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The bleomycin-induced scleroderma model: what have we learned for scleroderma pathogenesis?

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Abstract

Scleroderma is a fibrotic condition characterized by immunologic abnormalities, vascular injury and increased accumulation of extracellular matrix (ECM) proteins in the skin. Although the etiology of scleroderma has not yet been fully elucidated, a growing body of evidence suggests that ECM overproduction by activated fibroblasts results from complex interactions among endothelial cells, lymphocytes, macrophages and fibroblasts, via a number of mediators, such as cytokines, chemokines and growth factors. For a better understanding of the pathophysiology of scleroderma, animal models are important tools. We established a murine model of cutaneous sclerosis by local treatment of bleomycin. This model reproduces several histological as well as biochemical aspects of human scleroderma. However, it must be emphasized that studying animal models cannot answer all the problems of human scleroderma. In this review, we introduce current insights into the pathogenesis of bleomycin-induced scleroderma, and discuss its contribution to our understanding of the pathogenesis of, and treatments for, human scleroderma.

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References

  1. Alecu M, Geleriu L, Coman G, Galatescu L (1998) The interleukin-1, interleukin-2, interleukin-6 and tumor necrosis factor α serological levels in localized and systemic sclerosis. Rom J Intern Med 36:251–259

    PubMed  CAS  Google Scholar 

  2. Asano Y, Ihn H, Yamane K, Kubo M, Tamaki K (2004) Impaired Smad7-Smurf-mediated negative regulation of TGF-beta signaling in scleroderma fibroblasts. J Clin Invest 113:253–264

    PubMed  CAS  Google Scholar 

  3. Asano Y, Ihn H, Yamane K, Jinnin M, Mimura Y, Tamaki K (2004) Phosphatidylinositol 3-kinase is involved in α2(I) collagen gene expression in normal and scleroderma fibroblasts. J Immunol 172:7123–7135

    PubMed  CAS  Google Scholar 

  4. Azuma A, Takahashi S, Nose M, Araki K, Araki M, Takahashi T, Hirose M, Kawashima H, Miyasaka M, Kudoh S (2000) Role of E-selectin in bleomycin induced lung fibrosis in mice. Thorax 55:147–152

    PubMed  CAS  Google Scholar 

  5. Belperio JA, Dy M, Burdick MD, Xue YY, Li K, Elias JA, Keane MP (2002) Interaction of IL-13 and C10 in the pathogenesis of bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 27:419–427

    PubMed  CAS  Google Scholar 

  6. Birkland TP, Cheavens MD, Pincus SH (1994) Human eosinophils stimulate DNA synthesis and matrix production in dermal fibroblasts. Arch Dermatol Res 286:312–318

    PubMed  CAS  Google Scholar 

  7. Breen E, Shull S, Burne S, Absher M, Kelley J, Phan S, Cutroneo KR (1992) Bleomycin regulation of transforming growth factor-β mRNA in rat lung fibroblasts. Am J Respir Cell Mol Biol 6:146–152

    PubMed  CAS  Google Scholar 

  8. Casciola-Rosen L, Wigley F, Rosen A (1997) Scleroderma autoantigens are uniquely fragmented by metal-catalyzed oxidation reactions: implications for pathogenesis. J Exp Med 185:71–79

    PubMed  CAS  Google Scholar 

  9. Cepeda EJ, Reveille JD (2004) Autoantibodies in systemic sclerosis and fibrosing syndromes: clinical indications and relevance. Curr Opin Rheumatol 16:723–732

    PubMed  CAS  Google Scholar 

  10. Choi ET, Callow AD, Sehgal NL, Brown DM, Ryan US (1995) Halofuginone, a specific collagen type I inhibitor, reduces anastomotic intima hyperplasia. Arch Surg 130:257–261

    PubMed  CAS  Google Scholar 

  11. Claman HN, Giorno RC, Seibold JR (1991) Endothelial and fibroblast activation in scleroderma: the myth of the “uninvolved skin”. Arthritis Rheum 34:1495–1501

    PubMed  CAS  Google Scholar 

  12. Clark JC, Starcher BC, Uitto J (1980) Bleomycin-induced synthesis of type I procollagen by human lung skin fibroblasts in culture. Biochim Biophys Acta 631:359–370

    PubMed  CAS  Google Scholar 

  13. Denholm EM, Phan SH (1989) The effects of bleomycin on alveolar macrophage growth factor secretion. Am J Pathol 134:355–363

    PubMed  CAS  Google Scholar 

  14. Distler O, Pap T, Kowal-Bielecka O, Meyringer R, Guiducci S, Landthaler M, Schölmerich J, Michel BA, Gay RE, Matucci-Cerinic M, Gay S, Müller-Ladner U (2001) Overexpression of monocyte chemoattractant protein 1 in systemic sclerosis: role of platelet-derived growth factor and effects of monocyte chemotaxis and collagen synthesis. Arthritis Rheum 44:2665–2678

    PubMed  CAS  Google Scholar 

  15. Dong C, Zhu S, Wang T, Yoon W, Li Z, Alvarez R, ten Dijke P, White B, Wigley FM, Goldschmidt-Clermont PJ (2002) Deficient Smad7 expression: a putative molecular defect in scleroderma. Proc Natl Acad Sci USA 99:3908–3913

