Seminars in Immunopathology

, Volume 30, Issue 3, pp 329–337 | Cite as

Oxidative stress and the pathogenesis of scleroderma: the Murrell’s hypothesis revisited

  • Armando Gabrielli
  • Silvia Svegliati
  • Gianluca Moroncini
  • Giovanni Pomponio
  • Mariarosaria Santillo
  • Enrico V. Avvedimento


Systemic sclerosis (SSc, scleroderma) is a devastating, immune-mediated, multisystem disorder characterized by microvasculature damage, circulating autoantibodies, and fibroblast activation, leading to massive fibrosis of skin, vessels, muscles, and visceral organs. Scleroderma causes disability and death as the result of end-stage organ failure. At present, no specific diagnostic nor therapeutic tools are available to handle the disease. In spite of significant effort, the etiology and pathogenesis of SSc remain obscure and, consequently, the disease outcome is unpredictable. Several years ago, Murrell suggested a unifying hypothesis linking the pathogenesis of scleroderma to the generation of a large excess of reactive oxygen species. This hypothesis has been substantiated by several reports indicating the presence of an abnormal redox state in patients with scleroderma. This review will summarize the available evidence supporting the link between free radicals and the main pathological features of scleroderma.


Oxidative stress Tissue fibrosis Systemic sclerosis Autoantibodies to PDGF receptor 


  1. 1.
    Jimenez AS, Derk TC (2004) Following the molecular pathway toward an understanding of the pathogenesis of systemic sclerosis. Ann Intern Med 140:37–50PubMedGoogle Scholar
  2. 2.
    Varga J, Abraham D (2007) Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest 117:557–567PubMedGoogle Scholar
  3. 3.
    Murrell DF (1993) A radical proposal for the pathogenesis of scleroderma. J Am Acad Dermatol 28:78–85PubMedGoogle Scholar
  4. 4.
    Herrick AL, Rieley F, Schofield D et al (1994) Micronutrient antioxidant status in patients with primary Raynaud’s phenomenon and systemic sclerosis. J Rheumatol 21:1477–1483PubMedGoogle Scholar
  5. 5.
    Lundberg AC, Akesson A, Akesson B (1992) Dietary intake and nutritional status in patients with systemic sclerosis. Ann Rheum Dis 51:1143–1148PubMedCrossRefGoogle Scholar
  6. 6.
    Bruckdorfer KR, Hillary JB, Bunce T et al (1995) Increased susceptibility to oxidation of low-density lipoproteins isolated from patients with systemic sclerosis. Arthritis Rheum 38:1060–1067PubMedGoogle Scholar
  7. 7.
    Iwata Y, Ogawa F, Komura K et al (2007) Autoantibody against peroxiredoxin I, an antioxidant enzyme, in patients with systemic sclerosis: possible association with oxidative stress. Rheumatology 46:790–795PubMedGoogle Scholar
  8. 8.
    Tikly M, Channa K, Theodorou P et al (2006) Lipid peroxidation and trace elements in systemic sclerosis. Clin Rheumatol 25:320–324PubMedGoogle Scholar
  9. 9.
    Stein CM, Tanner SB, Awad JA et al (1996) Evidence of free radical-mediated injury (isoprostane overproduction) in scleroderma. Arthritis Rheum 39:1146–1150PubMedGoogle Scholar
  10. 10.
    Cracowski JL, Marpeau C, Carpentier PH et al (2001) Enhanced in vivo lipid peroxidation in scleroderma spectrum disorders. Arthritis Rheum 44:1143–1148PubMedGoogle Scholar
  11. 11.
    Cracowski JL, Carpentier PH, Imbert B et al (2002) Increased urinary F2-isoprostanes in systemic sclerosis, but not in primary Raynaud’s phenomenon: effect of cold exposure. Arthritis Rheum 4:1319–1323Google Scholar
  12. 12.
