Skip to main content
Top
Published in: Archives of Dermatological Research 8/2006

01-02-2006 | Review

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

Author: Toshiyuki Yamamoto

Published in: Archives of Dermatological Research | Issue 8/2006

Login to get access

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.
Literature
1.
go back to reference 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 36:251–259PubMed 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 36:251–259PubMed
2.
go back to reference 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 113:253–264PubMed 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 113:253–264PubMed
3.
go back to reference 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 172:7123–7135PubMed 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 172:7123–7135PubMed
4.
go back to reference 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 55:147–152PubMed 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 55:147–152PubMed
5.
go back to reference 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 27:419–427PubMed 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 27:419–427PubMed
6.
go back to reference Birkland TP, Cheavens MD, Pincus SH (1994) Human eosinophils stimulate DNA synthesis and matrix production in dermal fibroblasts. Arch Dermatol Res 286:312–318PubMed Birkland TP, Cheavens MD, Pincus SH (1994) Human eosinophils stimulate DNA synthesis and matrix production in dermal fibroblasts. Arch Dermatol Res 286:312–318PubMed
7.
go back to reference 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 6:146–152PubMed 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 6:146–152PubMed
8.
go back to reference Casciola-Rosen L, Wigley F, Rosen A (1997) Scleroderma autoantigens are uniquely fragmented by metal-catalyzed oxidation reactions: implications for pathogenesis. J Exp Med 185:71–79PubMed Casciola-Rosen L, Wigley F, Rosen A (1997) Scleroderma autoantigens are uniquely fragmented by metal-catalyzed oxidation reactions: implications for pathogenesis. J Exp Med 185:71–79PubMed
9.
go back to reference Cepeda EJ, Reveille JD (2004) Autoantibodies in systemic sclerosis and fibrosing syndromes: clinical indications and relevance. Curr Opin Rheumatol 16:723–732PubMed Cepeda EJ, Reveille JD (2004) Autoantibodies in systemic sclerosis and fibrosing syndromes: clinical indications and relevance. Curr Opin Rheumatol 16:723–732PubMed
10.
go back to reference Choi ET, Callow AD, Sehgal NL, Brown DM, Ryan US (1995) Halofuginone, a specific collagen type I inhibitor, reduces anastomotic intima hyperplasia. Arch Surg 130:257–261PubMed Choi ET, Callow AD, Sehgal NL, Brown DM, Ryan US (1995) Halofuginone, a specific collagen type I inhibitor, reduces anastomotic intima hyperplasia. Arch Surg 130:257–261PubMed
11.
go back to reference Claman HN, Giorno RC, Seibold JR (1991) Endothelial and fibroblast activation in scleroderma: the myth of the “uninvolved skin”. Arthritis Rheum 34:1495–1501PubMed Claman HN, Giorno RC, Seibold JR (1991) Endothelial and fibroblast activation in scleroderma: the myth of the “uninvolved skin”. Arthritis Rheum 34:1495–1501PubMed
12.
go back to reference Clark JC, Starcher BC, Uitto J (1980) Bleomycin-induced synthesis of type I procollagen by human lung skin fibroblasts in culture. Biochim Biophys Acta 631:359–370PubMed Clark JC, Starcher BC, Uitto J (1980) Bleomycin-induced synthesis of type I procollagen by human lung skin fibroblasts in culture. Biochim Biophys Acta 631:359–370PubMed
13.
go back to reference Denholm EM, Phan SH (1989) The effects of bleomycin on alveolar macrophage growth factor secretion. Am J Pathol 134:355–363PubMed Denholm EM, Phan SH (1989) The effects of bleomycin on alveolar macrophage growth factor secretion. Am J Pathol 134:355–363PubMed
14.
go back to reference 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 44:2665–2678PubMed 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 44:2665–2678PubMed
15.
go back to reference 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 99:3908–3913PubMed 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 99:3908–3913PubMed
16.
go back to reference 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 101:2129–2139PubMed 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 101:2129–2139PubMed
17.
go back to reference 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 10:1421–1433PubMed 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 10:1421–1433PubMed
18.
go back to reference 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 79:1318–1324PubMed 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 79:1318–1324PubMed
19.
go back to reference 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 97:232–237PubMed 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 97:232–237PubMed
20.
go back to reference 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 160:6121–6127PubMed 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 160:6121–6127PubMed
21.
go back to reference 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 157:408–412PubMed 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 157:408–412PubMed
22.
