Skip to main content
SpringerLink
Log in

Fibrotic Skin Diseases

  • Chapter
Clinical and Basic Immunodermatology

  • Dermal fibrosis is excessive scarring of the skin, and is a result of a pathologic wound healing response.

  • There is a wide spectrum of fibrotic skin diseases: scleroderma, nephrogenic fibrosing dermopathy, mixed connective tissue disease, scleromyxedema, scleredema, and eosinophilic fasciitis. Exposures to chemicals or physical agents are also potential causes of fibrotic skin disease.

  • Dermal fibrosis may be driven by immune, autoimmune, and inflammatory mechanisms.

  • The balance of collagen production and degradation by fibroblasts plays a critical role in the pathophysiology of fibrotic processes in the skin.

  • Certain cytokines promote would healing and fibrosis, such as transforming growth factor-β (TGF-β) and interleukin-4 (IL-4), whereas others are antifibrotic, such as interferon-γ (IFN-γ) and transforming growth factor-α (TNF-α).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Razzaque MS, Ahmed AR. Collagens, collagen-binding heat shock protein 47 and transforming growth factorbeta 1 are induced in cicatricial pemphigoid: possible role(s) in dermal fibrosis. Cytokine 2002;17:311–6.

    Article  PubMed  CAS  Google Scholar 

  2. Ricard-Blum S, Hartmann DJ, Esterre P. Monitoring of extracellular matrix metabolism and cross-linking in tissue, serum and urine of patients with chromoblastomycosis, a chronic skin fibrosis. Eur J Clin Invest 1998;28:748–54.

    Article  PubMed  CAS  Google Scholar 

  3. Zhou L, Askew D, Wu C, Gilliam AC. Cutaneous gene expression by DNA microarray in murine sclerodermatous graft-versus-host disease, a model for human scleroderma. J Invest Dermatol 2007;127:281–92.

    Article  PubMed  CAS  Google Scholar 

  4. Zhou X, Tan FK, Xiong M, et al. Systemic sclerosis (scleroderma): specific autoantigen genes are selectively overexpressed in scleroderma fibroblasts. J Immunol 2001;167:7126–33.

    PubMed  CAS  Google Scholar 

  5. Whitfield ML, Finlay DR, Murray JI, Troyanskaya, et al. Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci USA 2003;100:12319–24.

    Article  PubMed  CAS  Google Scholar 

  6. Degiorgio-Miller AM, Treharne LJ, McAnulty RJ, et al. Procollagen type I gene expression and cell proliferation are increased in lipodermatosclerosis. Br J Dermatol 2005;152:242–9.

    Article  PubMed  CAS  Google Scholar 

  7. Herouy Y, May AE, Pornschlegel G, et al. Lipodermatosclerosis is characterized by elevated expression and activation of matrix metalloproteinases: implications for venous ulcer formation. J Invest Dermatol 1998;111:822–7.

    Article  PubMed  CAS  Google Scholar 

  8. Quatresooz P, Henry F, Paquet P, et al. Deciphering the impaired cytokine cascades in chronic leg ulcers (review). Int J Mol Med 2003;11:411–8.

    PubMed  CAS  Google Scholar 

  9. Atamas SP, White B. The role of chemokines in the pathogenesis of scleroderma. Curr Opin Rheumatol 2003;15:772–7.

    Article  PubMed  CAS  Google Scholar 

  10. Atamas SP, White B. Cytokine regulation of pulmonary fibrosis in scleroderma. Cytokine Growth Factor Rev 2003;14:537–50.

    Article  PubMed  CAS  Google Scholar 

  11. Atamas SP. Complex cytokine regulation of tissue fibrosis. Life Sci 2002;72:631–43.

    Article  PubMed  CAS  Google Scholar 

  12. Jelaska A, Strehlow D, Korn JH. Fibroblast heterogeneity in physiological conditions and fibrotic disease. Springer Semin Immunopathol 1999;21:385–95.

    PubMed  CAS  Google Scholar 

  13. Tan FK, Arnett FC, Reveille JD, et al. Autoantibodies to fibrillin 1 in systemic sclerosis: ethnic differences in antigen recognition and lack of correlation with specific clinical features or HLA alleles. Arthritis Rheum 2000;43:2464–71.