    PubMed  CAS  Google Scholar 

  16. Doucet C, Brouty-Boye D, Pottin-Clemenceau C, Canonica GW, Jasmin C, Azzarone B (1998) Interleukin (IL)-4 and IL-13 act on human lung fibroblasts. J Clin Invest 101:2129–2139

    PubMed  CAS  Google Scholar 

  17. Doucet C, Brouty-Boye D, Pottin-Clemenceau C, Jasmin C, Canonica GW, Azzarone B (1998) IL-4 and IL-13 specifically increase adhesion molecule and inflammatory cytokine expression in human lung fibroblasts. Int Immunol 10:1421–1433

    PubMed  CAS  Google Scholar 

  18. Duncan MR, Berman B (1987) Persistence of a reduced-collagen-producing phenotype in cultured scleroderma fibroblasts after short term exposure to interferons. J Clin Invest 79:1318–1324

    PubMed  CAS  Google Scholar 

  19. Eitzman DT, McCoy RD, Zheng X, Fay WP, Shen T, Ginsburg D, Simon RH (1996) Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest 97:232–237

    PubMed  CAS  Google Scholar 

  20. Elovic AE, Ohyama H, Sauty A, McBride J, Tsuji T, Nagai M, Weller PF, Wong DT (1998) IL-4-dependent regulation of TGF-alpha and TGF-beta1 expression in human eosinophils. J Immunol 160:6121–6127

    PubMed  CAS  Google Scholar 

  21. Falanga V, Martin TA, Takagi H, Kirsner RS, Helfman T, Pardes J, Ochoa MS (1993) Low oxygen tension increases mRNA levels of alpha1(I) procollagen in human dermal fibroblasts. J Cell Physiol 157:408–412

    PubMed  CAS  Google Scholar 

  22. Fleischmajer R, Perlish JS, Reeves JRT (1977) Cellular infiltrates in scleroderma skin. Arthritis Rheum 20:975–984

    PubMed  CAS  Google Scholar 

  23. Galindo M, Santiago B, Rivero M, Rullas J, Alcami J, Pablos JL (2001) Chemokine expression by systemic sclerosis fibroblasts: abnormal regulation of monocyte chemoattractant protein 1 expression. Arthritis Rheum 44:1382–1386

    PubMed  CAS  Google Scholar 

  24. Galindo M, Santiago B, Alcami J, Riyero M, Martin-Serrano J, Pablos JL (2001) Hypoxia induces expression of the chemokines monocyte chemoattractant protein-1 (MCP-1) and IL-8 in human dermal fibroblasts. Clin Exp Immunol 123:36–41

    PubMed  CAS  Google Scholar 

  25. Gharaee-Kermani M, Denholm EM, Phan SH (1996) Costimulation of fibroblast collagen and transforming growth factor β1 gene expression by monocyte chemoattractant protein-1 via specific receptors. J Biol Chem 271:17779–17784

    PubMed  CAS  Google Scholar 

  26. Granot I, Halevy O, Hurwitz S, Pines M (1993) Halofuginone: an inhibitor of collagen type I synthesis. Biochim Biophys Acta 1156:107–112

    PubMed  CAS  Google Scholar 

  27. Gruber BL, Marchese MJ, Kew RR (1994) Transforming growth factor β1 mediates mast cell chemotaxis. J Immunol 152:5860–5867

    PubMed  CAS  Google Scholar 

  28. Gruschwitz M, Muller P, Sepp N, Hofer E, Fontana A, Wick G (1990) Transcription and expression of transforming growth factor type beta in the skin of progressive systemic sclerosis: a mediator of fibrosis? J Invest Dermatol 94:197–203

    PubMed  CAS  Google Scholar 

  29. Gruschwitz MS, Moormann S, Kromer G, Sgonc R, Dietrich H, Boeck G, Gershwin ME, Boyd R, Wick G (1991) Phenotypic analysis of skin infiltrates in comparison with peripheral blood lymphocytes, spleen cells and thymocytes in early avian scleroderma. J Autoimmun 4:577–593

    PubMed  CAS  Google Scholar 

  30. Gustafsson R, Fredens K, Nettelbladt O, Hallgren R (1991) Eosinophil activation in systemic sclerosis. Arthritis Rheum 34:414–422

    PubMed  CAS  Google Scholar 

  31. Hao H, Cohen DA, Jennings CD, Bryson JS, Kaplan AM (2000) Bleomycin-induced pulmonary fibrosis is independent of eosinophils. J Leukoc Biol 68:515–521

    PubMed  CAS  Google Scholar 

  32. Hasegawa M, Fujimoto M, Kikuchi K, Takehara K (1997) Elevated serum levels of interleukin 4 (IL-4), IL-10, and IL-13 in patients with systemic sclerosis. J Rheumatol 24:328–332

    PubMed  CAS  Google Scholar 

  33. Hasegawa M, Fujimoto M, Kikuchi K, Takehara K (1997) Elevated serum tumor necrosis factor-alpha levels in patients with systemic sclerosis: association with pulmonary fibrosis. J Rheumatol 24:663–665

    PubMed  CAS  Google Scholar 

  34. Hasegawa M, Sato S, Takehara K (1999) Augmentation of production of chemokines (monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α) and MIP-1β) in patients with systemic sclerosis: MCP-1 and MIP-1α may be involved in the development of pulmonary fibrosis. Clin Exp Immunol 117:159–165