go back to reference Fleischmajer R, Perlish JS, Reeves JRT (1977) Cellular infiltrates in scleroderma skin. Arthritis Rheum 20:975–984PubMed Fleischmajer R, Perlish JS, Reeves JRT (1977) Cellular infiltrates in scleroderma skin. Arthritis Rheum 20:975–984PubMed
23.
go back to reference 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 44:1382–1386PubMed 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 44:1382–1386PubMed
24.
go back to reference 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 123:36–41PubMed 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 123:36–41PubMed
25.
go back to reference 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 271:17779–17784PubMed 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 271:17779–17784PubMed
26.
go back to reference Granot I, Halevy O, Hurwitz S, Pines M (1993) Halofuginone: an inhibitor of collagen type I synthesis. Biochim Biophys Acta 1156:107–112PubMed Granot I, Halevy O, Hurwitz S, Pines M (1993) Halofuginone: an inhibitor of collagen type I synthesis. Biochim Biophys Acta 1156:107–112PubMed
27.
go back to reference Gruber BL, Marchese MJ, Kew RR (1994) Transforming growth factor β1 mediates mast cell chemotaxis. J Immunol 152:5860–5867PubMed Gruber BL, Marchese MJ, Kew RR (1994) Transforming growth factor β1 mediates mast cell chemotaxis. J Immunol 152:5860–5867PubMed
28.
go back to reference 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 94:197–203PubMed 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 94:197–203PubMed
29.
go back to reference 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 4:577–593PubMed 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 4:577–593PubMed
30.
go back to reference Gustafsson R, Fredens K, Nettelbladt O, Hallgren R (1991) Eosinophil activation in systemic sclerosis. Arthritis Rheum 34:414–422PubMed Gustafsson R, Fredens K, Nettelbladt O, Hallgren R (1991) Eosinophil activation in systemic sclerosis. Arthritis Rheum 34:414–422PubMed
31.
go back to reference Hao H, Cohen DA, Jennings CD, Bryson JS, Kaplan AM (2000) Bleomycin-induced pulmonary fibrosis is independent of eosinophils. J Leukoc Biol 68:515–521PubMed Hao H, Cohen DA, Jennings CD, Bryson JS, Kaplan AM (2000) Bleomycin-induced pulmonary fibrosis is independent of eosinophils. J Leukoc Biol 68:515–521PubMed
32.
go back to reference 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 24:328–332PubMed 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 24:328–332PubMed
33.
go back to reference 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 24:663–665PubMed 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 24:663–665PubMed
34.
go back to reference 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 117:159–165PubMed 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 117:159–165PubMed
35.
go back to reference 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 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
36.
go back to reference 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 39:1161–1165PubMed 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 39:1161–1165PubMed
37.
go back to reference 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 171:5470–5481PubMed 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 171:5470–5481PubMed
38.
go back to reference 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 36:433–435PubMed 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 36:433–435PubMed
39.
go back to reference 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 168:1895–1902PubMed 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 168:1895–1902PubMed
40.
go back to reference Ihn H, Yamane K, Tamaki K (2005) Increased phosphorylation and activation of mitogen-activated protein kinase p38 in scleroderma fibroblasts. J Invest Dermatol 125:247–255PubMed Ihn H, Yamane K, Tamaki K (2005) Increased phosphorylation and activation of mitogen-activated protein kinase p38 in scleroderma fibroblasts. J Invest Dermatol 125:247–255PubMed
41.
go back to reference 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 184:88–97PubMed 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 184:88–97PubMed
42.
go back to reference Ishikawa O, Ishikawa H (1992) Macrophage infiltration in the skin of patients with systemic sclerosis. J Rheumatol 19:1202–1206PubMed Ishikawa O, Ishikawa H (1992) Macrophage infiltration in the skin of patients with systemic sclerosis. J Rheumatol 19:1202–1206PubMed
43.
go back to reference 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 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
44.
go back to reference Jelaska A, Korn JH (2000) Role of apoptosis and transforming growth factor β1 in fibroblast selection and activation in systemic sclerosis. Arthritis Rheum 43:2230–2239PubMed Jelaska A, Korn JH (2000) Role of apoptosis and transforming growth factor β1 in fibroblast selection and activation in systemic sclerosis. Arthritis Rheum 43:2230–2239PubMed
45.
