Denton, Christopher Paul; (1997) Endothelial cell-fibroblast interactions in scleroderma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Scleroderma (systemic sclerosis; SSc) is a connective tissue disease of unknown aetiology and uncertain pathogenesis. Pathologically it is characterised by immune cell activation, vascular damage and fibroblast dysfunction leading to excessive deposition of extracellular matrix in lesional tissues. Considerable indirect evidence suggests that there is functional interplay between the different cell types implicated in scleroderma pathogenesis. Work described in this thesis explores paracrine interactions between endothelial cells and fibroblasts in tissue culture, and investigates altered endothelial cell-fibroblast interactions in scleroderma, addressing the hypothesis that cytokine mediated cross-talk between endothelial cells and fibroblasts may initiate or maintain phenotypic abnormalities observed in both cell types in this disease. To study modulation of fibroblast properties by endothelial cells a co-culture system was developed in which human umbilical vein endothelial cells were grown in proximity to, but separately from, dermal fibroblasts. Modulation of fibroblast confluent cell density, thymidine incorporation and collagen biosynthesis was demonstrated. In general scleroderma fibroblasts showed greater responsiveness to endothelial cell-derived factors than matched control fibroblast strains. Having demonstrated modulation of fibroblast properties in co-culture, a series of conditioned-medium transfer experiments were performed confirming similar patterns of endothelial cell-induced modulation. Using neutralising antibodies, or pharmacological antagonists, three candidate endothelial cell-derived mediators were investigated; basic fibroblast growth factor (bFGF), interleukin-1 and endothelin-1. These mediators appear to act independently in modulating DNA or protein synthesis, ICAM-1 expression and 3-dimensional collagen gel retraction by dermal fibroblasts. Later experiments examined the effect of fibroblast products on endothelial cell properties using similar methodologies. Fibroblast-derived soluble factors upregulated endothelial cell surface adhesion molecule expression, and scleroderma fibroblasts promoted leucocyte migration across endothelial cell monolayers, including peripheral blood mononuclear cells obtained from scleroderma patients. Taken together, these results suggest an altered pattern of endothelial cell-fibroblast interactions in scleroderma and, for the first time, provide direct laboratory evidence for a link between endothelial cell and fibroblast dysfunction in this disease.

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