Toda Kyoko, Kumagai Naoki, Kaneko Fumihiko, Tsunematsu Satoshi, Tsuchimoto Kanji, Saito Hidetsugu, Hibi Toshifumi
Division of Basic Research, Bio Medical Laboratory, Kitasato University, Tokyo, Japan.
J Gastroenterol Hepatol. 2009 May;24(5):860-5. doi: 10.1111/j.1440-1746.2008.05749.x. Epub 2009 Feb 12.
BACKGROUND/AIM: Pig serum-induced rat liver fibrosis is a model of liver fibrosis in the absence of obvious hepatocyte injury. Penoxifylline (PTX), a xanthine derivative, which is a well-known suppressor of tumor necrosis factor-alpha (TNF-alpha) production from inflammatory cells, has also been shown to inhibit the growth of hepatic stellate cells and to inhibit collagen synthesis in these cells in vitro. We investigated the effect of PTX on pig serum-induced liver fibrosis in vivo, and assessed the mechanisms of prevention of fibrogenesis by this drug.
Male Wistar rats were given intraperitoneal injections of 0.5 ml normal pig serum twice a week for 10 weeks with or without concomitant oral administration of PTX (20 mg/kg).
Rats that received pig serum showed significant liver fibrosis, and their serum interleukin-6 (IL-6) and hyaluronic acid levels were significantly increased. The serum levels of IL-6 were well correlated with the serum levels of hyaluronic acid, and increased as the liver fibrosis progressed. Penoxifylline prevented the development of fibrosis in this animal model and reduced the serum levels of IL-6 in a dose-dependent manner. In vitro, by the addition of PTX to the culture medium of the rat hepatic stellate cells (HSCs), the proliferation of the HSCs was significantly inhibited and IL-6 in the culture supernatant was also reduced significantly. Exogenous addition of IL-6 partially restored the proliferation.
Penoxifylline prevents pig serum-induced rat liver fibrosis by inhibiting the proliferation of HSCs and by inhibiting the production of IL-6 from HSCs.
背景/目的：猪血清诱导的大鼠肝纤维化是一种无明显肝细胞损伤的肝纤维化模型。己酮可可碱（PTX）是一种黄嘌呤衍生物，是炎症细胞肿瘤坏死因子-α（TNF-α）产生的著名抑制剂，体外实验还表明它能抑制肝星状细胞的生长并抑制这些细胞中的胶原合成。我们研究了PTX对猪血清诱导的体内肝纤维化的影响，并评估了该药预防纤维化形成的机制。
雄性Wistar大鼠每周两次腹腔注射0.5 ml正常猪血清，持续10周，同时或不同时口服PTX（20 mg/kg）。
接受猪血清的大鼠出现明显的肝纤维化，其血清白细胞介素-6（IL-6）和透明质酸水平显著升高。IL-6的血清水平与透明质酸的血清水平密切相关，并随着肝纤维化的进展而升高。己酮可可碱可预防该动物模型中的纤维化发展，并以剂量依赖的方式降低血清IL-6水平。在体外，向大鼠肝星状细胞（HSCs）的培养基中添加PTX，可显著抑制HSCs的增殖，培养上清液中的IL-6也显著降低。外源性添加IL-6可部分恢复增殖。
己酮可可碱通过抑制HSCs的增殖和抑制HSCs产生IL-6来预防猪血清诱导的大鼠肝纤维化。
