 26.
    Maslen CL, Hall ND, Woolf AD, Maddison PJ: Enhanced oxidative metabolism of neutrophils from patients with systemic sclerosis. Br J Rheumatol 26: 113–117,1987PubMedCrossRefGoogle Scholar
  27. 27.
    Czirjak L, Danko K, Sipka S, Zeher M, Szegedi G: Polymorphonuclear neutrophil function in systemic sclerosis. Ann Rheum Dis 46: 302–306, 1987PubMedCrossRefGoogle Scholar
  28. 28.
    Murrel GAC, Francis MJO, Bromley L: Modulation of fibroblast proliferation by oxygen free radicals. Biochem J 265: 659–665, 1990Google Scholar
  29. 29.
    Del Maestro RF, Thaw HH, Bjork J: Free radicals as mediators of tissue injury. Acta Physiol Scand 492: 43–57, 1980Google Scholar
  30. 30.
    LeRoy EC, Black C, Fleischmajer R: Scleroderma (systemic sclerosis): Classification, subsets and pathogenesis. J Rheumatol 15:202–205, 1988PubMedGoogle Scholar
  31. 31.
    Esterbauer H, Cheeseman KH: Determination of aldehydic lipid peroxidation products: Malonaldehyde and 4-hydroxynonenal. Met Enzymol 186: 407–413, 1990CrossRefGoogle Scholar
  32. 32.
    Virella G, Virella I, Lennon RB, Prior MB, Virella M: Anti oxidised low density apoprotein antibodies in patients with coronary heart disease and normal healthy volunteers. Int J Clin Lab Res 23: 95–101, 1993PubMedCrossRefGoogle Scholar
  33. 33.
    Esterbauer H, Striegel G, Pahl H, Rotheneder M: Continuous monitoring of in vitro oxidation of human low density lipoprotein. Free Radical Res Commun 6: 67–75, 1989CrossRefGoogle Scholar
  34. 34.
    Rosen A, Casciola-Rosen L, Wigley F: Role of metal-catalyzed oxidation reactions in the early pathogenesis of scleroderma. Curr Opin Rheumatol 9: 538–543, 1997PubMedCrossRefGoogle Scholar
  35. 35.
    Stein CM, Tanner SB, Awad JA, Roberts LJ II, Morrow JD: Evidence of free radical-mediated injury (isoprostane overproduction) in scleroderma. Arth Rheum 39: 1146–1150, 1996CrossRefGoogle Scholar
  36. 36.
    Emerit I: Reactive oxygen species, chromosome mutation and cancer: Possible role of clastogenic factor in carcinogenesis. J Clin Invest 16: 99–109, 1994Google Scholar
  37. 37.
    Casciola-Rosen L, Wigley F, Rosen A: Scleroderma autoantigens are uniquely fragmented by metal catalyzed oxidation reactions: Implications for pathogenesis. J Exp Med 185: 71–79, 1997PubMedCrossRefGoogle Scholar
  38. 38.
    Herrick AL, Rieley F, Schofield D, Hollis S, Braganza JM, Jayson MI: Micronutrient antioxidant status in patients with primary Raynaud’s phenomenon and systemic sclerosis. J Rheumatol 21:1477–1483, 1994PubMedGoogle Scholar
  39. 39.
    Lundberg AC, Akesson A, Akesson B: Dietary intake and nutritional status in patients with systemic sclerosis. Ann Rheum Dis 51: 1143–1148, 1992PubMedCrossRefGoogle Scholar
  40. 40.
    Herrick AL, Worthington H, Rieley F, Clarke D, Schofield D, Braganza JM, Jayson MIV: Dietary intake of micronutrient antioxidant in relation to blood levels in patients with systemic sclerosis. J Rheumatol 23: 650–653, 1996PubMedGoogle Scholar
  41. 41.
    Herrik AL, Rieley F, Braganza JM, Jayson MIV: Difficulty in detecting reperfusion injury increment in oxidative stress among patients with primary Raynaud’s phenomenon and systemic sclerosis. J Rheumatol 22: 374–375, 1995Google Scholar