go back to reference Jimenez SA, Freundlich B, Rosenbloom J (1984) Selective inhibition of human diploid fibroblast collagen by interferons. J Clin Invest 74:1112–1116PubMed Jimenez SA, Freundlich B, Rosenbloom J (1984) Selective inhibition of human diploid fibroblast collagen by interferons. J Clin Invest 74:1112–1116PubMed
46.
go back to reference 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 279:41783–41791PubMed 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 279:41783–41791PubMed
47.
go back to reference Kawaguchi Y, Hara M, Wright TM (1999) Endogenous IL-1α from systemic sclerosis fibroblasts induces IL-6 and PDGF-A. J Clin Invest 103:1253–1260PubMed Kawaguchi Y, Hara M, Wright TM (1999) Endogenous IL-1α from systemic sclerosis fibroblasts induces IL-6 and PDGF-A. J Clin Invest 103:1253–1260PubMed
48.
go back to reference 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 263:3111–3115PubMed 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 263:3111–3115PubMed
49.
go back to reference 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 33:973–978PubMed 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 33:973–978PubMed
50.
go back to reference 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 108:281–284PubMed 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 108:281–284PubMed
51.
go back to reference 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 269:13156–13161PubMed 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 269:13156–13161PubMed
52.
go back to reference 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 270:3423–3428PubMed 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 270:3423–3428PubMed
53.
go back to reference Kovacs EJ (1991) Fibrogenic cytokines: the role of immune mediators in the development of scar tissue. Immunol Today 12:17–23PubMed Kovacs EJ (1991) Fibrogenic cytokines: the role of immune mediators in the development of scar tissue. Immunol Today 12:17–23PubMed
54.
go back to reference 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 63:48–56PubMedCrossRef 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 63:48–56PubMedCrossRef
55.
go back to reference Krieg T, Meurer M (1988) Systemic scleroderma. Clinical and pathophysiological aspects. J Am Acad Dermatol 18:457–481PubMed Krieg T, Meurer M (1988) Systemic scleroderma. Clinical and pathophysiological aspects. J Am Acad Dermatol 18:457–481PubMed
56.
go back to reference 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 86:917–922PubMed 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 86:917–922PubMed
57.
go back to reference 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 289:567–572PubMed 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 289:567–572PubMed
58.
go back to reference 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 104:13–19PubMed 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 104:13–19PubMed
59.
go back to reference 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 165:203–217PubMed 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 165:203–217PubMed
60.
go back to reference 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 174:5740–5749PubMed 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 174:5740–5749PubMed
61.
go back to reference 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 194:809–821PubMed 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 194:809–821PubMed
62.
go back to reference Leonard EJ, Yoshimura T (1990) Human monocyte chemoattractant protein-1 (MCP-1). Immunol Today 11:97–101PubMed Leonard EJ, Yoshimura T (1990) Human monocyte chemoattractant protein-1 (MCP-1). Immunol Today 11:97–101PubMed
63.
go back to reference LeRoy EC, Trojanowska M, Smith EA (1992) The pathogenesis of scleroderma (systemic sclerosis, SSc). Clin Exp Rheumatol 51:286–288 LeRoy EC, Trojanowska M, Smith EA (1992) The pathogenesis of scleroderma (systemic sclerosis, SSc). Clin Exp Rheumatol 51:286–288
64.
go back to reference 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 106:84–88PubMed 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 106:84–88PubMed
65.
go back to reference 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 107:856–859PubMed 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 107:856–859PubMed
66.
go back to reference Matsumoto K, Nakamura T (2001) Hepatocyte growth factor: renotropic role and potential therapeutics for renal diseases. Kidney Int 59:2023–2038PubMed Matsumoto K, Nakamura T (2001) Hepatocyte growth factor: renotropic role and potential therapeutics for renal diseases. Kidney Int 59:2023–2038PubMed
67.
go back to reference 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 135:348–356PubMed 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 135:348–356PubMed
68.
go back to reference 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 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
69.
go back to reference 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 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
70.
go back to reference 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 163:5693–5699PubMed 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 163:5693–5699PubMed
71.
go back to reference 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 118:461–470PubMed 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 118:461–470PubMed
72.
go back to reference 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 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
73.
go back to reference Mori Y, Chen SJ, Varga J (2003) Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts. Arthritis Rheum 48:1964–1978PubMed Mori Y, Chen SJ, Varga J (2003) Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts. Arthritis Rheum 48:1964–1978PubMed
74.
