Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities.
Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities.
复制标题
DOI：
10.1038/nrrheum.2011.149
复制
发表时间：
2011-10-25
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
多个器官的纤维化是系统性硬化症（SSc）的一个突出的病理表现和区别标志。过去 5 年的研究结果有助于更全面地了解 SSc 纤维化的复杂细胞和分子基础。成纤维细胞是主要的效应细胞，在促纤维化细胞环境中被细胞因子和生长因子、发育途径、内皮素 1 和凝血酶激活。通过 Toll 样受体的先天免疫信号、通过整合素的基质产生的生物力学应激信号、缺氧和氧化应激似乎与这一过程的持续存在有关。除了慢性成纤维细胞活化之外，纤维化还代表着组织修复失败，以及源自骨髓的间充质细胞群体的扩大以及上皮细胞、内皮细胞和周细胞的转分化。此外，研究还发现了 SSc 成纤维细胞因表观遗传变化而发生的内在改变，以及 microRNA 表达的改变，这些改变可能是这些细胞的细胞自主、持续激活表型的基础。精确表征导致 SSc 纤维化的失调的细胞外和细胞内信号通路、介质和细胞分化程序将有助于开发选择性、有针对性的治疗策略。有效的抗纤维化治疗最终将涉及新的化合物以及已批准用于其他适应症的药物的重新利用。
Fibrosis in multiple organs is a prominent pathological finding and distinguishing hallmark of systemic sclerosis (SSc). Findings during the past 5 years have contributed to a more complete understanding of the complex cellular and molecular underpinning of fibrosis in SSc. Fibroblasts, the principal effector cells, are activated in the profibrotic cellular milieu by cytokines and growth factors, developmental pathways, endothelin 1 and thrombin. Innate immune signaling via Toll-like receptors, matrix-generated biomechanical stress signaling via integrins, hypoxia and oxidative stress seem to be implicated in perpetuating the process. Beyond chronic fibroblast activation, fibrosis represents a failure to terminate tissue repair, coupled with an expanded population of mesenchymal cells originating from bone marrow and transdifferentiation of epithelial cells, endothelial cells and pericytes. In addition, studies have identified intrinsic alterations in SSc fibroblasts resulting from epigenetic changes, as well as altered microRNA expression that might underlie the cell-autonomous, persistent activation phenotype of these cells. Precise characterization of the deregulated extracellular and intracellular signaling pathways, mediators and cellular differentiation programs that contribute to fibrosis in SSc will facilitate the development of selective, targeted therapeutic strategies. Effective antifibrotic therapy will ultimately involve novel compounds and repurposing of drugs that are already approved for other indications.
登录
查看更多内容
影响因子：
4.9
作者：
Agarwal SK;Wu M;Livingston CK;Parks DH;Mayes MD;Arnett FC;Tan FK
通讯作者：
Tan FK
影响因子：
15.9
作者：
Asano, Y;Ihn, H;Tamaki, K
通讯作者：
Tamaki, K
影响因子：
--
作者：
Chen, Yunliang;Leask, Andrew;Eastwood, Mark
通讯作者：
Eastwood, Mark
影响因子：
6
作者：
Bhattacharyya, Swati;Chen, Shu-Jen;Varga, John
通讯作者：
Varga, John
在硬皮病小鼠模型中通过基因缺失或溶血磷脂酸受体 1 的药理学拮抗作用改善真皮纤维化。
影响因子：
--
作者：
Castelino, Flavia V.;Seiders, Jon;Bain, Gretchen;Brooks, Sarah F.;King, Christopher D.;Swaney, James S.;Lorrain, Daniel S.;Chun, Jerold;Luster, Andrew D.;Tager, Andrew M.
通讯作者：
Tager, Andrew M.