  42. 42.
    Morita A, Minami H, Sakakibara N, Sato K, Tsuji TAD: Elevated plasma superoxide dismutase activity in patients with systemic sclerosis. J Dermatol Sci 11: 196–201, 1996PubMedCrossRefGoogle Scholar
  43. 43.
    Blann AD, Illingworth K, Jayson MIV: Mechanisms of endothelial cell damage in systemic sclerosis and Raynaud’s Phenomenon. J Rheumatol 20: 1325–1330, 1993PubMedGoogle Scholar
  44. 44.
    Bruckdorfer KR, Hillary JB, Bunce T, Vancheeswaran R, Black CM: Increased susceptibility to oxidation of low density lipoproteins isolated from patients with systemic sclerosis. Arth Rheum 38: 1060–1067, 1995CrossRefGoogle Scholar
  45. 45.
    Halliwell B, Chirico S: Lipid peroxidation: Its mechanism, measurement, and significance. Am J Clin Nutr 57: 0, 1993Google Scholar
  46. 46.
    Andrews B, Burnand K, Paganga G, Browse N, Rice-Evans C, Sommerville K, Leake D, Taub N: Oxidisability of low density lipoproteins in patients with carotid or femoral artery atherosclerosis. Atherosclerosis 112: 77–84, 1995PubMedCrossRefGoogle Scholar
  47. 47.
    Hamilton CA: Low-density lipoprotein and oxidised low-density lipoprotein: Their role in the development of atherosclerosis. Pharmacol Ther 74: 55–72, 1997PubMedCrossRefGoogle Scholar
  48. 48.
    Gokce N, Frei B: Basis research in antioxidant inhibition of steps in atherogenesis. J Cardiovasc Risk 3: 352–357, 1996PubMedCrossRefGoogle Scholar
  49. 49.
    Gorog P: Modified low density lipoprotein is a potent stimulus for smooth muscle cell outgrowth from rat aortic expiant in vitro. Atherosclerosis 129: 1–7, 1997PubMedCrossRefGoogle Scholar
  50. 50.
    Thorne SA, Abbot SE, Winyard PG, Blake DR, Mills PG: Extent of oxidative modification of low density lipoprotein determines the degree of cytotoxicity to human coronary artery cells. Heart 75: 11–16, 1996PubMedCrossRefGoogle Scholar
  51. 51.
    Massaeli H, Pierce GN: Involvement of lipoproteins, free radicals, and calcium in cardiovascular disease processes. Cardiovasc Res 29: 597–603, 1995PubMedGoogle Scholar
  52. 52.
    Maggi E, Perani G, Falaschi F, Frattoni A, Martignoni A, Finardi G, Stefano PL, Simeone F, Paolini G, DeVecchi E: Autoantibodies against oxidised low density lipoproteins in patients with coronary disease. Press Med 23: 1158–1162, 1994Google Scholar
  53. 53.
    Blake DR, Winyard P, Scott DGI, Brailsford S, Blann A, Lunec J: Endothelial cell cytotoxicity in inflammatory vascular disease: The possible role of oxidised lipoproteins. Ann Rheum Dis 44: 176–184, 1985PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1999

Authors and Affiliations

  • Gabriele Simonini
    • 1
    • 5
  • Marco Matucci Cerinic
    • 2
  • Sergio Generini
    • 2
  • Massimo Zoppi
    • 2
  • Mario Anichini
    • 3
  • C. Cesaretti
    • 3
  • Alberto Pignone
    • 2
  • Fernanda Falcini
    • 1
  • Torello Lotti
    • 4
  • Mario Cagnoni
  1. 1.Department of PediatricsUniversity of FlorenceItaly
  2. 2.Departments of Medicine, Division of RheumatologyUniversity of FlorenceItaly
  3. 3.INRCAFlorenceItaly
  4. 4.Clinic of DermatologyUniversity of FlorenceItaly
  5. 5.Department of PediatricsRheumatology UnitFlorenceItaly

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