go back to reference 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 108:679–686PubMed 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 108:679–686PubMed
75.
go back to reference 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 48:1117–1125PubMed 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 48:1117–1125PubMed
76.
go back to reference Murrell GAC, Francis MJO, Bromley L (1990) Modulation of fibroblast proliferation by oxygen free radicals. Biochem J 265:659–665PubMed Murrell GAC, Francis MJO, Bromley L (1990) Modulation of fibroblast proliferation by oxygen free radicals. Biochem J 265:659–665PubMed
77.
go back to reference 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 104:5–11PubMed 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 104:5–11PubMed
78.
go back to reference 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 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
79.
go back to reference Nishioka K, Kobayashi Y, Katayama I, Takijiri C (1987) Mast cell numbers in diffuse scleroderma. Arch Dermatol 123:205–208PubMed Nishioka K, Kobayashi Y, Katayama I, Takijiri C (1987) Mast cell numbers in diffuse scleroderma. Arch Dermatol 123:205–208PubMed
80.
go back to reference 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 263:7741–7746PubMed 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 263:7741–7746PubMed
81.
go back to reference Oberley LW, Buettner GR (1979) The production of hydroxyl radicals by bleomycin and iron(II). FEBS Lett 97:47–49 Oberley LW, Buettner GR (1979) The production of hydroxyl radicals by bleomycin and iron(II). FEBS Lett 97:47–49
82.
go back to reference 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 67:350–356PubMed 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 67:350–356PubMed
83.
go back to reference 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 51:7–17PubMed 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 51:7–17PubMed
84.
go back to reference Onuma T, Holland JF, Masuda H, Waligunda JA, Goldberg GA (1974) Microbiological assay of bleomycin: inactivation, tissue distribution, and clearance. Cancer 22:1230–1238 Onuma T, Holland JF, Masuda H, Waligunda JA, Goldberg GA (1974) Microbiological assay of bleomycin: inactivation, tissue distribution, and clearance. Cancer 22:1230–1238
85.
go back to reference 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 292:988–994PubMed 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 292:988–994PubMed
86.
go back to reference 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 94:365–371PubMed 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 94:365–371PubMed
87.
go back to reference 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 87:148–154PubMed 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 87:148–154PubMed
88.
go back to reference Phan SH, Kunkel SL (1992) Lung cytokine production in bleomycin-induced pulmonary fibrosis. Exp Lung Res 18:29–43PubMed Phan SH, Kunkel SL (1992) Lung cytokine production in bleomycin-induced pulmonary fibrosis. Exp Lung Res 18:29–43PubMed
89.
go back to reference 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 170:655–663PubMed 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 170:655–663PubMed
90.
go back to reference Pincus SH, Ramesh KS, Wyler DJ (1987) Eosinophils stimulate fibroblast DNA synthesis. Blood 70:572–574PubMed Pincus SH, Ramesh KS, Wyler DJ (1987) Eosinophils stimulate fibroblast DNA synthesis. Blood 70:572–574PubMed
91.
go back to reference 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 62:1221–1227PubMed 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 62:1221–1227PubMed
92.
go back to reference 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 90:1479–1485PubMed 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 90:1479–1485PubMed
93.
go back to reference 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 76:1733–1739PubMed 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 76:1733–1739PubMed
94.
go back to reference 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 83:4167–4170PubMed 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 83:4167–4170PubMed
95.
go back to reference 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 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.
go back to reference 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 29:851–856PubMed 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 29:851–856PubMed
97.
go back to reference 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 112:78–84PubMed 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 112:78–84PubMed
98.
go back to reference 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 44:2653–2664PubMed 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 44:2653–2664PubMed
99.
go back to reference Santiago B, Galindo M, Rivero M, Pablos JL (2001) Decreased susceptibility to Fas-induced apoptosis of systemic sclerosis dermal fibroblasts. Arthritis Rheum 44:1667–1676PubMed Santiago B, Galindo M, Rivero M, Pablos JL (2001) Decreased susceptibility to Fas-induced apoptosis of systemic sclerosis dermal fibroblasts. Arthritis Rheum 44:1667–1676PubMed
100.
go back to reference 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 125:450–455PubMed 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 125:450–455PubMed
101.
go back to reference Sappino A-P, Masouye I, Saurat J-H, Gabbiani G (1990) Smooth muscle differentiation in scleroderma fibroblastic cells. Am J Pathol 137:585–591PubMed Sappino A-P, Masouye I, Saurat J-H, Gabbiani G (1990) Smooth muscle differentiation in scleroderma fibroblastic cells. Am J Pathol 137:585–591PubMed
102.