    PubMed  CAS  Google Scholar 

  35. Hawkins RA, Claman HN, Clark RAF, Steigerwald JC (1985) Increased dermal mast cell populations in progressive systemic sclerosis: a link in chronic fibrosis? Ann Intern Med 102:1182–1186

    Google Scholar 

  36. Hebbar M, Gillot JM, Hachulla E, Lassalle P, Hatron PY, Devulder B, Janin A (1996) Early expression of E-selectin, tumor necrosis factorα, and mast cell infiltration in the salivary glands of patients with systemic sclerosis. Arthritis Rheum 39:1161–1165

    PubMed  CAS  Google Scholar 

  37. Huaux F, Liu T, McGarry B, Ullenbruch M, Xing Z, Phan SH (2003) Eosinophils and T lymphocytes possess distinct roles in bleomycin-induced lung injury and fibrosis. J Immunol 171:5470–5481

    PubMed  CAS  Google Scholar 

  38. Hunzelmann N, Anders S, Fierlbeck G, Hein R, Terrmann K, Albrecht M, Bell S, Muche R, Wehner-Caroli J, Gaus W, Krieg T (1997) Double-blind, placebo-controlled study of intralesional interferon gamma for the treatment of localized scleroderma. J Am Acad Dermatol 36:433–435

    PubMed  CAS  Google Scholar 

  39. Ihn H, Yamane K, Asano Y, Kubo M, Tamaki K (2002) IL-4 up-regulates the expression of tissue inhibitor of metalloproteinase-2 in dermal fibroblasts via the p38 mitogen-activated protein kinase-dependent pathway. J Immunol 168:1895–1902

    PubMed  CAS  Google Scholar 

  40. Ihn H, Yamane K, Tamaki K (2005) Increased phosphorylation and activation of mitogen-activated protein kinase p38 in scleroderma fibroblasts. J Invest Dermatol 125:247–255

    PubMed  CAS  Google Scholar 

  41. Ishii H, Takada K (2002) Bleomycin induces E-selectin expression in cultured umbilical vein endothelial cells by increasing its mRNA levels through activation of NF-κB/Rel. Toxicol Appl Pharmacol 184:88–97

    PubMed  CAS  Google Scholar 

  42. Ishikawa O, Ishikawa H (1992) Macrophage infiltration in the skin of patients with systemic sclerosis. J Rheumatol 19:1202–1206

    PubMed  CAS  Google Scholar 

  43. Jaffee BD, Claman HN (1983) Chronic graft-versus-host-disease (GVHD) as a model for scleroderma. I. Description of model system. Cell Immunol 73:1–12

    Google Scholar 

  44. Jelaska A, Korn JH (2000) Role of apoptosis and transforming growth factor β1 in fibroblast selection and activation in systemic sclerosis. Arthritis Rheum 43:2230–2239

    PubMed  CAS  Google Scholar 

  45. Jimenez SA, Freundlich B, Rosenbloom J (1984) Selective inhibition of human diploid fibroblast collagen by interferons. J Clin Invest 74:1112–1116

    PubMed  CAS  Google Scholar 

  46. Jinnin M, Ihn H, Yamane K, Tamaki K (2004) Interleukin-13 stimulates the transcription of the human alpha2(I) collagen gene in human dermal fibroblasts. J Biol Chem 279:41783–41791

    PubMed  CAS  Google Scholar 

  47. Kawaguchi Y, Hara M, Wright TM (1999) Endogenous IL-1α from systemic sclerosis fibroblasts induces IL-6 and PDGF-A. J Clin Invest 103:1253–1260

    PubMed  CAS  Google Scholar 

  48. Keski-Oja J, Raghow R, Sawdey M, Loskutoff DJ, Postlethwaite AE, Kang AH, Moses HL (1988) Regulation of mRNAs for type-1 plasminogen activator inhibitor, fibronectin, and type I procollagen by transforming growth factor-beta: divergent responses in lung fibroblasts and carcinoma cells. J Biol Chem 263:3111–3115

    PubMed  CAS  Google Scholar 

  49. Kikuchi K, Kubo M, Sato S, Fujimoto M, Tamaki K (1995) Serum tissue inhibitor of metalloproteinases in patients with systemic sclerosis. J Am Acad Dermatol 33:973–978

    PubMed  CAS  Google Scholar 

  50. Kikuchi K, Kadono T, Furue M, Tamaki K (1997) Tissue inhibitor of metalloproteinase 1 (TIMP-1) may be an autocrine growth factor in scleroderma fibroblasts. J Invest Dermatol 108:281–284

    PubMed  CAS  Google Scholar 

  51. King SL, Lichtler AC, Rowe DW, Xie R, Long GL, Absher MP, Cutroneo KR (1994) Bleomycin stimulates proα1(I) collagen promoter through transforming growth factor-β response element by intracellular and extracellular signaling. J Biol Chem 269:13156–13161

    PubMed  CAS  Google Scholar 

  52. Kirk TZ, Mark ME, Chua CC, Chua BH, Mayers MD (1995) Myofibroblasts from scleroderma skin synthesize elevated levels of collagen and tissue inhibitor of metalloproteinase (TIMP-1) with two forms of TIMP-1. J Biol Chem 270:3423–3428