    Volpe A, Biasi D, Caramaschi P et al (2006) Levels of F2-isoprostanes in systemic sclerosis: correlation with clinical features. Rheumatology 45:314–320PubMedGoogle Scholar
  13. 13.
    Balbir-Gurman A, Braun-Moscovici Y, Livshitz V et al (2007) Antioxidant status after iloprost treatment in patients with Raynaud’s phenomenon secondary to systemic sclerosis. Clin Rheumatol 26:1517–1521PubMedGoogle Scholar
  14. 14.
    Beckman JS, Beckman TW, Chen J et al (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Aca Sci U S A 87:1620–24Google Scholar
  15. 15.
    Clancy RM, Amin AR, Abramson SB (1998) The role of nitric oxide in inflammation and immunity. Arthritis Rheum 41:1141–1151PubMedGoogle Scholar
  16. 16.
    Matucci CM, Kahaleh MB (2002) Beauty and the beast. The nitric oxide paradox in systemic sclerosis. Rheumatology 41:843–847Google Scholar
  17. 17.
    Yamamoto Y, Katayama I, Nishioka K (1998) Nitric oxide production and inducible nitric oxide synthase expression in systemic sclerosis. J Rheumatol 25:314–317PubMedGoogle Scholar
  18. 18.
    Dooley A, Gao B, Bradley N et al (2006) Abnormal nitric oxide metabolism in systemic sclerosis: increased levels of nitrated proteins and asymmetric dimethylarginine. Rheumatology 45:676–684PubMedGoogle Scholar
  19. 19.
    Takagi K, Kawaguchi Y, Hara M et al (2003) Serum nitric oxide (NO) levels in systemic sclerosis patients: correlation between NO levels and clinical features. Clin Exp Immunol 134:538–544PubMedGoogle Scholar
  20. 20.
    Allanore Y, Borderie D, Hilliquin P et al (2001) Low levels of nitric oxide (NO) in systemic sclerosis: inducible NO synthase production is decreased in cultured peripheral blood monocyte/macrophage cells. Rheumatology 40:1089–1096PubMedGoogle Scholar
  21. 21.
    Cotton A, Herrick AL, Jayson MI et al (1999) Endothelial expression of nitric oxide synthases and nitrotyrosine in systemic sclerosis. J Pathol 189:273–278PubMedGoogle Scholar
  22. 22.
    Kharitonov SA, Cailes JB, Black CM et al (1997) Decreased nitric oxide in the exhaled air of patients with systemic sclerosis with pulmonary hypertension. Thorax 52:1051–1055PubMedCrossRefGoogle Scholar
  23. 23.
    Moodley YP, Lalloo UG (2001) Exhaled nitric oxide is elevated in patients with progressive systemic sclerosis without interstitial lung disease. Chest 119:1449–1454PubMedGoogle Scholar
  24. 24.
    Malerba M, Radaeli A, Ragnoli B et al (2007) Exhaled nitric oxide levels in systemic sclerosis with and without pulmonary involvement. Chest 132:575–580PubMedGoogle Scholar
  25. 25.
    Tiev KP, Cabane J, Aubourg F et al (2007) Severity of scleroderma lung disease is related to alveolar concentration of nitric oxide. Eur Respir J 30:26–30PubMedGoogle Scholar
  26. 26.
    Rolla G, Colagrande P, Scappaticci E et al (2000) Exhaled nitric oxide in systemic sclerosis: relationships with lung involvement and pulmonary hypertension. J Rheumatol 27:1693–1698PubMedGoogle Scholar
  27. 27.
    Sambo P, Amico D, Giacomelli R et al (2001) Intravenous N-acetylcysteine for treatment of Raynaud’s phenomenon secondary to systemic sclerosis: a pilot study. J Rheumatol 28:2257–2262PubMedGoogle Scholar
  28. 28.
    Herrick AL, Hollis S, Schofield D et al (2000) A double-blind placebo-controlled trial of antioxidant therapy in limited cutaneous systemic sclerosis. Clin Exp Rheumatol 18:349–356PubMedGoogle Scholar
  29. 29.