go back to reference 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 18:9–17PubMed 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 18:9–17PubMed
103.
go back to reference 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 160:5719–5728PubMed 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 160:5719–5728PubMed
104.
go back to reference Selvan RS, Butterfield JH, Krangel MS (1994) Expression of multiple chemokine genes by human mast cells. J Biol Chem 269:13893–13898PubMed Selvan RS, Butterfield JH, Krangel MS (1994) Expression of multiple chemokine genes by human mast cells. J Biol Chem 269:13893–13898PubMed
105.
go back to reference 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 109:158–162PubMed 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 109:158–162PubMed
106.
go back to reference 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 98:785–792PubMed 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 98:785–792PubMed
107.
go back to reference 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 42:581–584PubMed 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 42:581–584PubMed
108.
go back to reference 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 42:3502–3506PubMed 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 42:3502–3506PubMed
109.
go back to reference 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 121:41–50PubMed 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 121:41–50PubMed
110.
go back to reference Takeda A, Nonaka M, Ishikawa A, Higuchi D (1999) Immunohistochemical localization of the neutral cysteine protease bleomycin hydrolase in human skin. Arch Dermatol Res 291:238–240PubMed Takeda A, Nonaka M, Ishikawa A, Higuchi D (1999) Immunohistochemical localization of the neutral cysteine protease bleomycin hydrolase in human skin. Arch Dermatol Res 291:238–240PubMed
111.
go back to reference 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 30:348–355PubMed 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 30:348–355PubMed
112.
go back to reference 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 20:221–224PubMed 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 20:221–224PubMed
113.
go back to reference 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 190:100–106PubMed 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 190:100–106PubMed
114.
go back to reference Ulloa L, Doody J, Massagué J (1999) Inhibition of transforming growth factor-β/SMAD signaling by the interferon-γ/STAT pathway. Nature 397:710–713PubMed Ulloa L, Doody J, Massagué J (1999) Inhibition of transforming growth factor-β/SMAD signaling by the interferon-γ/STAT pathway. Nature 397:710–713PubMed
115.
go back to reference Umezawa H, Maeda K, Takeuchi T, Okami Y (1966) New antibiotics, bleomycin A and B. J Antibiot 19:200–209PubMed Umezawa H, Maeda K, Takeuchi T, Okami Y (1966) New antibiotics, bleomycin A and B. J Antibiot 19:200–209PubMed
116.
go back to reference Walker M, Harley R, LeRoy EC (1987) Inhibition of fibrosis in Tsk mice by blocking mast cell degranulation. J Rheumatol 14:299–301PubMed Walker M, Harley R, LeRoy EC (1987) Inhibition of fibrosis in Tsk mice by blocking mast cell degranulation. J Rheumatol 14:299–301PubMed
117.
go back to reference 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 24:1463–1466PubMed 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 24:1463–1466PubMed
118.
go back to reference 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 54:805–812PubMedCrossRef 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 54:805–812PubMedCrossRef
119.
go back to reference 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 92:632–637PubMed 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 92:632–637PubMed
120.
go back to reference 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 11:170–180PubMed 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 11:170–180PubMed
121.
go back to reference Yamamoto T, Katayama I, Nishioka K (1998) Expression of stem cell factor in the lesional skin of systemic sclerosis. Dermatology 197:109–114PubMed Yamamoto T, Katayama I, Nishioka K (1998) Expression of stem cell factor in the lesional skin of systemic sclerosis. Dermatology 197:109–114PubMed
122.
go back to reference 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 112:456–462PubMed 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 112:456–462PubMed
123.
go back to reference 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 26:2628–2634PubMed 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 26:2628–2634PubMed
124.
go back to reference Yamamoto T, Katayama I, Nishioka K (1999) Fibroblast proliferation by bleomycin stimulated peripheral blood mononuclear cell factors. J Rheumatol 26:609–615PubMed Yamamoto T, Katayama I, Nishioka K (1999) Fibroblast proliferation by bleomycin stimulated peripheral blood mononuclear cell factors. J Rheumatol 26:609–615PubMed
125.
go back to reference 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 92:6–13PubMed 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 92:6–13PubMed
126.
go back to reference 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 113:843–847PubMed 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 113:843–847PubMed
127.