    PubMed  CAS  Google Scholar 

  53. Kovacs EJ (1991) Fibrogenic cytokines: the role of immune mediators in the development of scar tissue. Immunol Today 12:17–23

    PubMed  CAS  Google Scholar 

  54. Kraling BM, Maul GG, Jemenez SA (1995) Mononuclear cellular infiltrates in clinically involved skin from patients with systemic sclerosis of recent onset predominantly consist of monocytes/macrophages. Pathobiology 63:48–56

    Article  PubMed  CAS  Google Scholar 

  55. Krieg T, Meurer M (1988) Systemic scleroderma. Clinical and pathophysiological aspects. J Am Acad Dermatol 18:457–481

    PubMed  CAS  Google Scholar 

  56. Kulozik M, Hogg A, Lankat-Buttgereit B, Krieg T (1990) Co-localization of transforming growth factor β2 with α1(I) procollagen mRNA in tissue sections of patients with systemic sclerosis. J Clin Invest 86:917–922

    PubMed  CAS  Google Scholar 

  57. Kuroda K, Shinkai H (1997) Gene expression of types I and III collagen, decorin, matrix metalloproteinases and tissue inhibitors of metalloproteinases in skin fibroblasts from patients with systemic sclerosis. Arch Dermatol Res 289:567–572

    PubMed  CAS  Google Scholar 

  58. Kuwano K, Hagimoto N, Kawasaki M, Yatomi T, Nakamura N, Nagata S, Suda T, Kunitake R, Maeyama T, Miyazaki H, Hara N (1999) Essential role of the Fas–Fas ligand pathway in the development of pulmonary fibrosis. J Clin Invest 104:13–19

    PubMed  CAS  Google Scholar 

  59. Lakos G, Takagawa S, Chen SJ, Ferreira AM, Han G, Masuda K, Wang XJ, DiPietro LA, Varga J (2004) Targeted disruption of TGF-beta/Smad3 signaling modulates skin fibrosis in a mouse model of scleroderma. Am J Pathol 165:203–217

    PubMed  CAS  Google Scholar 

  60. Laplante P, Raymond M-A, Gagnon G, Vigneault N, Sasseville AM-J, Langelier Y, Bernard M, Raymond Y, Hebert M-J (2005) Novel fibrogenic pathway are activated in response to endothelial apoptosis: Implications in the pathophysiology of systemic sclerosis. J Immunol 174:5740–5749

    PubMed  CAS  Google Scholar 

  61. Lee CG, Homer RJ, Zhu Z, Lanone S, Wang X, Koteliansky V, Shipley JM, Gotwals P, Noble P, Chen Q, Senior RM, Elias JA (2001) Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor β1. J Exp Med 194:809–821

    PubMed  CAS  Google Scholar 

  62. Leonard EJ, Yoshimura T (1990) Human monocyte chemoattractant protein-1 (MCP-1). Immunol Today 11:97–101

    PubMed  CAS  Google Scholar 

  63. LeRoy EC, Trojanowska M, Smith EA (1992) The pathogenesis of scleroderma (systemic sclerosis, SSc). Clin Exp Rheumatol 51:286–288

    CAS  Google Scholar 

  64. Levi-Schaffer F, Nagler A, Slavin S, Knopov V, Pines M (1996) Inhibition of collagen synthesis and changes in skin morphology in murine graft-versus-host disease and tight skin mice: effect of halofuginone. J Invest Dermatol 106:84–88

    PubMed  CAS  Google Scholar 

  65. Makhluf HA, Stepniakowska J, Hoffman S, Smith E, LeRoy EC, Trojanowska M (1996) IL-4 upregulates tenascin synthesis in scleroderma and healthy skin fibroblasts. J Invest Dermatol 107:856–859

    PubMed  CAS  Google Scholar 

  66. Matsumoto K, Nakamura T (2001) Hepatocyte growth factor: renotropic role and potential therapeutics for renal diseases. Kidney Int 59:2023–2038

    PubMed  CAS  Google Scholar 

  67. Matsushita M, Yamamoto T, Nishioka K (2004) Upregulation of interleukin-13 and its receptor in a murine model of bleomycin-induced scleroderma. Int Arch Allergy Immunol 135:348–356

    PubMed  CAS  Google Scholar 

  68. Mauch C, Eckes B, Hunzelmann N, Oono T, Kozlowska E, Krieg T (1993) Control of fibrosis in systemic scleroderma. J Invest Dermatol 100:92–96

    Google Scholar 

  69. Mavilia C, Scaletti C, Romagnani P, Carossino AM, Pignone A, Emmi L, Pupilli C, Pizzolo G, Maggi E, Romagnani S (1997) Type 2 helper T-cell predominance and high CD30 expression in systemic sclerosis. Am J Pathol 151:1751–1758

    Google Scholar 

  70. Mccormick LL, Zhang Y, Tootell E, Gilliam AC (1999) Anti-TGF-β treatment prevents skin and lung fibrosis in murine sclerodermatous graft-versus-host disease: a model for human scleroderma. J Immunol 163:5693–5699