    Article  PubMed  CAS  Google Scholar 

  14. Zhou X, Tan FK, Milewicz DM, et al. Autoantibodies to fibrillin-1 activate normal human fibroblasts in culture through the TGF-beta pathway to recapitulate the “scleroderma phenotype.” J Immunol 2005;175:4555–60.

    PubMed  CAS  Google Scholar 

  15. Kuwana M, Kaburaki J, Medsger TA Jr, et al. An immunodominant epitope on DNA topoisomerase I is conformational in nature: heterogeneity in its recognition by systemic sclerosis sera. Arthritis Rheum 1999;42:1179–88.

    Article  PubMed  CAS  Google Scholar 

  16. Henry PA, Atamas S P, Yurovsky V V, et al. Diversity and plasticity of the anti-DNA topoisomerase I autoantibody response in scleroderma. Arthritis Rheum 2000;43:2733–42.

    Article  PubMed  CAS  Google Scholar 

  17. Warrington KJ, Nair U, Carbone LD, et al. Characterisation of the immune response to type I collagen in scleroderma. Arthritis Res Ther 2006;8:R136.

    Article  PubMed  CAS  Google Scholar 

  18. Hu PQ, Oppenheim JJ, Medsger TA Jr, et al. T cell lines from systemic sclerosis patients and healthy controls recognize multiple epitopes on DNA topoisomerase I. J Autoimmun 2006;26:258–67.

    Article  PubMed  CAS  Google Scholar 

  19. Marie I, Cordel N, Lenormand B, et al. Clonal T cells in the blood of patients with systemic sclerosis. Arch Dermatol 2005;141:88–9.

    Article  PubMed  Google Scholar 

  20. Sakkas LI, Xu B, Artlett CM, et al. Oligoclonal T cell expansion in the skin of patients with systemic sclerosis. J Immunol 2002;168:3649–59.

    PubMed  CAS  Google Scholar 

  21. Skert C, Patriarca F, Sperotto A, et al. Sclerodermatous chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: incidence, predictors and outcome. Haematologica 2006;91:258–61.

    PubMed  Google Scholar 

  22. Schaffer JV, McNiff JM, Seropian S, et al. Lichen sclerosus and eosinophilic fasciitis as manifesta-tions of chronic graft-versus-host disease: expanding the sclerodermoid spectrum. J Am Acad Dermatol 2005;53:591–601.

    Article  PubMed  Google Scholar 

  23. Zhang Y, McCormick LL, Desai SR, et al. Murine sclerodermatous graft-versus-host disease, a model for human scleroderma: cutaneous cytokines, chemokines, and immune cell activation. J Immunol 2002;168:3088– 98.

    PubMed  CAS  Google Scholar 

  24. Kaplan DH, Anderson BE, McNiff JM, et al. Target antigens determine graft-versus-host disease pheno-type. J Immunol 2004;173:5467–75.

    PubMed  CAS  Google Scholar 

  25. Jimenez SA, Artlett CM, Sandorfi N, et al. Dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy): study of inflammatory cells and transforming growth factor beta1 expression in affected skin. Arthritis Rheum 2004;50:2660–6.

    Article  PubMed  CAS  Google Scholar 

  26. Levine JM, Taylor RA, Elman LB, et al. Involvement of skeletal muscle in dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy). Muscle Nerve 2004;30:569–77.

    Article  PubMed  Google Scholar 

  27. Tredget EE, Yang L, Delehanty M, et al. Polarized Th2 cytokine production in patients with hypertrophic scar following thermal injury. J Interferon Cytokine Res 2006;26:179–89.

    Article  PubMed  CAS  Google Scholar 

  28. Liu W, Ding I, Chen K, et al. Interleukin 1beta (IL1B) signaling is a critical component of radiationinduced skin fibrosis. Radiat Res 2006;165:181–91.

    Article  PubMed  CAS  Google Scholar 

  29. Martin M, Lefaix JL, Pinton P, et al. Temporal modulation of TGF-beta 1 and beta-actin gene expression in pig skin and muscular fibrosis after ionizing radiation. Radiat Res 1993;134:63–70.

