Demirci G, Nashan B, Pichlmayr R
Klinik für Abdominal- und Transplantationschirurgie, Medizinische Hochschule Hannover, Germany.
Transplantation. 1996 Dec 27;62(12):1776-83. doi: 10.1097/00007890-199612270-00016.
Activation and transformation of lipocytes (Ito cells, stellate cells) into alpha-actin-positive myofibroblast-like cells is an essential step in the initiation of liver fibrosis. Transforming growth factor-beta (TGF-beta) is considered an important mediator of this process. In order to determine mechanisms of fibrotic deposition in a hepatic transplant setting, we analyzed 10 chronically rejected human liver allografts for the expression of extracellular matrix (ECM) molecules, myofibroblast-like cells (alpha-actin), macrophages, and TGF-beta1 and -beta3. Using single- and double-immunohistochemical staining techniques, all specimens investigated showed increased deposition of the ECM proteins fibronectin, tenascin, undulin, and collagen VI with a characteristic densification especially in pericentral areas. Likewise, strong accumulation of alpha-actin-positive cells and TGF-beta1-expressing macrophages was observed in the same fields, supporting the concept of lipocyte activation/transformation and subsequent ECM production fostered by macrophage-derived TGF-beta1. In contrast, TGF-beta3 was found to be mainly expressed by a markedly increased number of lipocytes. Interestingly, distribution of TGF-beta3 corresponded to that of tenascin, an ECM molecule known to be involved in early matrix organization, suggesting that TGF-beta3 may likewise act mainly in early stages of fibrogenesis. Furthermore, TGF-beta3 restriction to high numbers of a single cell type (i.e., lipocytes) implied a possible role in cell proliferation through autocrine loops. In conclusion, fibrosis in chronic rejection seems to follow similar mechanisms as in non-transplanted livers but additionally suggests differential temporal and functional roles for the TGF-beta isoforms 1 and 3 in the course of a multistep process leading to lipocyte transformation and ECM production.
脂肪细胞（伊托细胞、星状细胞）激活并转化为α-肌动蛋白阳性的肌成纤维细胞样细胞是肝纤维化起始过程中的关键步骤。转化生长因子-β（TGF-β）被认为是这一过程的重要介质。为了确定肝移植环境中纤维化沉积的机制，我们分析了10例慢性排斥反应的人肝同种异体移植，检测细胞外基质（ECM）分子、肌成纤维细胞样细胞（α-肌动蛋白）、巨噬细胞以及TGF-β1和-β3的表达情况。使用单免疫组化和双免疫组化染色技术，所有研究标本均显示ECM蛋白纤连蛋白、腱生蛋白、波形蛋白和胶原蛋白VI的沉积增加，尤其是在中央静脉周围区域出现特征性致密化。同样，在相同区域观察到α-肌动蛋白阳性细胞和表达TGF-β1的巨噬细胞大量积聚，支持了脂肪细胞激活/转化以及随后由巨噬细胞衍生的TGF-β1促进ECM产生的概念。相比之下，发现TGF-β3主要由明显增多的脂肪细胞表达。有趣的是，TGF-β3的分布与腱生蛋白一致，腱生蛋白是一种已知参与早期基质组织的ECM分子，这表明TGF-β3可能同样主要在纤维化形成的早期阶段起作用。此外，TGF-β3局限于大量单一细胞类型（即脂肪细胞）意味着它可能通过自分泌环在细胞增殖中发挥作用。总之，慢性排斥反应中的纤维化似乎遵循与非移植肝脏相似的机制，但另外表明TGF-β亚型1和3在导致脂肪细胞转化和ECM产生的多步骤过程中具有不同的时间和功能作用。