    PubMed  CAS  Google Scholar 

  71. McGaha TL, Phelps RG, Spiera H, Bona C (2002) Halofuginone, an inhibitor of type-I collagen synthesis and skin sclerosis, blocks transforming-growth-factor-β-mediated Smad3 activation in fibroblasts. J Invest Dermatol 118:461–470

    PubMed  CAS  Google Scholar 

  72. Mori H, Kawada K, Zhang P, Uesugi Y, Sakamoto O, Koda A (1991) Bleomycin-induced pulmonary fibrosis in genetically mast cell-deficient WBB6F1-W/Wv mice and mechanism of the suppressive effect of tranilast, an antiallergic drug inhibiting mediator release from mast cells, on fibrosis. Int J Arch Allergy Appl Immunol 95:195–201

    CAS  Google Scholar 

  73. Mori Y, Chen SJ, Varga J (2003) Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts. Arthritis Rheum 48:1964–1978

    PubMed  CAS  Google Scholar 

  74. Mountz JD, Downs Minor MB, Turner R, Thomas MB, Richards F, Pisko E (1983) Bleomycin-induced cutaneous toxicity in the rat: analysis of histopathology and ultrastructure compared with progressive systemic sclerosis (scleroderma). Br J Dermatol 108:679–686

    PubMed  CAS  Google Scholar 

  75. Murota H, Hamasaki Y, Nakashima T, Yamamoto K, Katayama I, Matsuyama T (2003) Disruption of tumor necrosis factor receptor p55 impairs collagen turnover in experimentally induced sclerodermic skin fibroblasts. Arthritis Rheum 48:1117–1125

    PubMed  CAS  Google Scholar 

  76. Murrell GAC, Francis MJO, Bromley L (1990) Modulation of fibroblast proliferation by oxygen free radicals. Biochem J 265:659–665

    PubMed  CAS  Google Scholar 

  77. Nakao A, Fujii M, Matsumura R, Kumano K, Saito Y, Miyazono K, Iwamoto I (1999) Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice. J Clin Invest 104:5–11

    PubMed  CAS  Google Scholar 

  78. Needlemann BW, Wigley FM, Stair RW (1985) Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor α, and interferon-γ levels in sera from patients with scleroderma. Arthritis Rheum 28:775–780

    Google Scholar 

  79. Nishioka K, Kobayashi Y, Katayama I, Takijiri C (1987) Mast cell numbers in diffuse scleroderma. Arch Dermatol 123:205–208

    PubMed  CAS  Google Scholar 

  80. Obberghen-Schilling EV, Roche NS, Flanders KC, Sporn MB, Roberts AB (1988) Transforming growth factor β1 positively regulates its own expression in normal and transformed cells. J Biol Chem 263:7741–7746

    PubMed  Google Scholar 

  81. Oberley LW, Buettner GR (1979) The production of hydroxyl radicals by bleomycin and iron(II). FEBS Lett 97:47–49

    CAS  Google Scholar 

  82. Olsson N, Piek E, ten Dijke P, Nilsson G (2000) Human mast cell migration in response to members of the transforming growth factor-β family. J Leukoc Biol 67:350–356

    PubMed  CAS  Google Scholar 

  83. Oi M, Yamamoto T, Nishioka K (2004) Increased expression of TGF-β1 in the sclerotic skin in bleomycin-’susceptible’ mouse strains. J Med Dent Sci 51:7–17

    PubMed  Google Scholar 

  84. Onuma T, Holland JF, Masuda H, Waligunda JA, Goldberg GA (1974) Microbiological assay of bleomycin: inactivation, tissue distribution, and clearance. Cancer 22:1230–1238

    Google Scholar 

  85. Oriente A, Fedarko NS, Pacocha SE, Huang SK, Lichtenstein LM, Essayan DM (2000) Interleukin-13 modulates collagen homeostasis in human skin and keloid fibroblasts. J Pharmacol Exp Ther 292:988–994

    PubMed  CAS  Google Scholar 

  86. Peltonen J, Kahari L, Jaakkola S, Kahari V-M, Varga J, Uitto J, Jimenez SA (1990) Evaluation of transforming growth factor β and type I procollagen gene expression in fibrotic skin diseases by in situ hybridization. J Invest Dermatol 94:365–371

    PubMed  CAS  Google Scholar 

  87. Phan SH, Gharaee-Kermani M, Wolber F, Ryan US (1991) Stimulation of rat endothelial cell transforming growth factor-β production by bleomycin. J Clin Invest 87:148–154

    PubMed  CAS  Google Scholar 

  88. Phan SH, Kunkel SL (1992) Lung cytokine production in bleomycin-induced pulmonary fibrosis. Exp Lung Res 18:29–43

    PubMed  CAS  Google Scholar 

  89. Piguet PF, Collart MA, Gran GE, Kapanci Y, Vassalli P (1989) Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J Exp Med 170:655–663

    PubMed  CAS  Google Scholar 

  90. Pincus SH, Ramesh KS, Wyler DJ (1987) Eosinophils stimulate fibroblast DNA synthesis. Blood 70:572–574

    PubMed  CAS  Google Scholar 

  91. Pines M, Domb A, Ohara M, Inbar J, Genina O, Alexiev R, Nagler A (2001) Reduction in dermal fibrosis in the tight-skin (Tsk) mouse after local application of halofuginone. Biochem Pharmacol 62:1221–1227