    Article  PubMed  CAS  Google Scholar 

  30. Lafuma C, El Nabout RA, Crechet F, et al. Expression of 72-kDa gelatinase (MMP-2), collagenase (MMP1), and tissue metalloproteinase inhibitor (TIMP) in primary pig skin fibroblast cultures derived from radiation-induced skin fibrosis. J Invest Dermatol 1994;102:945–50.

    Article  PubMed  CAS  Google Scholar 

  31. Flanders KC, Sullivan CD, Fujii M, et al. Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am J Pathol 2002;160:1057–68.

    PubMed  CAS  Google Scholar 

  32. Saito E, Fujimoto M, Hasegawa M, et al. CD19dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse. J Clin Invest 2002;109:1453–62.

    PubMed  CAS  Google Scholar 

  33. Muryoi T, Kasturi KN, Kafina MJ, et al. Antitopoisomerase I monoclonal autoantibodies from scleroderma patients and tight skin mouse interact with similar epitopes. J Exp Med 1992;175:1103–9.

    Article  PubMed  CAS  Google Scholar 

  34. Wang HW, Tedla N, Hunt JE, et al. Mast cell accumulation and cytokine expression in the tight skin mouse model of scleroderma. Exp Dermatol 2005;14:295–302.

    Article  PubMed  CAS  Google Scholar 

  35. Kodera T, McGaha TL, Phelps R, et al. Disrupting the IL-4 gene rescues mice homozygous for the tight-skin mutation from embryonic death and diminishes TGF-beta production by fibroblasts. Proc Natl Acad Sci USA 2002;99:3800–5.

    Article  PubMed  CAS  Google Scholar 

  36. McGaha TL, Le M, Kodera T, et al. Molecular mechanisms of interleukin-4-induced up-regulation of type I collagen gene expression in murine fibroblasts. Arthritis Rheum 2003;48:2275–84.

    Article  PubMed  CAS  Google Scholar 

  37. McGaha T, Saito S, Phelps RG, et al. Lack of skin fibrosis in tight skin (TSK) mice with targeted mutation in the interleukin-4R alpha and transforming growth factor-beta genes. J Invest Dermatol 2001;116:136–43.

    Article  PubMed  CAS  Google Scholar 

  38. Christner PJ, Hitraya EG, Peters J, et al. Transcriptional activation of the alpha1(I) procollagen gene and upregulation of alpha1(I) and alpha1(III) procollagen messenger RNA in dermal fibroblasts from tight skin 2 mice. Arthritis Rheum 1998;41:2132–42.

    Article  PubMed  CAS  Google Scholar 

  39. Christner PJ, Peters J, Hawkins D, et al. The tight skin 2 mouse. An animal model of scleroderma displaying cutaneous fibrosis and mononuclear cell infiltration Arthritis Rheum 1995;38:1791–8.

    Article  PubMed  CAS  Google Scholar 

  40. Gentiletti J, McCloskey LJ, Artlett CM, et al. Demonstration of autoimmunity in the tight skin2 mouse: a model for scleroderma. J Immunol 2005;175:2418–26.

    PubMed  CAS  Google Scholar 

  41. Wallace VA, Kondo S, Kono T, et al. A role for CD4+ T cells in the pathogenesis of skin fibrosis in tight skin mice. Eur J Immunol 1994;24:1463–6.

    Article  PubMed  CAS  Google Scholar 

  42. Wooley PH, Sud S, Langendorfer A, et al. T cells infiltrating the skin of Tsk2 scleroderma-like mice exhibit T cell receptor bias. Autoimmunity 1998;27:91–8.

    Article  PubMed  CAS  Google Scholar 

  43. Sugerman PB, Faber SB, Willis LM, et al. Kinetics of gene expression in murine cutaneous graft-versushost disease. Am J Pathol 2004;164:2189–202.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  45. Yamamoto T, Nishioka K. Role of monocyte chemoattractant protein-1 and its receptor, CCR-2, in the pathogenesis of bleomycin-induced scleroderma. J Invest Dermatol 2003;121:510–6.

