Vancheeswaran, Rama; (1995) A comparative study of the mechanism leading to dermal and lung disease in systemic sclerosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Systemic sclerosis (SSc) is a multi-system disease of unknown aetiology, characterised by abnormalities in endothelial cell function, immune regulation and connective tissue metabolism. Skin sclerosis is the most apparent and studied feature but lung involvement is the major cause of death. Histo- pathological studies have revealed differences between the skin and lung suggesting distinct organ-specific mechanisms which have been further examined in this project by comparing the in vivo expression of Endothelin-1 (ET- 1), ET-1 receptors and the major adhesion molecules in the two organs. The characteristics of fibroblasts derived from the two organs were also studied in vitro. Circulating levels of ET-1 were elevated in SSc patients with widepread fibrosis (dcSSc). Lesional biopsies taken from the skin in dcSSc and the lung in fibrosing alveolitis (FASSc) showed a significant increase in the vascular expression of ET-1 and ET-1 receptors. Circulating levels of E-selectin and VCAM-1 were markedly raised in SSc. DcSSc skin biopsies showed a high vascular expression of E-selectin and ICAM-1 while FASSc vessels showed increased levels of VCAM-1 and ICAM-1. A strikingly high expression of ET-1, ET-1 receptors and ICAM-1 was also shown by hyperplastic alveolar epithelial type II cells in FASSc. Substantial differences in cell size and rate of cell proliferation were observed between SSc skin and SSc lung fibroblasts. SSc skin fibroblasts also showed markedly higher levels of matrix production, cell surface antigens including ICAM-1, CDw49d, ectoenzymes, 5A3, 3D3 and 3C4 and T lymphocyte interactions compared with SSc lung cells. However, a subpopulation of ICAM-1-high and 3C4-high expressing cells was expanded in both SSc skin and SSc lung fibroblasts compared with normal cells. This project provides evidence for different cellular abnormalities in the skin and lung which suggest organ-specific disease processes in SSc.

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