    PubMed  CAS  Google Scholar 

  92. Postlethwaite AE, Holness MA, Katai H, Raghow R (1992) Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4. J Clin Invest 90:1479–1485

    PubMed  CAS  Google Scholar 

  93. Raghow R, Lurie S, Seyer JM, Kang AH (1985) Profiles steady state levels of messenger RNAs coding for type I procollagen, elastin, and fibronectin in hamster lungs undergoing bleomycin-induced interstitial pulmonary fibrosis. J Clin Invest 76:1733–1739

    PubMed  CAS  Google Scholar 

  94. Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH, Fauci AS (1986) Transforming growth factor type β: rapid induction of fibroblasts and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA 83:4167–4170

    PubMed  CAS  Google Scholar 

  95. Roberts AB, Sporn MB (1990) The transforming growth factor βs. In: Sporn MB, Roberts AB (eds) Handbook of experimental pharmacology. Peptide growth factors and their receptors, vol 95. Springer, Berlin Heidelberg New York, pp 419–472

  96. Rosenbloom J, Feldman G, Freundlich B, Jimenez SA (1986) Inhibition of excessive scleroderma fibroblast collagen production by recombinant gamma-interferon. Association with a coordinate decrease in types I and III procollagen messenger RNA levels. Arthritis Rheum 29:851–856

    PubMed  CAS  Google Scholar 

  97. Sambo P, Jannino L, Candela M, Salvi A, Donini M, Dusi S, Luchetti MM, Gabrielli A (1999) Monocytes of patients with systemic sclerosis (scleroderma) spontaneously release in vitro increased amounts of superoxide anion. J Invest Dermatol 112:78–84

    PubMed  CAS  Google Scholar 

  98. Sambo P, Baroni SS, Luchetti M, Paroncini P, Dusi S, Orlandini G, Gabrielli A (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 44:2653–2664

    PubMed  CAS  Google Scholar 

  99. Santiago B, Galindo M, Rivero M, Pablos JL (2001) Decreased susceptibility to Fas-induced apoptosis of systemic sclerosis dermal fibroblasts. Arthritis Rheum 44:1667–1676

    PubMed  CAS  Google Scholar 

  100. Santiago B, Gutierrez-Canas I, Dotor J, Palao G, Lasarte JJ, Ruiz J, Borras-Cuesta F, Pablos JL (2005) Topical application of a peptide inhibitor of transforming growth factor-beta1 ameliorates bleomycin-induced skin fibrosis. J Invest Dermatol 125:450–455

    PubMed  CAS  Google Scholar 

  101. Sappino A-P, Masouye I, Saurat J-H, Gabbiani G (1990) Smooth muscle differentiation in scleroderma fibroblastic cells. Am J Pathol 137:585–591

    PubMed  CAS  Google Scholar 

  102. Scharffetter K, Lankat-Buttgereit B, Krieg T (1988) Localization of collagen mRNA in normal and scleroderma skin by in-situ hybridization. Eur J Clin Invest 18:9–17

    PubMed  CAS  Google Scholar 

  103. Seder RA, Marth T, Sieve MC, Strober W, Letterio JJ, Roberts AB, Lelsall B (1998) Factors involved in the differentiation of TGF-beta-producing cells from naive CD4+ T cells: IL-4 and IFN-gamma have opposite effects, while TGF-beta positively regulates its own production. J Immunol 160:5719–5728

    PubMed  CAS  Google Scholar 

  104. Selvan RS, Butterfield JH, Krangel MS (1994) Expression of multiple chemokine genes by human mast cells. J Biol Chem 269:13893–13898

    PubMed  CAS  Google Scholar 

  105. Serpier H, Gillery P, Salmon-Ehr V, Garnotel R, Georges N, Kalis B, Maquart FX (1997) Antagonistic effect of interferon-gamma and interleukin-4 on fibroblast cultures. J Invest Dermatol 109:158–162

    PubMed  CAS  Google Scholar 

  106. Sgonc R, Gruschwitz MS, Dietrich H, Recheis H, Gershwin ME, Wick G (1996) Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J Clin Invest 98:785–792

    PubMed  CAS  Google Scholar 

  107. Sgonc R, Dietrich H, Sieberer C, Wick G, Christner PJ, Jimenez SA (1999) Lack of endothelial cell apoptosis in the dermis of tight skin 1 and tight skin 2 mice. Arthritis Rheum 42:581–584

    PubMed  CAS  Google Scholar 

  108. Sterling KM Jr, DiPetrillo TA, Kotch JP, Cutroneo KR (1982) Bleomycin-induced increase of collagen turnover in IMR-90 fibroblasts: an in vitro model of connective tissue restructing during lung fibrosis. Cancer Res 42:3502–3506

    PubMed  CAS  Google Scholar 

  109. Takagawa S, Lakos G, Mori Y, Yamamoto T, Nishioka K, Varga J (2003) Sustained activation of fibroblast transforming growth factor-β/Smad signaling in a murine model of scleroderma. J Invest Dermatol 121:41–50

    PubMed  CAS  Google Scholar 

  110. Takeda A, Nonaka M, Ishikawa A, Higuchi D (1999) Immunohistochemical localization of the neutral cysteine protease bleomycin hydrolase in human skin. Arch Dermatol Res 291:238–240