go back to reference 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 292:535–541PubMed 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 292:535–541PubMed
128.
go back to reference 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 292:556–561PubMed 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 292:556–561PubMed
129.
go back to reference 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 164:6174–6179PubMed 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 164:6174–6179PubMed
130.
go back to reference Yamamoto T, Takagawa S, Kuroda M, Nishioka K (2000) Effect of interferon-γ on experimental scleroderma induced by bleomycin. Arch Dermatol Res 292:362–365PubMed Yamamoto T, Takagawa S, Kuroda M, Nishioka K (2000) Effect of interferon-γ on experimental scleroderma induced by bleomycin. Arch Dermatol Res 292:362–365PubMed
131.
go back to reference Yamamoto T, Nishioka K (2001) Animal model of sclerotic skin. IV: Induction of dermal sclerosis by bleomycin is T cell independent. J Invest Dermatol 117:999–1001PubMed Yamamoto T, Nishioka K (2001) Animal model of sclerotic skin. IV: Induction of dermal sclerosis by bleomycin is T cell independent. J Invest Dermatol 117:999–1001PubMed
132.
go back to reference Yamamoto T, Eckes B, Krieg T (2001) High expression and autoinduction of monocyte chemoattractant protein-1 in scleroderma fibroblasts. Eur J Immunol 31:2936–2941PubMed Yamamoto T, Eckes B, Krieg T (2001) High expression and autoinduction of monocyte chemoattractant protein-1 in scleroderma fibroblasts. Eur J Immunol 31:2936–2941PubMed
133.
go back to reference 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 26:133–139PubMed 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 26:133–139PubMed
134.
go back to reference 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 26:106–111PubMed 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 26:106–111PubMed
135.
go back to reference 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 102:77–83PubMed 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 102:77–83PubMed
136.
go back to reference Yamamoto T, Nishioka K (2002) Analysis of the effect of halofuginone on bleomycin-induced scleroderma. Rheumatology 41:594–596PubMed Yamamoto T, Nishioka K (2002) Analysis of the effect of halofuginone on bleomycin-induced scleroderma. Rheumatology 41:594–596PubMed
137.
go back to reference 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 121:510–516PubMed 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 121:510–516PubMed
138.
go back to reference Yamamoto T, Nishioka K (2004) Animal model of sclerotic skin. VI: Evaluation of bleomycin-induced skin sclerosis in nude mice. Arch Dermatol Res 295:453–456PubMed Yamamoto T, Nishioka K (2004) Animal model of sclerotic skin. VI: Evaluation of bleomycin-induced skin sclerosis in nude mice. Arch Dermatol Res 295:453–456PubMed
139.
go back to reference 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 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
140.
go back to reference Yamamoto T, Nishioka K (2004) Possible role of apoptosis in the pathogenesis of bleomycin-induced scleroderma. J Invest Dermatol 122:44–50PubMed Yamamoto T, Nishioka K (2004) Possible role of apoptosis in the pathogenesis of bleomycin-induced scleroderma. J Invest Dermatol 122:44–50PubMed
141.
go back to reference 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 442:61–64PubMed 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 442:61–64PubMed
142.
go back to reference Zhang K, Flanders KS, Phan SH (1995) Cellular localization of transforming growth factor-β expression in bleomycin-induced pulmonary fibrosis. Am J Pathol 147:352–361PubMed Zhang K, Flanders KS, Phan SH (1995) Cellular localization of transforming growth factor-β expression in bleomycin-induced pulmonary fibrosis. Am J Pathol 147:352–361PubMed
143.
go back to reference 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 158:954–959PubMed 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 158:954–959PubMed
144.
go back to reference 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 168:3088–3098PubMed 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 168:3088–3098PubMed
145.
go back to reference 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 121:713–719PubMed 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 121:713–719PubMed
146.
go back to reference 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 168:2953–2962PubMed 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 168:2953–2962PubMed
Metadata
Title
The bleomycin-induced scleroderma model: what have we learned for scleroderma pathogenesis?
Author
Toshiyuki Yamamoto
Publication date
01-02-2006
Publisher
Springer-Verlag
Published in
Archives of Dermatological Research / Issue 8/2006
Print ISSN: 0340-3696
Electronic ISSN: 1432-069X
DOI
https://doi.org/10.1007/s00403-005-0635-z

Other articles of this Issue 8/2006

Archives of Dermatological Research 8/2006 Go to the issue