    Denton CP, Bunce TD, Dorado MB et al (1999) Probucol improves symptoms and reduces lipoprotein oxidation susceptibility in patients with Raynaud’s phenomenon. Rheumatology 38:309–315PubMedGoogle Scholar
  30. 30.
    Becker LB (2004) New concepts in reactive oxygen species and cardiovascular reperfusion physiology. Cardiovasc Res 61:461–470PubMedGoogle Scholar
  31. 31.
    Sambo P, Jannino L, Candela M et al (1999) Monocytes of patients with systemic sclerosis (scleroderma) spontaneously release in vitro increased amounts of superoxide anion. J Invest Dermatol 112:78–84PubMedGoogle Scholar
  32. 32.
    Cracowski JL, Kom GD, Salvat-Melis M et al (2006) Postocclusive reactive hyperemia inversely correlates with urinary 15-F2t-isoprostane levels in systemic sclerosis. Free Radic Biol Med 40:1732–1737PubMedGoogle Scholar
  33. 33.
    Sambo P, Svegliati Baroni S, Luchetti M et al (2001) Oxidative stress in scleroderma. Maintenance of scleroderma fibroblast phenotype by the constitutive up-regulation of reactive oxygen species generation through the NADPH oxidase complex pathway. Arthritis Rheum 44:2653–2664PubMedGoogle Scholar
  34. 34.
    Svegliati Baroni S, Cancello R, Sambo P et al (2005) PDGF and reactive oxygen species (ROS) regulate Ras protein levels in primary human fibroblasts via ERK 1/2. Amplification of ROS-ERK-Ras signalling in systemic sclerosis fibroblasts. J Biol Chem 280:36474–36482Google Scholar
  35. 35.
    Allanore Y, Borderie D, Périanin A et al (2005) Nifedipine protects against overproduction of superoxide anion by monocytes from patients with systemic sclerosis. Arthritis Res Ther 7:R93–R100PubMedGoogle Scholar
  36. 36.
    Failli P, Palmieri L, D’Alfonso C et al (2002) Effect of N-acetyl-l-cysteine on peroxynitrite and superoxide anion production pf lung alveolar macrophage in systemic sclerosis. Nitric Oxide 7:277–282PubMedGoogle Scholar
  37. 37.
    Yamamoto T, Sawada Y, Katayama I et al (1998) Increased production of nitric oxide stimulated by interleukin-1beta in peripheral blood mononuclear cells in patients with systemic sclerosis. Br J Rheumatol 37:1123–1125PubMedGoogle Scholar
  38. 38.
    Bedard K, Krause KE (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313PubMedGoogle Scholar
  39. 39.
    Lassegue B, Sorescu D, Szocs K et al (2001) Novel gp91 (phox) homologues in vascular smooth muscle cells: nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signalling pathway. Circ Res 88:888–894PubMedGoogle Scholar
  40. 40.
    Touyz RM, Chen X, Tabet F et al (2002) Expression of a functionally active gp91phox-containing neutrophil-type NAD(P)H oxidase in smooth muscle cells from human resistance arteries: regulation by angiotensin II. Circ Res 90:1205–1213PubMedGoogle Scholar
  41. 41.
    Cucoranu I, Clempus R, Dikalova A et al (2005) NAD(P)H oxidase 4 mediates transforming growth factor-beta-1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res 97:900–907PubMedGoogle Scholar
  42. 42.
    Sturrock A, Cahill B, Norman K et al (2005) Transforming growth factor beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 290:L661–L673PubMedGoogle Scholar
  43. 43.
    Neufeld G, Cohen T, Gengrinovitch S et al (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13:9–22PubMedGoogle Scholar
  44. 44.
    Thannickal VJ, Fanburg BL (1995) Activation of an H2O2-generating NADH in human lung fibroblasts by transforming growth factor-beta 1. J Biol Chem 270:30334–30338PubMedGoogle Scholar
  45. 45.
