Gressner A M, Bachem M G
Department of Clinical Chemistry, Philipps University, Marburg, Germany.
Digestion. 1995;56(5):335-46. doi: 10.1159/000201257.
During the last few years, considerable progress has been made in the dissection of cellular and molecular mechanisms of hepatic fibrogenesis. The disease, initiated by hepatocellular damage and perpetuated by inflammatory reactions, results not only in an overall increase in extracellular matrix (ECM) but also in molecular and histological rearrangement of virtually all matrix molecules including collagens, structural glycoproteins, proteoglycans and hyaluronan. These alterations of ECM cause severe clinical (e.g. hemodynamic) complications and further metabolic changes in the whole organ. Perisinusoidal fat (retinoid)-storing cells have been identified as the (precursor) cell type mainly responsible for matrix production in the diseased liver. However, these cells have to be activated, i.e. stimulated to proliferate, to transform phenotypically to myofibroblasts and to express matrix genes before full competency for fibrogenesis is reached. Multiple cell interactions with Kupffer cells, platelets, endothelial cells and hepatocytes mediated by various cytokines and growth factors (e.g. TGF-beta 1, TGF-alpha, PDGF, FGF, IGF-1) are involved in the mechanism of fat-storing cell activation which is the common and central pathogenetic mechanism in fibrogenesis. A three-step cascade model of fat-storing cell activation is proposed, which offers target mechanisms for possible anti-fibrotic interventions.
在过去几年中，肝纤维化发生的细胞和分子机制剖析方面取得了显著进展。该疾病由肝细胞损伤引发，并因炎症反应持续存在，不仅导致细胞外基质（ECM）总量增加，还导致几乎所有基质分子（包括胶原蛋白、结构糖蛋白、蛋白聚糖和透明质酸）发生分子和组织学重排。ECM的这些改变会引发严重的临床（如血液动力学）并发症，并导致整个器官进一步发生代谢变化。肝窦周脂肪（类视黄醇）储存细胞已被确定为患病肝脏中主要负责基质产生的（前体）细胞类型。然而，这些细胞必须被激活，即被刺激增殖，发生表型转变为肌成纤维细胞，并在达到完全的纤维化能力之前表达基质基因。由多种细胞因子和生长因子（如转化生长因子-β1、转化生长因子-α、血小板衍生生长因子、成纤维细胞生长因子、胰岛素样生长因子-1）介导的储存细胞与库普弗细胞、血小板、内皮细胞和肝细胞之间的多种细胞相互作用参与了储存细胞激活机制，这是纤维化发生中常见且核心的发病机制。本文提出了一个储存细胞激活的三步级联模型，该模型为可能的抗纤维化干预提供了靶点机制。