    PubMed  CAS  Google Scholar 

  111. Terada N, Hamano N, Nomura T, Numata T, Hirai K, Nakajima T, Yamada H, Yoshie O, Ikeda-Ito T, Konno A (2000) Interleukin 13 and tumor necrosis factor-alpha synergistically induce eotaxin production in human nasal fibroblasts. Clin Exp Allergy 30:348–355

    PubMed  CAS  Google Scholar 

  112. Toubi E, Kessel A, Grushko G, Sabo E, Rozenbaum M, Rosner I (2002) The association of serum matrix metalloproteinases and their tissue inhibitor levels with scleroderma disease severity. Clin Exp Rheumatol 20:221–224

    PubMed  CAS  Google Scholar 

  113. Trautmann A, Toksoy A, Engelhardt E, Bröcker EB, Gillitzer R (2000) Mast cell involvement in normal human skin wound healing: expression of monocyte chemoattractant protein-1 is correlated with recruitment of mast cells which synthesize interleukin-1 in vivo. J Pathol 190:100–106

    PubMed  CAS  Google Scholar 

  114. Ulloa L, Doody J, Massagué J (1999) Inhibition of transforming growth factor-β/SMAD signaling by the interferon-γ/STAT pathway. Nature 397:710–713

    PubMed  CAS  Google Scholar 

  115. Umezawa H, Maeda K, Takeuchi T, Okami Y (1966) New antibiotics, bleomycin A and B. J Antibiot 19:200–209

    PubMed  CAS  Google Scholar 

  116. Walker M, Harley R, LeRoy EC (1987) Inhibition of fibrosis in Tsk mice by blocking mast cell degranulation. J Rheumatol 14:299–301

    PubMed  CAS  Google Scholar 

  117. Wallace VA, Kondo S, Kono T, Xing Z, Timms E, Furlonger C, Keystone E, Gauldie J, Sauder DN, Mak TW, Paige CJ (1994) A role for CD4+ T cells in the pathogenesis of skin fibrosis in tight skin mice. Eur J Immunol 24:1463–1466

    PubMed  CAS  Google Scholar 

  118. Wang Q, Wang Y, Hyde DM, Gotwals PJ, Koteliansky VE, Ryan ST, Giri SN (1999) Reduction of bleomycin induced lung fibrosis by transforming growth factor β soluble receptor in hamsters. Thorax 54:805–812

    Article  PubMed  CAS  Google Scholar 

  119. Westergren-Thorsson G, Hernnas J, Sarnstrand B, Oldberg A, Heinegard D, Malmstrom A (1993) Altered expression of small proteoglycans, collagen, and transforming growth factor-β1 in developing bleomycin-induced pulmonary fibrosis in rats. J Clin Invest 92:632–637

    PubMed  CAS  Google Scholar 

  120. Wu M-H, Yokozeki H, Takagawa S, Yamamoto T, Satoh T, Kaneda Y, Nishioka K (2004) Hepatocyte growth factor both prevents and ameliorates the symptoms of dermal sclerosis in a mouse model of scleroderma. Gene Ther 11:170–180

    PubMed  CAS  Google Scholar 

  121. Yamamoto T, Katayama I, Nishioka K (1998) Expression of stem cell factor in the lesional skin of systemic sclerosis. Dermatology 197:109–114

    PubMed  CAS  Google Scholar 

  122. Yamamoto T, Takagawa S, Katayama I, Yamazaki K, Hamazaki Y, Shinkai H, Nishioka K (1999) Animal model of sclerotic skin. I: Local injections of bleomycin induce sclerotic skin mimicking scleroderma. J Invest Dermatol 112:456–462

    PubMed  CAS  Google Scholar 

  123. Yamamoto T, Takahashi Y, Takagawa S, Katayama I, Nishioka K (1999) Animal model of sclerotic skin. II: Bleomycin induced scleroderma in genetically mast cell deficient WBB6F1-W/Wv mice. J Rheumatol 26:2628–2634

    PubMed  CAS  Google Scholar 

  124. Yamamoto T, Katayama I, Nishioka K (1999) Fibroblast proliferation by bleomycin stimulated peripheral blood mononuclear cell factors. J Rheumatol 26:609–615

    PubMed  CAS  Google Scholar 

  125. Yamamoto T, Takagawa S, Katayama I, Nishioka K (1999) Anti-sclerotic effect of anti-transforming growth factor-β antibody in bleomycin-induced scleroderma. Clin Immunol 92:6–13

    PubMed  CAS  Google Scholar 

  126. Yamamoto T, Takagawa S, Mizushima Y, Nishioka K (1999) Effect of superoxide dismutase on bleomycin-induced dermal sclerosis: implications for the treatment of systemic sclerosis. J Invest Dermatol 113:843–847

    PubMed  CAS  Google Scholar 

  127. Yamamoto T, Kuroda M, Takagawa S, Nishioka K (2000) Animal model of sclerotic skin. III: Histopathological comparison of bleomycin-induced scleroderma in various mice strains. Arch Dermatol Res 292:535–541

    PubMed  CAS  Google Scholar 

  128. Yamamoto T, Eckes B, Krieg T (2000) Bleomycin increases steady-state levels of type I collagen, fibronectin and decorin gene expression in human skin fibroblasts. Arch Dermatol Res 292:556–561