    Article  PubMed  CAS  Google Scholar 

  46. Takagawa S, Lakos G, Mori Y, et al. Sustained activation of fibroblast transforming growth factor-beta/ Smad signaling in a murine model of scleroderma. J Invest Dermatol 2003;121:41–50.

    Article  PubMed  CAS  Google Scholar 

  47. Lakos G, Takagawa S, Chen SJ, et al. Targeted disruption of TGF-beta/Smad3 signaling modulates skin fibrosis in a mouse model of scleroderma. Am J Pathol 2004;165:203–17.

    PubMed  CAS  Google Scholar 

  48. Atamas SP. Alternative splice variants of cytokines: making a list. Life Sci 1997;61:1105–12.

    Article  PubMed  CAS  Google Scholar 

  49. Postlethwaite AE, Shigemitsu H, Kanangat S. Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic sclerosis. Curr Opin Rheumatol 2004;16:733–8.

    Article  PubMed  Google Scholar 

  50. Chesney J, Metz C, Stavitsky AB, et al. Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes. J Immunol 1998;160:419–25.

    PubMed  CAS  Google Scholar 

  51. Yang L, Scott PG, Dodd C, et al. Identification of fibrocytes in postburn hypertrophic scar. Wound Repair Regen 2005;13:398–404.

    Article  PubMed  Google Scholar 

  52. Ishii G, Sangai T, Sugiyama K, et al. In vivo characterization of bone marrow-derived fibroblasts recruited into fibrotic lesions. Stem Cells 2005;23:699–706.

    Article  PubMed  CAS  Google Scholar 

  53. Yamamoto T, Eckes B, Krieg T. High expression and autoinduction of monocyte chemoattractant protein-1 in scleroderma fibroblasts. Eur J Immunol 2001;31:2936–41.

    Article  PubMed  CAS  Google Scholar 

  54. Yamamoto T, Eckes B, Mauch C, et al. Monocyte chemoattractant protein-1 enhances gene expression and synthesis of matrix metalloproteinase-1 in human fibroblasts by an autocrine IL-1 alpha loop. J Immunol 2000;164:6174–9.

    PubMed  CAS  Google Scholar 

  55. Asano Y, Ihn H, Yamane K, et al. Increased expression of integrin alphavbeta5 induces the myofibroblastic differentiation of dermal fibroblasts. Am J Pathol 2006;168:499–510.

    Article  PubMed  CAS  Google Scholar 

  56. Asano Y, Ihn H, Yamane K, et al. Increased expression of integrin alpha(v)beta3 contributes to the establishment of autocrine TGF-beta signaling in scleroderma fibroblasts. J Immunol 2005;175:7708–18.

    PubMed  CAS  Google Scholar 

  57. Asano Y, Ihn H, Yamane K, et al. Impaired Smad7– Smurf-mediated negative regulation of TGF-beta signaling in scleroderma fibroblasts. J Clin Invest 2004;113:253–64.

    PubMed  CAS  Google Scholar 

  58. Jelaska A, Korn JH. Role of apoptosis and transforming growth factor beta1 in fibroblast selection and activation in systemic sclerosis. Arthritis Rheum 2000;4310:2230–9.

    Article  Google Scholar 

  59. Moulin V, Larochelle S, Langlois C, et al. Normal skin wound and hypertrophic scar myofibroblasts have differential responses to apoptotic inductors. J Cell Physiol 2004;198:350–8.

    Article  PubMed  CAS  Google Scholar 

  60. Chizzolini C, Rezzonico R, Ribbens C, et al. Inhibition of type I collagen production by dermal fibroblasts upon contact with activated T cells: different sensitivity to inhibition between systemic sclerosis and control fibroblasts. Arthritis Rheum 1998;41:2039–47.

    Article  PubMed  CAS  Google Scholar 

  61. Chizzolini C, Parel Y, De Luca C, et al. Systemic sclerosis Th2 cells inhibit collagen production by dermal fibroblasts via membrane-associated tumor necrosis factor alpha. Arthritis Rheum 2003;48:2593–604.