    Chapple ILC (1997) Reactive oxygen species and antioxidants in inflammatory diseases. J Clin Periodontol 24:287–296PubMedGoogle Scholar
  46. 46.
    Datla RS, Peshavariya H, Dusting GJ et al (2007) Important role of Nox4 type NADPH oxidase in angiogenic responses in human microvascular endothelial cells in vitro. Arterioscler Thromb Vasc Biol 27:2319–2324PubMedGoogle Scholar
  47. 47.
    Ago T, Kitazono T, Ooboshi H et al (2004) Nox4 as the major catalytic component of an endothelial NAD(P)H oxidase. Circulation 109:227–233PubMedGoogle Scholar
  48. 48.
    Ago T, Kitazono T, Kuroda J et al (2005) NAD(P)H oxidase in rat basilar arterial endothelial cells. Stroke 36:1040–1046PubMedGoogle Scholar
  49. 49.
    Banfi B, Malgrange B, Knisz J et al (2004) Nox3: a superoxide-generating NADPH oxidase of the inner ear. J Biol Chem 279:46065–46072PubMedGoogle Scholar
  50. 50.
    Furst R, Brueckl C, Kuebler WM et al (2005) Atrial natriuretic peptide induces mitogen-activated protein kinase phosphatase-1 in human endothelial cells via Rac1 and NAD(P)H oxidase/Nox2-activation. Circ Res 96:43–53PubMedGoogle Scholar
  51. 51.
    Goyal P, Weissmann N, Grimminger F et al (2004) Upregulation of NAD(P)H oxidase 1 in hypoxia activates hypoxia-inducible factor 1 via increase in reactive oxygen species. Free Radic Biol Med 36:1279–1288PubMedGoogle Scholar
  52. 52.
    Higgings DF, Kimura K, Bernhardt WM et al (2007) Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 117:3810–3820Google Scholar
  53. 53.
    Colston JT, de la Rosa SD, Strader JR et al (2005) H2O2 activates Nox4 through PLA2-dependent arachidonic acid production in adult cardiac fibroblasts. FEBS Lett 579:2533–2540PubMedGoogle Scholar
  54. 54.
    Dhaunsi GS, Paintlia MK, Kaur J et al (2004) NADPH oxidase in human lung fibroblasts. J Biomed Sci 11:617–622PubMedGoogle Scholar
  55. 55.
    Chamseddine AH, Miller JFJ (2003) gp91phox contributes to NADPH oxidase activity in aortic fibroblasts, but not smooth muscle cells. Am J Physiol Heart Circ Physiol 285:H2284–H2289PubMedGoogle Scholar
  56. 56.
    Harris ML, Rosen A (2003) Autoimmunity in scleroderma: the origin, pathogenetic role and clinical significance of autoantibodies. Curr Opin Rheumatol 15:778–784PubMedGoogle Scholar
  57. 57.
    Hasegawa M, Sato S, Fujimoto M et al (1998) Serum levels of interleukin 6 (IL-6) oncostatin M, soluble IL-6 receptor, and soluble gp130 in patients with systemic sclerosis. J Rheumatol 25:308–313PubMedGoogle Scholar
  58. 58.
    Hasegawa M, Fujimoto M, Kikuchi K et al (1997) Elevated serum levels of interleukin 4 (IL-4), IL-10 and IL-13 in patients with systemic sclerosis. J Rheumatol 24:328–332PubMedGoogle Scholar
  59. 59.
    Valentini G, Baroni A, Esposito K et al (2001) Peripheral blood T lymphocytes from systemic sclerosis patients show both Th1 and Th2 activation. J Clin Immunol 21:210–217PubMedGoogle Scholar
  60. 60.
    Hesegawa M, Sato S, Ihn H et al (1999) Enhanced production of interleukin-6 (IL-6) oncostatin M and soluble IL-6 receptor by cultured peripheral blood mononuclear cells from patients with systemic sclerosis. Rheumatology 38:612–617Google Scholar
  61. 61.
