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首页> 外文期刊>Rheumatic diseases clinics of North America >Pathogenesis of scleroderma. Collagen.
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Pathogenesis of scleroderma. Collagen.

机译：硬皮病的发病机理。胶原。

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It is now evident that persistent overproduction of collagen and other connective tissue macromolecules results in excessive tissue deposition, and is responsible for the progressive nature of fibrosis in SSc. Up-regulation of collagen gene expression in SSc fibroblasts appears to be a critical event in the development of tissue fibrosis. The coordinate transcriptional activation of a number of extracellular matrix genes suggests a fundamental alteration in the regulatory control of gene expression in SSc fibroblasts. Trans-acting nuclear factors that bind to cis-acting elements in enhancer and promoter regions of the genes modulate the basal and inducible transcriptional activity of the collagen genes. The identity of the nuclear transcriptional factors that regulate normal collagen gene expression remains to be firmly established, and to date, no alterations in the level or in the activity of such DNA binding factors has been demonstrated in SSc fibroblasts. In addition to important interactions between fibroblasts and the extracellular matrix, cytokines and other cellular mediators can positively and negatively influence fibroblast collagen synthesis. Some of these signaling molecules may have physiologic roles, and their aberrant expression, or altered responsiveness of SSc fibroblasts to them, may result in the acquisition of the activated phenotype. The rapid expansion of knowledge regarding the effects of cytokines on extracellular matrix synthesis has led to an appreciation of the enormous complexity of regulatory networks that operate in the physiologic maintenance of connective tissue and which may be responsible for the occurrence of pathologic fibrosis. The ubiquitous growth factor TGF beta is the most potent inducer of collagen gene expression and connective tissue accumulation yet discovered. The expression of TGF beta in activated infiltrating mononuclear cells suggests a role for this cytokine as a mediator of fibroblast activation in SSc. Furthermore, the recognition that TGF beta is capable of inducing its own expression in a variety of cell types, coupled with the demonstration that a subpopulation of SSc dermal fibroblasts produces TGF beta, indicates the existence of a possible autocrine loop whereby lymphocyte-derived TGF beta in early SSc not only signals biosynthetic activation of fibroblasts in a paracrine manner, but autoinduces endogenous TGF beta production by the target fibroblasts themselves. Such an autocrine loop involving TGF beta may explain the persistent activation of collagen gene expression in SSc fibroblasts, and could be responsible for the progressive nature of fibrosis in SSc. Numerous other cytokines, as well as cell-matrix interactions, also modify collagen gene expression and can significantly influence the effects of TGF beta. Although their physiologic function in tissue remodeling or their involvement in abnormal fibrogenesis has not yet been conclusively demonstrated, the study of the biologic effects of these cytokines may provide important clues to understanding the pathogenesis of SSc, and to the development of rational drug therapy aimed at interrupting the abnormal fibrogenic process in this disease.
机译：现在很明显，胶原蛋白和其他结缔组织大分子的持续过量生产会导致组织沉积过多，并导致SSc中纤维化的进行性。 SSc成纤维细胞中胶原基因表达的上调似乎是组织纤维化发展中的关键事件。许多细胞外基质基因的协调转录激活表明SSc成纤维细胞中基因表达的调控中的根本改变。与基因的增强子和启动子区域中的顺式作用元件结合的反式作用核因子调节胶原基因的基础和诱导型转录活性。调节正常胶原蛋白基因表达的核转录因子的身份仍有待确定，迄今为止，尚未在SSc成纤维细胞中证明这种DNA结合因子的水平或活性发生改变。除了成纤维细胞与细胞外基质之间的重要相互作用外，细胞因子和其他细胞介体还可以对成纤维细胞胶原蛋白的合成产生正向和负面影响。这些信号分子中的某些可能具有生理作用，它们的异常表达或SSc成纤维细胞对它们的反应性改变可能导致活化表型的获得。关于细胞因子对细胞外基质合成的影响的知识的迅速扩展，导致人们认识到在结缔组织的生理维持中起作用的调节网络的巨大复杂性，这可能是病理性纤维化发生的原因。普遍存在的生长因子TGFβ是迄今为止尚未发现的最有效的胶原蛋白基因表达和结缔组织积累的诱导剂。 TGFβ在活化的浸润性单核细胞中的表达表明该细胞因子作为SSc中成纤维细胞活化的介质。此外，认识到TGFβ能够在各种细胞类型中诱导其自身表达，并证明SSc真皮成纤维细胞的亚群产生TGFβ，这表明存在可能的自分泌环，淋巴细胞衍生的TGFβ在早期SSc中，不仅以旁分泌方式发出信号，表明成纤维细胞的生物合成活化，而且通过目标成纤维细胞本身自动诱导内源性TGFβ的产生。这种涉及TGFβ的自分泌环可能解释了SSc成纤维细胞中胶原基因表达的持续激活，并且可能是SSc中纤维化的进行性原因。许多其他细胞因子以及细胞与基质之间的相互作用也改变了胶原蛋白基因的表达，并且可以显着影响TGFβ的作用。尽管尚未确定其在组织重塑中的生理功能或参与异常纤维发生，但对这些细胞因子的生物学作用的研究可能为理解SSc的发病机理以及开发针对性的药物疗法提供重要线索。中断这种疾病的异常纤维化过程。

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