    Article  PubMed  CAS  Google Scholar 

  62. Ong C, Wong C, Roberts CR, et al. Anti-IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma. Eur J Immunol 1998;28:2619–29.

    Article  PubMed  CAS  Google Scholar 

  63. Atamas SP. FCP (http://fibro.biobitfield.com/fcp. php): a bioinformatic tool assisting in PubMed searches for literature on fibrosis-related cytokines. Arthritis Rheum 2003;48:2083–4.

    Article  PubMed  Google Scholar 

  64. Atamas SP, Luzina IG, Dai H, et al. Synergy between CD40 ligation and IL-4 on fibroblast proliferation involves IL-4 receptor signaling. J Immunol 2002;168:1139–45.

    PubMed  CAS  Google Scholar 

  65. Atamas SP, Yurovsky V V, Wise R, et al. Production of type 2 cytokines by CD8+ lung cells is associated with greater decline in pulmonary function in patients with systemic sclerosis. Arthritis Rheum 1999;42:1168–78.

    Article  PubMed  CAS  Google Scholar 

  66. Rezzonico R, Burger D, Dayer JM. Direct contact between T lymphocytes and human dermal fibroblasts or synoviocytes down-regulates types I and III collagen production via cell-associated cytokines. J Biol Chem 1998;273:18720–8.

    Article  PubMed  CAS  Google Scholar 

  67. De Palma R, Del Galdo F, Lupoli S, et al. Peripheral T lymphocytes from patients with early systemic sclerosis co-cultured with autologous fibroblasts undergo an oligoclonal expansion similar to that occurring in the skin. Clin Exp Immunol 2006;144:169–76.

    Article  PubMed  Google Scholar 

  68. Hasegawa M, Hamaguchi Y, Yanaba K, et al. B-lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis. Am J Pathol 2006;169:954–66.

    Article  PubMed  CAS  Google Scholar 

  69. Sato S, Hasegawa M, Fujimoto M, et al. Quantitative genetic variation in CD19 expression correlates with autoimmunity. J Immunol 2000;165:6635–43.

    PubMed  CAS  Google Scholar 

  70. Yamamoto T, Hartmann K, Eckes B, et al. Role of stem cell factor and monocyte chemoattractant protein-1 in the interaction between fibroblasts and mast cells in fibrosis. J Dermatol Sci 2001;26:106–11.

    Article  PubMed  CAS  Google Scholar 

  71. Trautmann A, Krohne G, Brocker EB, et al. Human mast cells augment fibroblast proliferation by heterotypic cell-cell adhesion and action of IL-4. J Immunol 1998;160:5053–7.

    PubMed  CAS  Google Scholar 

  72. Kakizoe E, Shiota N, Tanabe Y, et al. Isoform-selective upregulation of mast cell chymase in the development of skin fibrosis in scleroderma model mice. J Invest Dermatol 2001;116:118–23.

    Article  PubMed  CAS  Google Scholar 

  73. Abe M, Kurosawa M, Ishikawa O, et al. Effect of mast cell-derived mediators and mast cell-related neutral proteases on human dermal fibroblast proliferation and type I collagen production. J Allergy Clin Immunol 2000;106:S78–84.

    Article  PubMed  CAS  Google Scholar 

  74. Shephard P, Martin G, Smola-Hess S, et al. Myofibroblast differentiation is induced in keratinocyte-fibroblast co-cultures and is antagonistically regulated by endogenous transforming growth factor-beta and interleukin-1. Am J Pathol 2004;164:2055–66.

    PubMed  CAS  Google Scholar 

  75. Bellemare J, Roberge CJ, Bergeron D, et al. Epidermis promotes dermal fibrosis: role in the pathogenesis of hypertrophic scars. J Pathol 2005;206:1–8.

    Article  PubMed  Google Scholar 

  76. Funayama E, Chodon T, Oyama A, et al. Keratinocytes promote proliferation and inhibit apoptosis of the under-lying fibroblasts: an important role in the pathogenesis of keloid. J Invest Dermatol 2003;121:1326–31.

