Xu, Shi-Wen; (1998) Differential modulation of fibroblast properties in scleroderma. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Connective tissue fibrosis is a hallmark of many human diseases. One of these is scleroderma (SSc), where the skin and various internal organs undergo a progressive scarring or fibrosis leading to the loss of normal tissue structure and function. The underlying cause(s) of SSc are not known but autoimmune, vascular abnormalities, fibrogenic cytokines, genetic susceptibility and environmental factors have all been implicated. An early pathogenic event in SSc is infiltration of inflammatory cells into affected tissues, following endothelial cell damage. Subsequently, immune cell derived cytokines and growth factors are likely to be early modulators of fibroblast phenotype. The work described in this thesis focuses on fibroblast matrix synthesis and adhesion molecule expression, the extrinsic modulation of these properties, and the altered patterns of modulation observed in SSc. Modulation of fibroblast phenotype by growth factors e.g. endothelin-1 (ET-1), connective tissue growth factor (CTGF), extracellular matrix (3-dimensional collagen gel culture) and direct leucocyte- fibroblast interactions (Intercellular adhesion molecule-1, ICAM-1) expression were investigated. As part of this project, long-term temperature sensitive SSc fibroblast cell lines were generated. Since SSc is characterised by excessive collagen deposition the fibroblasts have been cultured and studied. Both dermal and lung fibroblasts from SSc patient lesions exhibit elevated collagen type (I) production, and fail to down-regulate collagen type I mRNA in gel culture despite normal gel contraction. An increased activation of the collagen gene is observed in SSc cell strains compared with controls, suggesting that the elevated collagen (I) mRNA levels are due, at least partly, to transcriptional activation. The production of CTGF, which is selectively induced by transforming growth factor beta (TGFβ), was markedly greater for SSc fibroblasts than normal strains and was correlated with the increased collagen synthesis. In contrast, modulation of fibroblast synthesis of collagen and other matrix molecules by ET-1 shown reduced responses for SSc fibroblasts. Impaired SSc fibroblast response to ET-1 was associated with reduced expression of ETA receptors. SSc fibroblasts express elevated levels of surface and steady-state mRNA of ICAM-1 and shed higher levels of sICAM-1 in vitro. ET-1 also operated as a pro-inflammatory mediator, up-regulating fibroblast ICAM-1 expression. Finally, long-term temperature sensitive SSc fibroblast cell lines retain high collagen biosynthesis and ICAM-1 expression following retroviral transduction with the SV40 tsT antigen. In conclusion, the data presented in this thesis provide further information regarding the abnormalities in the phenotype of fibroblasts from SSc and support the hypothesis that an alteration in the production of cytokines and in the response they provoke are related to the scarring and fibrosis seen in SSc.

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