Human Fibrotic Diseases: Current Challenges in Fibrosis Research
Human Fibrotic Diseases: Current Challenges in Fibrosis Research
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DOI：
10.1007/978-1-4939-7113-8_1
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发表时间：
2017-01-01
期刊：
影响因子：
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通讯作者：
Jimenez, Sergio A.
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文献类型：
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作者：
Rosenbloom, Joel;Macarak, Edward;Jimenez, Sergio A.
人类纤维化疾病构成了世界范围内的主要健康问题，这是由于大量受影响的个体、对纤维化过程发病机制的不完全了解、其病因学和临床表现的显著异质性、缺乏适当和充分验证的生物标志物，以及最重要的是，目前缺乏有效的疾病修饰治疗剂。纤维化病症涵盖广泛的临床实体，包括系统性纤维化疾病，如系统性硬化症（SSc）、硬皮病移植物抗宿主病和肾源性系统性纤维化，以及许多器官特异性病症，包括辐射诱导的纤维化和心脏、肺、肝和肾纤维化。虽然它们的致病机制是相当不同的，在一些情况下仍然难以捉摸，这些疾病的共同特征是纤维化组织在受影响的器官中不受控制和进行性积累，导致其功能障碍和最终失败。尽管纤维化疾病的发病机制及其临床表现存在显著的异质性，但许多研究已将活化的肌成纤维细胞确定为最终导致正常组织被非功能性纤维化组织替代的常见细胞成分。主要由转化生长因子-β（TGF-β）启动的关键信号级联，但也涉及刺激肌成纤维细胞中促纤维化反应的许多细胞因子和信号分子，提供了潜在的治疗靶点。在这里，我们简要地回顾了目前的知识，参与组织纤维化的发展的分子机制，并指出一些最重要的挑战，在纤维化疾病的研究和有效的治疗方法，这往往是致命的疾病组的发展。应鼓励进一步阐明纤维化过程的复杂发病机制，以实现为这些严重、无法治疗且往往致命的疾病开发有效疗法的难以捉摸的目标。
Human fibrotic diseases constitute a major health problem worldwide owing to the large number of affected individuals, the incomplete knowledge of the fibrotic process pathogenesis, the marked heterogeneity in their etiology and clinical manifestations, the absence of appropriate and fully validated biomarkers, and, most importantly, the current void of effective disease-modifying therapeutic agents. The fibrotic disorders encompass a wide spectrum of clinical entities including systemic fibrotic diseases such as systemic sclerosis (SSc), sclerodermatous graft vs. host disease, and nephrogenic systemic fibrosis, as well as numerous organ-specific disorders including radiation-induced fibrosis and cardiac, pulmonary, liver, and kidney fibrosis. Although their causative mechanisms are quite diverse and in several instances have remained elusive, these diseases share the common feature of an uncontrolled and progressive accumulation of fibrotic tissue in affected organs causing their dysfunction and ultimate failure. Despite the remarkable heterogeneity in the etiologic mechanisms responsible for the development of fibrotic diseases and in their clinical manifestations, numerous studies have identified activated myofibroblasts as the common cellular element ultimately responsible for the replacement of normal tissues with nonfunctional fibrotic tissue. Critical signaling cascades, initiated primarily by transforming growth factor-beta (TGF-beta), but also involving numerous cytokines and signaling molecules which stimulate profibrotic reactions in myofibroblasts, offer potential therapeutic targets. Here, we briefly review the current knowledge of the molecular mechanisms involved in the development of tissue fibrosis and point out some of the most important challenges to research in the fibrotic diseases and to the development of effective therapeutic approaches for this often fatal group of disorders. Efforts to further clarify the complex pathogenetic mechanisms of the fibrotic process should be encouraged to attain the elusive goal of developing effective therapies for these serious, untreatable, and often fatal disorders.