    Article  PubMed  CAS  Google Scholar 

  77. Khoo YT, Ong CT, Mukhopadhyay A, et al. Upregulation of secretory connective tissue growth factor (CTGF) in keratinocyte-fibroblast coculture contributes to keloid pathogenesis. J Cell Physiol 2006;208:336–43.

    Article  PubMed  CAS  Google Scholar 

  78. Sivan V, Vozenin-Brotons MC, Tricaud Y, et al. Altered proliferation and differentiation of human epidermis in cases of skin fibrosis after radiotherapy. Int J Radiat Oncol Biol Phys 2002;53:385–93.

    PubMed  Google Scholar 

  79. Gharaee-Kermani M, Phan SH. Role of cytokines and cytokine therapy in wound healing and fibrotic diseases. Curr Pharm Des 2001;7:1083–103.

    Article  PubMed  CAS  Google Scholar 

  80. McCormick LL, Zhang Y, Tootell E, et al. AntiTGF-beta treatment prevents skin and lung fibrosis in murine sclerodermatous graft-versus-host disease: a model for human scleroderma. J Immunol 1999;163:5693–9.

    PubMed  CAS  Google Scholar 

  81. Zhang Y, McCormick LL, Gilliam AC. Latency-associated peptide prevents skin fibrosis in murine sclerodermatous graft-versus-host disease, a model for human scleroderma. J Invest Dermatol 2003;21:713–9.

    Article  Google Scholar 

  82. Santiago B, Gutierrez-Canas I, Dotor J, et al. Topical application of a peptide inhibitor of transforming growth factor-beta1 ameliorates bleomycin-induced skin fibrosis. J Invest Dermatol 2005;125:450–5.

    Article  PubMed  CAS  Google Scholar 

  83. Wang XJ, Han G, Owens P, et al. Role of TGFbetamediated inflammation in cutaneous wound healing. J Invest Dermatol 2006;126:112–7.

    Google Scholar 

  84. Hakkinen L, Koivisto L, Gardner H, et al. Increased expression of beta6–integrin in skin leads to spontaneous development of chronic wounds. Am J Pathol 2004;164:229–42.

    PubMed  Google Scholar 

  85. Mori Y, Chen SJ, Varga J. Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts. Arthritis Rheum 2003;48:1964–78.

    Article  PubMed  CAS  Google Scholar 

  86. Gao Z, Wang Z, Shi Y, et al. Modulation of collagen synthesis in keloid fibroblasts by silencing Smad2 with siRNA. Plast Reconstr Surg 2006;118:1328–37.

    Article  PubMed  CAS  Google Scholar 

  87. Distler JH, Jungel A, Huber LC, et al. Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis. Arthritis Rheum 2007;56:311–22.

    Article  PubMed  CAS  Google Scholar 

  88. Chen SJ, Ning H, Ishida W, et al. The early-immediate gene EGR-1 is induced by transforming growth factor-beta and mediates stimulation of collagen gene expression. J Biol Chem 2006;281:21183–97.

    Article  PubMed  CAS  Google Scholar 

  89. Dong C, Zhu S, Wang T, et al. Deficient Smad7 expression: a putative molecular defect in scleroderma. Proc Natl Acad Sci USA 2002;99:3908–13.

    Article  PubMed  CAS  Google Scholar 

  90. Leask A, Denton CP, Abraham DJ. Insights into the molecular mechanism of chronic fibrosis: the role of connective tissue growth factor in scleroderma. J Invest Dermatol 2004;122:1–6.

    Article  PubMed  CAS  Google Scholar 

  91. Holmes A, Abraham DJ, Chen Y, et al. Constitutive connective tissue growth factor expression in scleroderma fibroblasts is dependent on Sp1. J Biol Chem 2003;278:41728–33.

    Article  PubMed  CAS  Google Scholar 

  92. Mori T, Kawara S, Shinozaki M, et al. J Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: A mouse fibrosis model. Cell Physiol 1999;181:153–9.

    Article  CAS  Google Scholar 

  93. Jinnin M, Ihn H, Yamane K, et al. Interleukin-13 stimulates the transcription of the human alpha2(I) collagen gene in human dermal fibroblasts. J Biol Chem 2004;279:41783–91.