    Mavalia C, Scaletti C, Romagnani P et al (1997) Type 2 helper T-cell predominance and high CD30 expression in systemic sclerosis. Am J Pathol 151:1751–1758PubMedGoogle Scholar
  62. 62.
    Li-Weber M, Giaisi M, Treiber MK et al (2002) Vitamin E inhibits IL-4 gene expression in peripheral blood T cells. Eur J Immunol 32:2401–2408PubMedGoogle Scholar
  63. 63.
    King MR, Ismail AS, Davis LS et al (2006) Oxidative stress promotes polarization of human T cell differentiation toward a T helper 2 phenotype. J Immunol 176:2765–2772PubMedGoogle Scholar
  64. 64.
    Ishikawa H, Carrasco D, Claudio E et al (1997) Gastric hyperplasia and increased proliferative responses of lymphocytes in mice lacking the COOH-terminal ankyrin domain of NF-kappaB2. J Exp Med 186:999–1014PubMedGoogle Scholar
  65. 65.
    Casciola-Rosen L, Wigley F, Rosen A (1997) Scleroderma autoantigens are uniquely fragmented by metal-catalyzed oxidation reactions: implication for pathogenesis. J Exp Med 185:71–79PubMedGoogle Scholar
  66. 66.
    Obata F, Hoshino A, Toyama A (2006) Hydrogen peroxide increases interleukin-12 p40/p70 molecular ratio and induces Th2 predominant responses in mice. Scand J Immunol 63:125–130PubMedGoogle Scholar
  67. 67.
    Peterson JD, Herzenberg LA, Vasquez K et al (1998) Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns. Proc Natl Acad Sci U S A 95:3071–3076PubMedGoogle Scholar
  68. 68.
    Jeannin P, Delneste Y, Lecoanet-Henchoz S et al (1995) Thiols decrease human interleukin (IL) 4 production and IL-4-induced immunoglobulin synthesis. J Exp Med 182:1785–1792PubMedGoogle Scholar
  69. 69.
    Prescott RJ, Freemont AJ, Jones CJ et al (1992) Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 166:255–263PubMedGoogle Scholar
  70. 70.
    Fleischmajer R, Perlish JS, Shaw KV et al (1976) Skin capillary changes in early systemic scleroderma. Electron microscopy and “in vitro” autoradiography with tritiated thymidine. Arch Dermatol 112:1553–1557PubMedGoogle Scholar
  71. 71.
    Fleischmajer R, Perlish JS (1980) Capillary alterations in scleroderma. J Am Acad Dermatol 2:161–170PubMedGoogle Scholar
  72. 72.
    Mitchell RN, Libby P (2007) Vascular remodelling in transplant vasculopathy. Circ Res 100:967–978PubMedGoogle Scholar
  73. 73.
    Kuwana M, Okazaki Y, Yasuoka H et al (2004) Defective vasculogenesis in systemic sclerosis. Lancet 364:603–610PubMedGoogle Scholar
  74. 74.
    Sgonc R, Gruschwitz MS, Dietrich H et al (1996) Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J Clin Invest 98:785–792PubMedGoogle Scholar
  75. 75.
    Herron GS, Luz I, Romero LI (1998) Vascular abnormalities in scleroderma. Semin Cutan Med Surg 17:12–17PubMedGoogle Scholar
  76. 76.
    Griendling KK, Sorescu D, Ushio-Fukai M (2000) NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 86:494–501PubMedGoogle Scholar
  77. 77.
    Lassègue B, Sorescu D, Szöcs K et al (2001) Novel gp91 (phox) homologues in vascular smooth muscle cells: nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways. Circ Res 88:888–894PubMedGoogle Scholar
  78. 78.
    Marumo T, Schini-Kerth VB, Fissilthaler B et al (1997) Platelet-derived growth factor-stimulated superoxide anion production modulates activation of transcription factor NF-kappaB and expression of monocyte chemoattractant protein 1 in human aortic smooth muscle cells. Circulation 96:2361–2367PubMedGoogle Scholar
  79. 79.
