Kondou Hiroki, Mushiake Sotaro, Etani Yuri, Miyoshi Yoko, Michigami Toshimi, Ozono Keiichi
Department of Developmental Medicine (Pediatrics), D-5, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City, Osaka 565-0871, Japan.
J Hepatol. 2003 Nov;39(5):742-8. doi: 10.1016/s0168-8278(03)00377-5.
BACKGROUND/AIMS: Thrombospondin-1 is a major activator of transforming growth factor-beta1 (TGF-beta1), and a peptide derived from the latency-associated peptide, Leu-Ser-Lys-Leu (LSKL), inhibits the activation of TGF-beta1. In this study, the effects of LSKL on the hepatocyte damage and fibrogenesis in dimethylnitrosamine (DMN)-induced rat liver fibrosis were examined.
Animals were given an intraperitoneal (i.p.) injection of DMN or saline three times per week for 4 weeks, and treated with LSKL, a control peptide, or saline i.p. daily.
Liver atrophy caused by DMN-injection was significantly inhibited in the DMN+LSKL group. The degrees of necrosis/degeneration and fibrosis scores were significantly lower in the DMN+LSKL group than in the control groups. The hydroxyproline content was significantly higher in the control groups than in the DMN+LSKL group. The amount of active TGF-beta1 was less in the DMN+LSKL group than in the control groups, and the active/total TGF-beta1 ratio in the DMN+LSKL group was suppressed in the control groups. Phosphorylation of Smad 2 in the liver was significantly decreased in the DMN+LSKL group.
The LSKL peptide prevented the progression of hepatic damage and fibrosis through the inhibition of TGF-beta1 activation and its signal transduction in vivo.
背景/目的：血小板反应蛋白-1是转化生长因子-β1（TGF-β1）的主要激活剂，一种源自潜伏相关肽的肽Leu-Ser-Lys-Leu（LSKL）可抑制TGF-β1的激活。在本研究中，检测了LSKL对二甲基亚硝胺（DMN）诱导的大鼠肝纤维化中肝细胞损伤和纤维化形成的影响。
动物每周腹腔注射（i.p.）DMN或生理盐水3次，共4周，并每天腹腔注射LSKL、对照肽或生理盐水。
DMN+LSKL组中由DMN注射引起的肝萎缩得到显著抑制。DMN+LSKL组的坏死/变性程度和纤维化评分显著低于对照组。对照组的羟脯氨酸含量显著高于DMN+LSKL组。DMN+LSKL组中活性TGF-β1的量少于对照组，且DMN+LSKL组的活性/总TGF-β1比值低于对照组。DMN+LSKL组肝脏中Smad 2的磷酸化显著降低。
LSKL肽通过在体内抑制TGF-β1激活及其信号转导，阻止了肝损伤和纤维化的进展。
