Kojima-Yuasa Akiko, Ohkita Tomoko, Yukami Kumiko, Ichikawa Hiroko, Takami Noriko, Nakatani Teruyo, Opare Kennedy David, Nishiguchi Shuhei, Matsui-Yuasa Isao
Department of Food and Human Health Sciences, Graduate School of Human Life Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan.
Chem Biol Interact. 2003 Jul 25;146(1):89-99. doi: 10.1016/s0009-2797(03)00087-5.
Hepatic stellate cells (HSC) play an important role in the development of liver cirrhosis. They are a major source of extracellular matrix and during fibrogenesis undergo an activation process characterized by increased proliferation and collagen synthesis. In this study, we investigated the anti-fibrogenic effect of zinc supplementation on zinc deficiency induced HSC activation. Isolated HSC were incubated with or without zinc chelator, diethylenetriamine penta-acetic acid (DTPA). Type I collagen expression in HSC was detected by immunohistochemistry. The involvement of glutathione (GSH) homeostasis in the anti-fibrogenic action of zinc was also investigated, as GSH is implicated in many cellular events, such as regulation of cell proliferation, remodeling of extracellular matrix and oxidative stress. Intracellular GSH was measured by HPLC. Enhanced type I collagen expression, apoptosis and cell cycle arrest were found in HSC when DTPA was added, but they were inhibited with supplementation with zinc. Zinc deficiency caused a reduction in intracellular GSH 8 h after the addition of DTPA compared with control levels. The results of this study show that in HSC, the chelation of zinc triggers a progression of collagen synthesis and this involves the depletion of intracellular GSH levels after the addition of DTPA.
肝星状细胞（HSC）在肝硬化的发展过程中起重要作用。它们是细胞外基质的主要来源，在纤维化形成过程中经历一个以增殖增加和胶原蛋白合成增加为特征的激活过程。在本研究中，我们调查了补充锌对锌缺乏诱导的HSC激活的抗纤维化作用。将分离的HSC与或不与锌螯合剂二乙三胺五乙酸（DTPA）一起孵育。通过免疫组织化学检测HSC中I型胶原蛋白的表达。还研究了谷胱甘肽（GSH）稳态在锌的抗纤维化作用中的参与情况，因为GSH参与许多细胞事件，如细胞增殖调节、细胞外基质重塑和氧化应激。通过高效液相色谱法测量细胞内GSH。添加DTPA时，HSC中I型胶原蛋白表达增强、细胞凋亡和细胞周期停滞，但补充锌可抑制这些现象。与对照水平相比，添加DTPA 8小时后，锌缺乏导致细胞内GSH减少。本研究结果表明，在HSC中，锌螯合会触发胶原蛋白合成的进展，这涉及添加DTPA后细胞内GSH水平的消耗。