    Article  PubMed  CAS  Google Scholar 

  94. Granel B, Chevillard C, Allanore Y, et al. Evaluation of interleukin 13 polymorphisms in systemic sclerosis. Immunogenetics 2006;58:693–9.

    Article  PubMed  CAS  Google Scholar 

  95. Gharaee-Kermani M, Denholm EM, Phan SH. Costimulation of fibroblast collagen and transforming growth factor beta1 gene expression by monocyte chemoattractant protein-1 via specific receptors. J Biol Chem 1996;271:17779–84.

    Article  PubMed  CAS  Google Scholar 

  96. Carulli MT, Ong VH, Ponticos M, et al. Chemokine receptor CCR2 expression by systemic sclerosis fibroblasts: evidence for autocrine regulation of myofibrob-last differentiation. Arthritis Rheum 2005;52:3772–82.

    Article  PubMed  CAS  Google Scholar 

  97. Distler JH, Jungel A, Caretto D, et al. Monocyte chemoattractant protein 1 released from glycosaminoglycans mediates its profibrotic effects in systemic sclerosis via the release of interleukin-4 from T cells. Arthritis Rheum 2006;54:214–25.

    Article  PubMed  CAS  Google Scholar 

  98. Distler O, Pap T, Kowal-Bielecka O, et al. Overexpression of monocyte chemoattractant protein 1 in systemic sclerosis: role of platelet-derived growth factor and effects on monocyte chemotaxis and collagen synthesis. Arthritis Rheum 2001;44:2665–78.

    Article  PubMed  CAS  Google Scholar 

  99. Luzina IG, Atamas SP, Wise R, et al. Gene expression in bronchoalveolar lavage cells from scleroderma patients. Am J Respir Cell Mol Biol 2002;26:549–57.

    PubMed  CAS  Google Scholar 

  100. Luzina IG, Highsmith K, Pochetuhen K, et al. PKCalpha mediates CCL18–stimulated collagen production in pulmonary fibroblasts. Am J Respir Cell Mol Biol 2006;35:298–305.

    Article  PubMed  CAS  Google Scholar 

  101. Luzina IG, Tsymbalyuk N, Choi J, et al. CCL18– stimulated upregulation of collagen production in lung fibroblasts requires Sp1 signaling and basal Smad3 activity. J Cell Physiol 2006;206:221–8.

    Article  PubMed  CAS  Google Scholar 

  102. Atamas SP, Luzina IG, Choi J, et al. Pulmonary and activation-regulated chemokine stimulates collagen production in lung fibroblasts. Am J Respir Cell Mol Biol 2003;29:743–9.

    Article  PubMed  CAS  Google Scholar 

  103. Luzina IG, Papadimitriou JC, Anderson R, et al. Induction of prolonged infiltration of T lymphocytes and transient T lymphocyte- dependent collagen deposition in mouse lungs following adenoviral gene transfer of CCL18. Arthritis Rheum 2006;54:2643–55.

    Article  PubMed  CAS  Google Scholar 

  104. Mori R, Kondo T, Ohshima T, et al. Accelerated wound healing in tumor necrosis factor receptor p55–deficient mice with reduced leukocyte infiltration. FASEB J 2002;16:963–74.

    Article  PubMed  CAS  Google Scholar 

  105. Lee RH, Efron DT, Tantry U, et al. Inhibition of tumor necrosis factor-alpha attenuates wound breaking strength in rats. Wound Repair Regen 2000;8:547–53.

    Article  PubMed  CAS  Google Scholar 

  106. Kouba DJ, Nakano H, Nishiyama T, et al. Tumor necrosis factor-alpha induces distinctive NF-kappa B signaling within human dermal fibroblasts. J Biol Chem 2001;276:6214–24.

    Article  PubMed  CAS  Google Scholar 

  107. Yamane K, Ihn H, Asano Y, et al. Antagonistic effects of TNF-alpha on TGF-beta signaling through down-regulation of TGF-beta receptor type II in human dermal fibroblasts. J Immunol 2003;171:3855–62.

    PubMed  CAS  Google Scholar 

  108. Verrecchia F, Pessah M, Atfi A, et al. Tumor necrosis factor-alpha inhibits transforming growth factor-beta /Smad signaling in human dermal fibroblasts via AP-1 activation. J Biol Chem 2000;275:30226–31.

