Ruehl Martin, Erben Ulrike, Kim Kiyoung, Freise Christian, Dagdelen Tarkan, Eisele Silke, Trowitzsch-Kienast Wolfram, Zeitz Martin, Jia Jidong, Stickel Felix, Somasundaram Rajan
Department of Gastroenterology, Charité - Campus Benjamin Franklin, 12200 Berlin, Germany.
J Nutr Biochem. 2009 Aug;20(8):597-606. doi: 10.1016/j.jnutbio.2008.06.003. Epub 2008 Sep 27.
Liver fibrosis is characterized by high expression of the key profibrogenic cytokine transforming growth factor (TGF)-beta and the natural tissue inhibitor of metalloproteinases (TIMP)-1, leading to substantial accumulation of extracellular matrix. Liver fibrosis originates from various chronic liver diseases, such as chronic viral hepatitis that, to date, cannot be treated sufficiently. Thus, novel therapeutics, for example, those derived from Oriental medicine, have gained growing attention. In Korea, extracts prepared from Lindera obtusiloba are used for centuries for treatment of inflammation, improvement of blood circulation and prevention of liver damage, but experimental evidence of their efficacy is lacking. We studied direct antifibrotic effects in activated hepatic stellate cells (HSCs), the main target cell in the fibrotic liver. L. obtusiloba extract (135 mug/ml) reduced the de novo DNA synthesis of activated rat and human HSCs by about 90%, which was not accompanied by cytotoxicity of HSC, primary hepatocytes and HepG2 cells, pointing to induction of cellular quiescence. As determined by quantitative polymerase chain reaction, simultaneous treatment of HSCs with TGF-beta and L. obtusiloba extract resulted in reduction of TIMP-1 expression to baseline level, disruption of the autocrine loop of TGF-beta autoinduction and increased expression of fibrolytic matrix metalloproteinase (MMP)-3. In addition, L. obtusiloba reduced gelatinolytic activity of HSC by interfering with profibrogenic MMP-2 activity. Since L. obtusiloba extract prevented intracellular oxidative stress experimentally induced by tert-butylhydroperoxide, we concluded that the direct antifibrotic effect of L. obtusiloba extract might be mediated by antioxidant activity. Thus, L. obtusiloba, traditionally used in Oriental medicine, may complement treatment of chronic liver disease.
肝纤维化的特征是关键的促纤维化细胞因子转化生长因子（TGF）-β和金属蛋白酶天然组织抑制剂（TIMP）-1的高表达，导致细胞外基质大量积聚。肝纤维化源于各种慢性肝病，如慢性病毒性肝炎，迄今为止，这些疾病仍无法得到充分治疗。因此，新型疗法，例如源自东方医学的疗法，越来越受到关注。在韩国，钝叶山胡椒提取物几个世纪以来一直用于治疗炎症、改善血液循环和预防肝损伤，但缺乏其疗效的实验证据。我们研究了钝叶山胡椒提取物对肝星状细胞（HSCs）的直接抗纤维化作用，肝星状细胞是纤维化肝脏中的主要靶细胞。钝叶山胡椒提取物（135微克/毫升）使活化的大鼠和人肝星状细胞的从头DNA合成减少了约90%，且这并未伴随肝星状细胞、原代肝细胞和HepG2细胞的细胞毒性，表明其诱导了细胞静止。通过定量聚合酶链反应测定，用TGF-β和钝叶山胡椒提取物同时处理肝星状细胞，导致TIMP-1表达降低至基线水平，破坏了TGF-β自诱导的自分泌环，并增加了纤溶基质金属蛋白酶（MMP）-3的表达。此外，钝叶山胡椒提取物通过干扰促纤维化的MMP-2活性降低了肝星状细胞的明胶分解活性。由于钝叶山胡椒提取物在实验中可预防叔丁基过氧化氢诱导的细胞内氧化应激，我们得出结论，钝叶山胡椒提取物的直接抗纤维化作用可能是由抗氧化活性介导的。因此，传统上用于东方医学的钝叶山胡椒可能对慢性肝病的治疗起到补充作用。