    Wang Z, Castresana MR, Newman WH (2004) Reactive oxygen species-sensitive p38 MAPK controls thrombin-induced migration of vascular smooth muscle cells. J Mol Cell Cardiol 36:49–56PubMedGoogle Scholar
  80. 80.
    Zhang H, Schmeisser A, Garlichs CD et al (1999) Angiotensin II-induced superoxide anion generation in human vascular endothelial cells: role of membrane-bound NADH-/NADPH-oxidases. Cardiovasc Res 44:215–222PubMedGoogle Scholar
  81. 81.
    Pedruzzi E, Guichard C, Ollivier V (2004) NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells. Mol Cell Biol 24:10703–10717PubMedGoogle Scholar
  82. 82.
    Ushio-Fukai M, Zafari AM, Fukui T, Ishizaka N, Griendling KK (1996) p22phox is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells. J Biol Chem 271:23317–23321PubMedGoogle Scholar
  83. 83.
    Rey FE, Pagano PJ (2002) The reactive adventitia: fibroblasts oxidase in vascular function. Thromb Vasc Biol 22:1962–1971Google Scholar
  84. 84.
    Kawaguchi Y, Takagi K, Hara M et al (2004) Angiotensin II in the lesional skin of systemic sclerosis patients contributes to tissue fibrosis via angiotensin II type 1 receptors. Arthritis Rheum 50:216–226PubMedGoogle Scholar
  85. 85.
    Holland JA, Meyer JW, Chang MM et al (1998) Thrombin stimulated reactive oxygen species production in cultured endothelial cells. Endothelium 6:113–121PubMedGoogle Scholar
  86. 86.
    Bogatkevich GS, Gustio E, Oates JC et al (2004) Distinct PKC isoforms mediate cell survival and DNA synthesis in thrombin-induced myofibroblasts. Am J Physiol Lung Cell Mol Physiol 288:L190–L201PubMedGoogle Scholar
  87. 87.
    Klareskog L, Gustaffson R, Scheynius A et al (1990) Increased expression of platelet-derived growth factor type B receptors in the skin of patients with systemic sclerosis. Arthritis Rheum 33:1534–1541PubMedGoogle Scholar
  88. 88.
    Xue-yi Z, Jan-zhong Z, Ping T et al (1998) Expression of platelet-derived growth factor B chain and platelet-derived growth factor b-receptor in fibroblasts of scleroderma. J Dermatol Sci 18:90–97Google Scholar
  89. 89.
    Abraham DJ, Varga J (2005) Scleroderma: from cell and molecular mechanisms to disease models. Trends Immunol 26:587–595PubMedGoogle Scholar
  90. 90.
    Murrell GAC, Francis MJO, Bromley L (1990) Modulation of fibroblast proliferation by oxygen free radicals. Biochem J 265:659–665PubMedGoogle Scholar
  91. 91.
    Falanga V, Martin TA, Takagi H et al (1993) Low oxygen tension increases mRNA levels of alpha 1(I) procollagen in human dermal fibroblasts. J Cell Physiol 157:408–412PubMedGoogle Scholar
  92. 92.
    Parola M, Pinzani M, Casini A et al (1993) Stimulation of lipid peroxidation or 4-hydroxynonenal treatment increases procollagen a(I) gene expression in human liver fat-storing cells. Biochem Biophys Res Commun 194:1044–1050PubMedGoogle Scholar
  93. 93.
    Kinnula VL, Fattman CL, Tan RJ et al (2005) Oxidative stress in pulmonary fibrosis. A possible role for redox modulatory therapy. Am J Respir Crit Care Med 172:417–422PubMedGoogle Scholar
  94. 94.
    Shi Y, Massagué J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700PubMedGoogle Scholar
  95. 95.
    Trojanowska M (2002) Molecular aspects of scleroderma. Front Biosci 7:608–618Google Scholar
  96. 96.