    Article  PubMed  CAS  Google Scholar 

  109. Abraham DJ, Shiwen X, Black CM, et al. Tumor necrosis factor alpha suppresses the induction of connective tissue growth factor by transforming growth factor-beta in normal and scleroderma fibroblasts. J Biol Chem 2000;275:15220–5.

    Article  PubMed  CAS  Google Scholar 

  110. Ghosh AK, Bhattacharyya S, Mori Y, et al. Inhibition of collagen gene expression by interferon-gamma: novel role of the CCAAT/enhancer binding protein beta (C/EBPbeta). J Cell Physiol 2006;207:251–60.

    Article  PubMed  CAS  Google Scholar 

  111. Ghosh AK, Yuan W, Mori Y, et al. Antagonistic regulation of type I collagen gene expression by interferon-gamma and transforming growth factor-beta. Integration at the level of p300/CBP transcriptional coactivators. J Biol Chem 2001;276:11041–8.

    Article  PubMed  CAS  Google Scholar 

  112. Higashi K, Inagaki Y, Fujimori K, et al. Interferongamma interferes with transforming growth factorbeta signaling through direct interaction of YB-1 with Smad3. J Biol Chem 2003;278:43470–9.

    Article  PubMed  CAS  Google Scholar 

  113. Ishida Y, Kondo T, Takayasu T, et al. The essential involvement of cross-talk between IFN-gamma and TGF-beta in the skin wound-healing process. J Immunol 2004;172:1848–55.

    PubMed  CAS  Google Scholar 

  114. Hasegawa T, Nakao A, Sumiyoshi K, et al. IFNgamma fails to antagonize fibrotic effect of TGF-beta on keloid-derived dermal fibroblasts. J Dermatol Sci 2003;32:19–24.

    Article  PubMed  CAS  Google Scholar 

  115. Hunzelmann N, Anders S, Fierlbeck G, et al. Doubleblind, placebo-controlled study of intralesional interferon gamma for the treatment of localized scleroderma. J Am Acad Dermatol 1997;36:433–5.

    Article  PubMed  CAS  Google Scholar 

  116. Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004;350:125–33.

    Article  PubMed  CAS  Google Scholar 

  117. Bolinger AM, Taeubel MA. Recombinant interferon gamma for treatment of chronic granulo-matous disease and other disorders. Clin Pharm 1992;11:834–50.

    PubMed  CAS  Google Scholar 

  118. Virtual Round Table on ten leading questions for network research. Eur Phys J [B] 2004;38:143–5.

    Google Scholar 

  119. Feldmann M, Bondeson J, Brennan FM, et al. The rationale for the current boom in anti-TNFalpha treatment. Is there an effective means to define therapeutic targets for drugs that provide all the benefits of anti-TNFalpha and minimise hazards? Ann Rheum Dis 1999;58:I27–31.

    Article  PubMed  CAS  Google Scholar 

  120. Denton CP, Merkel PA, Furst DE, et al. Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: A multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum 2007;56:323–33.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, University of Maryland School of Medicine, Baltimore, USA

    Irina G. Luzina & Sergei P. Atamas

Authors
  1. Irina G. Luzina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sergei P. Atamas
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Dermatology, University of Maryland School of Medicine, Baltimore, MD, USA

    Anthony A. Gaspari MD

  2. Department of Dermatology, University of Texas Medical School at Houston, Houston, TX, USA

    Stephen K. Tyring MD, PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer-Verlag London Limited

About this chapter

Cite this chapter

Luzina, I.G., Atamas, S.P. (2008). Fibrotic Skin Diseases. In: Gaspari, A.A., Tyring, S.K. (eds) Clinical and Basic Immunodermatology. Springer, London. https://doi.org/10.1007/978-1-84800-165-7_41

Download citation

  • DOI: https://doi.org/10.1007/978-1-84800-165-7_41

  • Publisher Name: Springer, London

  • Print ISBN: 978-1-84800-164-0

  • Online ISBN: 978-1-84800-165-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation