Translating an understanding of the pathogenesis of hepatic fibrosis to novel therapies.
Translating an understanding of the pathogenesis of hepatic fibrosis to novel therapies.
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DOI：
10.1016/j.cgh.2013.01.005
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发表时间：
2013-03
影响因子：
12.6
通讯作者：
Rockey, Don C.
中科院分区：
文献类型：
--
作者：
Rockey, Don C.
对损伤的反应是伤口愈合和纤维化，最终导致纤维化。对损伤的纤维化反应是几乎所有器官系统的普遍反应。在肝脏，损伤反应通常发生在较长的一段时间内，导致肝硬化(尽管需要指出的是，并不是所有的肝损伤患者都会发展为肝硬化)。许多不同的疾病会导致肝硬变，这一事实暗示了一种共同的发病机制。在过去的20年里，肝纤维化的研究非常活跃，导致人们对这一过程有了相当大的了解。已有研究表明，肝星状细胞是肝纤维化过程中的中心成分。人们还认识到，其他“效应”细胞在纤维化形成过程中也很重要，包括常驻成纤维细胞、骨髓源性细胞、纤维细胞，甚至可能是来源于上皮细胞的细胞(即通过上皮向间充质转化或EMT)。纤维化生物学的一个关键方面是纤维化过程是动态的；因此，即使是晚期纤维化(或肝硬变)也是可逆的。总之，对肝纤维化形成的细胞学基础的了解，以及肝纤维化基本发病机制的多个方面，突出了许多令人兴奋的潜在治疗机会。因此，虽然最有效的“抗纤维化”疗法是对潜在疾病的治疗，但在不可能的情况下，特定的抗纤维化疗法不仅可能变得可行，而且很快就会成为现实。这篇综述的目的是强调可能被转化为未来抗纤维化治疗的纤维化形成的潜在机制，并回顾临床发展的现状。
The response to injury is one of wound healing and fibrogenesis, which ultimately leads to fibrosis. The fibrogenic response to injury is a generalized one across virtually all organ systems. In the liver, the injury response, typically occuring over a prolonged period of time, leads to cirrhosis (although it should be pointed out that not all patients with liver injury develop cirrhosis). The fact that many different diseases result in cirrhosis suggests a common pathogenesis. The study of hepatic fibrogenesis over the past 2 decades has been remarkably active, leading to a considerable understanding of this process. It has been clearly demonstrated that the hepatic stellate cell is a central component in the fibrogenic process. It has also been recognized that other “effector” cells are important in the fibrogenic process, including resident fibroblasts, bone marrow derived cells, fibrocytes, and even perhaps cells derived from epithelial cells (i.e., through epithelial to mesenchymal transition or EMT). A key aspect of the biology of fibrogenesis is that the fibrogenic process is dynamic; thus, even advanced fibrosis (or cirrhosis) is reversible. Together, an understanding of the cellular basis for liver fibrogenesis, along with multiple aspects of the basic pathogenesis of fibrosis, have highlighted many exciting potential therapeutic opportunities. Thus, while the most effective “anti-fibrotic” therapy is treatment of the underlying disease, in situations in which this not possible, specific anti-fibrotic therapy is likely to not only become feasible, but will soon become a reality. The goal of this review is to highlight the mechanisms underlying fibrogenesis that may be translated into future anti-fibrotic therapies and to review the current state of clinical development.
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