    Bellocq A, Azoulay E, Marullo S et al (1999) Reactive oxygen species and nitrogen intermediates increase transforming growth factor-beta 1 release from human epithelial alveolar cells through two different mechanisms. Am J Respir Cell Mol Biol 21:128–136PubMedGoogle Scholar
  97. 97.
    Barcellos-Hoff MH, Dix TA (1996) Redox-mediated activation of latent transforming growth factor beta. Mol Endocrinol 10:1077–1083PubMedGoogle Scholar
  98. 98.
    Hancock JT, Desikan R, Neill SJ (2001) Role of reactive oxygen species in cell signalling pathways. Biochem Soc Trans 29:345–350PubMedGoogle Scholar
  99. 99.
    Sementchenko VI, Watson DK (2000) Ets target genes: past, present and future. Oncogene 19(55):6533–6548PubMedGoogle Scholar
  100. 100.
    Arsalane K, Dubois CM, Muanza T et al (1997) Transforming growth factor-beta 1 is a potent inhibitor of glutathione synthesis in the lung epithelial cell line A 549: transcription effect on the GSH rate-limiting enzyme gamma-glutamylcysteine synthetase. Am J Respir Cell Mol Biol 17:599–607PubMedGoogle Scholar
  101. 101.
    Factor VM, Kiss A, Woitach JT et al (1998) Disruption of redox homeostasis in the transforming growth factor-alpha/c-myc transgenic mouse model of accelerated hepatocarcinogenesis. J Biol Chem 273:15846–15853PubMedGoogle Scholar
  102. 102.
    Ask K, Martin GE, Kolb M et al (2006) Targeting genes for treatment in idiopathic pulmonary fibrosis: challenges and opportunities, promises and pitfalls. Proc Am Thorac Soc 3:389–393PubMedGoogle Scholar
  103. 103.
    Hoyle GW, Li J, Finkelstein JB et al (1999) Emphysematous lesions, inflammation, and fibrosis in the lungs of transgenic mice overexpressing platelet-derived growth factor. Am J Pathol 154:1763–1775PubMedGoogle Scholar
  104. 104.
    Bae SY, sung JY Kim OS et al (2000) Platelet-derived growth factor-induced H2O2 production requires the activation of phosphatidylinositol 3-kases. J Biol Chem 275:10527–10531PubMedGoogle Scholar
  105. 105.
    Park J, Ha H, Ahn HJ et al (2005) Sirolimus inhibits platelet-derived growth factor-induced collagen synthesis. Transplant Proc 37:3459–3462PubMedGoogle Scholar
  106. 106.
    Rajkumar VS, Howelll K, Csiszar K et al (2005) Shared expression of phenotypic markers in systemic sclerosis indicates convergence of pericytes and fibroblasts to a myofibroblast lineage in fibrosis. Arthritis Res Ther 7:R1113–R1123PubMedGoogle Scholar
  107. 107.
    Distler JH, Jungel A, Huber LC et al (2007) Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis. Arthritis Rheum 56:311–322PubMedGoogle Scholar
  108. 108.
    Svegliati Baroni SS, Santillo MR, Bevilacqua F et al (2006) Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis (scleroderma). N Engl J Med 354:2667–2676Google Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Armando Gabrielli
    • 1
    • 2
  • Silvia Svegliati
    • 1
  • Gianluca Moroncini
    • 1
  • Giovanni Pomponio
    • 1
  • Mariarosaria Santillo
    • 3
  • Enrico V. Avvedimento
    • 4
  1. 1.Dipartimento di Scienze Mediche e Chirurgiche, Clinica MedicaUniversità Politecnica delle MarcheAnconaItaly
  2. 2.Fondazione di Medicina MolecolareUniversità Politecnica delle MarcheAnconaItaly
  3. 3.Dipartimento di Neuroscienze e di Scienze del Comportamento-Sezione di FisiologiaUniversità Federico IINapoliItaly
  4. 4.Dipartimento di Biologia e Patologia Molecolare e Cellulare, Centro di Endocrinologia ed Oncologia Sperimentale del C.N.R.Università Federico IINapoliItaly

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