    PubMed  CAS  Google Scholar 

  129. Yamamoto T, Eckes B, Mauch C, Hartmann K, Krieg T (2000) Monocyte chemoattractant protein-1 enhances gene expression and synthesis of matrix metalloproteinase-1 in human fibroblasts by an autocrine IL-1α loop. J Immunol 164:6174–6179

    PubMed  CAS  Google Scholar 

  130. Yamamoto T, Takagawa S, Kuroda M, Nishioka K (2000) Effect of interferon-γ on experimental scleroderma induced by bleomycin. Arch Dermatol Res 292:362–365

    PubMed  CAS  Google Scholar 

  131. Yamamoto T, Nishioka K (2001) Animal model of sclerotic skin. IV: Induction of dermal sclerosis by bleomycin is T cell independent. J Invest Dermatol 117:999–1001

    PubMed  CAS  Google Scholar 

  132. Yamamoto T, Eckes B, Krieg T (2001) High expression and autoinduction of monocyte chemoattractant protein-1 in scleroderma fibroblasts. Eur J Immunol 31:2936–2941

    PubMed  CAS  Google Scholar 

  133. Yamamoto T, Eckes B, Hartmann K, Krieg T (2001) Expression of monocyte chemoattractant protein-1 in the lesional skin of systemic sclerosis. J Dermatol Sci 26:133–139

    PubMed  CAS  Google Scholar 

  134. Yamamoto T, Hartmann K, Eckes B, Krieg T (2001) Role of stem cell factor and monocyte chemoattractant protein-1 in the interaction between fibroblasts and mast cells in fibrosis. J Dermatol Sci 26:106–111

    PubMed  CAS  Google Scholar 

  135. Yamamoto T, Nishioka K (2002) Animal model of sclerotic skin. V: Increased expression of α-smooth muscle actin in fibroblastic cells in bleomycin-induced scleroderma. Clin Immunol 102:77–83

    PubMed  Google Scholar 

  136. Yamamoto T, Nishioka K (2002) Analysis of the effect of halofuginone on bleomycin-induced scleroderma. Rheumatology 41:594–596

    PubMed  CAS  Google Scholar 

  137. Yamamoto T, Nishioka K (2003) Role of monocyte chemoattractant protein-1 and its receptor, CCR-2, in the pathogenesis of bleomycin-induced scleroderma. J Invest Dermatol 121:510–516

    PubMed  CAS  Google Scholar 

  138. Yamamoto T, Nishioka K (2004) Animal model of sclerotic skin. VI: Evaluation of bleomycin-induced skin sclerosis in nude mice. Arch Dermatol Res 295:453–456

    PubMed  Google Scholar 

  139. Yamamoto T (2004) Experimental mouse model of scleroderma: induction by bleomycin. In: Lawrence SC (ed) Animal models of human inflammatory skin diseases. CRC Press, Boca Raton, FL, pp 535–547

    Google Scholar 

  140. Yamamoto T, Nishioka K (2004) Possible role of apoptosis in the pathogenesis of bleomycin-induced scleroderma. J Invest Dermatol 122:44–50

    PubMed  CAS  Google Scholar 

  141. Yokozeki M, Baba Y, Shimokawa H, Moriyama K, Kuroda T (1999) Interferon-γ inhibits the myofibroblastic phenotype of rat palatal fibroblasts induced by transforming growth factor-β1 in vitro. FEBS Lett 442:61–64

    PubMed  CAS  Google Scholar 

  142. Zhang K, Flanders KS, Phan SH (1995) Cellular localization of transforming growth factor-β expression in bleomycin-induced pulmonary fibrosis. Am J Pathol 147:352–361

    PubMed  CAS  Google Scholar 

  143. Zhang K, Gharaee-Kermani M, McGarry B, Remick D, Phan SH (1997) TNF-alpha-mediated lung cytokine networking and eosinophil recruitment in pulmonary fibrosis. J Immunol 158:954–959

    PubMed  CAS  Google Scholar 

  144. Zhang Y, Mccormick LL, Desai SR, Wu S, Gilliam AC (2002) Murine sclerodermatous graft-versus-host disease, a model for human scleroderma: cutaneous cytokines, chemokines, and immune cell activation. J Immunol 168:3088–3098

    PubMed  CAS  Google Scholar 

  145. Zhang Y, McCormick LL, Gilliam AC (2003) Latency-associated peptide prevents skin fibrosis in murine sclerodermatous graft-versus-host disease, a model for human scleroderma. J Invest Dermatol 121:713–719

    PubMed  CAS  Google Scholar 

  146. Zhu Z, Ma B, Zheng T, Homer RJ, Lee CG, Charo IF, Noble P, Elias JA (2002) IL-13-induced chemokine responses in the lung: role of CCR2 in the pathogenesis of IL-13-induced inflammation and remodeling. J Immunol 168:2953–2962

    PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (#16591090).

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  1. Department of Dermatology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, 160-0023, Tokyo, Japan

    Toshiyuki Yamamoto

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Yamamoto, T. The bleomycin-induced scleroderma model: what have we learned for scleroderma pathogenesis?. Arch Dermatol Res 297, 333–344 (2006). https://doi.org/10.1007/s00403-005-0635-z

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  • DOI: https://doi.org/10.1007/s00403-005-0635-z

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