Varga J, Bashey R I
Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Int Rev Immunol. 1995;12(2-4):187-99. doi: 10.3109/08830189509056712.
Excessive connective tissue deposition in the skin and other organs is the pathologic hallmark of systemic sclerosis (SSc), and fibrosis accounts for much of the chronic morbidity of this disease. Unregulated production of collagen in SSc skin fibroblasts has been demonstrated both in vivo and in vitro, and is considered to be a critical process in the development of fibrosis. In addition to collagen, other components of the extracellular matrix are also overexpressed in SSc fibroblasts, and may be important in the functional alterations of connective tissue. The transcriptional activity of several genes coding for matrix macromolecules is upregulated in SSc fibroblasts. The pleiotropic signaling molecule transforming growth factor-beta (TGF beta) is likely to be intimately involved in initiating and perhaps perpetuating the fibrotic response in SSc. TGF beta, a potent profibrotic cytokine, is highly expressed in endothelial cells, in fibroblasts near blood vessels, and in perivascular inflammatory cells in involved tissues in SSc. The apparent failure of SSc fibroblasts to down-regulate their collagen synthesis when cultured in a three-dimensional matrix suggest an additional mechanism for the maintenance of unregulated collagen production in these cells. Finally, subpopulations of fibroblasts with an activated biosynthetic phenotype may become dominant in SSc. Therefore, persistent elevation of extracellular matrix gene expression in SSc tissues may be the result of a series of events representing the interaction of genetic and hormonal factors. A precise delineation of the mechanisms of fibroblast activation is needed for understanding the pathogenesis of SSc, and for the rational design of therapeutic interventions aimed at interfering with the fibrotic process.
皮肤和其他器官中过多的结缔组织沉积是系统性硬化症（SSc）的病理标志，纤维化是该疾病慢性发病的主要原因。SSc皮肤成纤维细胞中胶原蛋白的不受调控产生已在体内和体外得到证实，并且被认为是纤维化发展中的关键过程。除了胶原蛋白外，细胞外基质的其他成分在SSc成纤维细胞中也过表达，并且可能在结缔组织的功能改变中起重要作用。几种编码基质大分子的基因的转录活性在SSc成纤维细胞中上调。多效性信号分子转化生长因子-β（TGF-β）可能密切参与启动并可能使SSc中的纤维化反应持续存在。TGF-β是一种有效的促纤维化细胞因子，在SSc受累组织的内皮细胞、血管附近的成纤维细胞和血管周围炎症细胞中高度表达。当在三维基质中培养时，SSc成纤维细胞未能下调其胶原蛋白合成，这表明这些细胞中维持不受调控的胶原蛋白产生的另一种机制。最后，具有活化生物合成表型的成纤维细胞亚群可能在SSc中占主导地位。因此，SSc组织中细胞外基质基因表达的持续升高可能是一系列代表遗传和激素因素相互作用的事件的结果。需要精确描述成纤维细胞活化的机制，以了解SSc的发病机制，并合理设计旨在干扰纤维化过程的治疗干预措施。
