Conclusions
The role of myofibroblasts in various fibrotic disorders is currently well established. These smooth-muscle-like fibroblasts promote deposition of ECM proteins and contractility of lung parenchyma. The present studies were performed to characterize the contractile activity of SSc lung fibroblasts. Previously, we demonstrated that the early stages of interstitial lung disease of SSc are characterized by a prominence of cells prossessing a myofibroblast phenotype. A major feature of such myofibroblasts is contractility, explained by an over-expression of α-smooth muscle actin. Here, we demonstrate for the first time that the contractility of SSc lung fibroblasts dependends on expression of CTGF as well, and that the VWC domain is primarily responsible for the contractile activity of CTGF in human lung fibroblasts. Future studies are required to identify the mechanisms by which CTGF stimulates collagen gel contraction.
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References
Silver RM, Bolster MB. Systemic sclerosis (scleroderma). In: Austen KF, Frank MM, Atkinson JP et al eds. Samter’s Immunologic Diseases. 6th ed. Philadelphia: Lippincott Williams and Wilkins, 2001:504–519.
Steen VD, Medsger Jr TA. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum 2000; 43:2437–2444.
Ward PA, Hunninghake GW. Lung inflammation and fibrosis. Am J Respir Crit Care Med 1998; 157:S123–S129.
Bouros D, Wells AU, Nicholson AG et al. Histopathologic subset of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med 2002; 165:1581–6.
Tomasek JJ, Gabbiani G, Hinz B et al. Myofibroblasts and mechano-regulation of connective tissue remodeling. Nature Rev Mol Cell Biol 2002; 3:349–363.
Pache JC, Chrstakos PG, Gannon DE et al. Myofibroblasts in diffuse alveolar damage of the lung. Modern Pathol 1998; 11:1064–70.
Low RB. Modulation of myofibroblast and smooth-muscle phenotypes in the lung. Curr Top Pathol 1999; 93:19–26.
Kapanci Y, Gabbiani G. Contractile cells in pulmonary alveolar tissue. In: Crystal RG, West JB, eds. The lung: Scientific foundation. Philadelphia: Lippincott-Raven, 1997:697–707.
Ludwicka A, Trojanowska M, Smith EA et al. Growth and characterization of fibroblasts obtained from bronchoalveolar lavage of scleroderma patients. J Rheumatol 1992; 19:1716–1723.
Ludwicka A, Ohba T, Trojanowska M et al. Elevated levels of TGF-β1 and PDGF in scleroderma bronchoalveolar lavage fluid. J Rheumatol 1995; 22:1876–1883.
Ludwicka-Bradley A, Bogatkevich GS, Silver RM. Thrombin-mediated cellular events in pulmonary fibrosis associated with systemic sclerosis (scleroderma). Clin Exp Rheumatol 2004; 22:S38–S46.
Zhang K, Rekhter MD, Gordon D et al. Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis: A combined immunohistochemical and in situ hybridization. Am J Pathol 1994; 145:114–25.
Walker GA, Guerrero IA, Leinwand LA. Myofibroblasts: Molecular crossdressers. Curr Top Dev Biol 2001; 51:91–107.
Zhang H, Gharaee-Kermani M, Zhang K et al. Lung fibroblast a-smooth muscle actin expression and contractile phenotype in bleomycin-induced pulmonary fibrosis. Am J Pathol 1996; 148:527–37.
Vyalov SL, Gabbiani G, Kapanci Y. Rat alveolar myofibroblasts acquire a-smooth muscle actin expression during bleomycin-induced pulmonary fibrosis. Am J Pathol 1993; 143:1754–1765.
Pittenger MF, Mackay AM, Beck SC et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284:143–147.
Iwano M, Plieth D, Danoff TM et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. I Clin Invest 2002; 110:341–350.
Phan SH. The myofibroblast in pulmonary fibrosis. Chest 2002; 122:286S–289S.
Vaugham MB, Howard EW, Tomasek JJ. Transforming growth factor-pi promotes the morphological and functional differentiation of the myofibroblast. Exp Cell Res 2000; 257:180–189.
Bogatkevich GS, Tourkina E, Silver RM et al. Thrombin differentiates normal lung fibroblasts to a myofibroblast phenotype via the proteolytically activated receptor-1 and a protein kinase C-dependent pathway. J Biol Chem 2001; 276:45184–92.
Bogatkevich GS, Tourkina E, Abrams CS et al. Contractile activity and smooth muscle-α actin organization in thrombin-induced human lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 2003; 285:L334–L343.
Leask A, Sa S, Holmes A et al. The control of ccn2 (CTGF) gene expression in normal and scleroderma fibroblasts. J Clin Pathol Mol Pathol 2001; 54:180–183.
Sato S, Nagaoka T, Hasegawa M et al. Serum levels of connective tissue growth factor are elevated in patients with systemic sclerosis: Association with extent of skin sclerosis and severity of pulmonary fibrosis. J Rheumatol 2000; 27:149–154.
Shi-wen X, Pennington D, Holmes A et al. Autocrine overexpression of CTGF maintains fibrosis: RDA analysis of fibrosis genes in systemic sclerosis. Exp Cell Res 2000; 259:213–224.
Chambers RC, Leoni P, Blanc-Brude OP et al. Thrombin is a potent inducer of connective tissue growth factor production via proteolytic activation of protease-activated receptor-1. J Biol Chem 2000; 275:35584–35591.
Leask A, Holmes A, Abraham DJ. Connective tissue growth factor: A new and important player in the pathogenesis of fibrosis. Current Rheumatol Reports 2002; 4:136–142.
Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 2003; 200:500–503.
Grinnell F. Signal transduction pathways activated during fibroblast contraction of collagen matrices. Curr Top Pathol 1999; 93:61–73.
Pawson T, Nash P. Assembly of cell regulatory systems through protein interaction domains. Science 2003; 300:445–452.
Abreu JG, Keptura NI, Reverside B et al. Connective tissue growth factor (CTGF) modulates cell signalling by BMP and TGFβ. Nature Cell Biol 2002; 4:599–604.
Brigstock DR, Steffen CL, Kim GY et al. Purification and characterization of novel heparin-binding growth factors in uterine secretory fluids. Identification as heparin-regulated Mr 10,000 forms of connective tissue growth factor. J Biol Chem 1997; 272:20275–20282.
Ball DK, Rachfal AW, Kemper SA et al. The heparin-binding 10 kDa fragment of connective tissue growth factor (CTGF) containing module 4 alone stimulates cell adhesion. J Endocrinol 2003; 176:R1–R7.
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Bogatkevich, G.S., Ludwicka-Bradley, A., Nietert, P.J., Silver, R.M. (2006). Scleroderma Lung Fibroblasts. In: Tissue Repair, Contraction and the Myofibroblast. Biotechnology Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/0-387-33650-8_3
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DOI: https://doi.org/10.1007/0-387-33650-8_3
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