Schuppan D, Atkinson J, Ruehl M, Riecken E O
Klinikum Benjamin Franklin, Abteilung für Gastroenterologie und Hepatologie, Freie Universität, Berlin, Germany.
Z Gastroenterol. 1995 Sep;33(9):546-50.
In Western societies roughly 50% of all cases of liver cirrhosis are related to alcohol abuse. The oxidative metabolite of ethanol, acetaldehyde, often in conjunction with viral or metabolic liver disease, is implicated as the major cause for liver fibrogenesis. Acetaldehyde damages cell membranes, initiates lipid peroxidation and forms noxious protein adducts, resulting in the activation of Kupffer cells and perisinusoidal lipocytes/portal fibroblasts. The activation of lipocytes and fibroblasts to a proliferative and collagen-producing myofibroblast-like phenotype is triggered by the release of fibrogenic factors such as platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) from the activated Kupffer cells. Due to the socioeconomic burden inflicted by cirrhosis, antifibrotic treatment is urgently needed. Strategies to prevent or reverse cirrhosis must interrupt the continuous process of pathological wound healing in the liver. An antifibrotic effect has been demonstrated for the interferons, prostaglandins E and relaxin. Polyunsaturated lecithin, silymarin and ursodeoxycholic acid, agents with a high hepatotropism and a good safety-profile, appear to have antifibrotic properties. Targeted approaches include the specific removal of matrix-bound fibrogenic growth factors and the induction of stress-relaxation of the activated mesenchymal cells by biologically active matrix-peptides and their stable analogues. Since serum tests for the non-invasive assessment of collagen synthesis and degradation in the liver are now available, rapid progress in the development and clinical application of antifibrotic drugs can be anticipated.
在西方社会，大约50%的肝硬化病例与酒精滥用有关。乙醇的氧化代谢产物乙醛，通常与病毒性或代谢性肝病共同作用，被认为是肝纤维化形成的主要原因。乙醛会损害细胞膜，引发脂质过氧化并形成有害的蛋白质加合物，从而导致库普弗细胞和肝血窦周脂肪细胞/门周成纤维细胞的激活。脂肪细胞和成纤维细胞向增殖性和产生胶原蛋白的肌成纤维细胞样表型的转变是由激活的库普弗细胞释放的促纤维化因子如血小板衍生生长因子（PDGF）和转化生长因子-β（TGF-β）触发的。由于肝硬化带来的社会经济负担，迫切需要抗纤维化治疗。预防或逆转肝硬化的策略必须中断肝脏中病理性伤口愈合的持续过程。干扰素、前列腺素E和松弛素已被证明具有抗纤维化作用。多不饱和卵磷脂、水飞蓟宾和熊去氧胆酸等对肝脏具有高度亲和性且安全性良好的药物似乎具有抗纤维化特性。靶向方法包括特异性去除与基质结合的促纤维化生长因子，以及通过生物活性基质肽及其稳定类似物诱导激活的间充质细胞产生应力松弛。由于现在已有用于肝脏胶原合成和降解无创评估的血清检测方法，预计抗纤维化药物的研发和临床应用将取得快速进展。
