Okimoto Sho, Kuroda Shintaro, Tashiro Hirotaka, Kobayashi Tsuyoshi, Taogoshi Takanori, Matsuo Hiroaki, Ohdan Hideki
Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Department of Surgery, National Hospital Organization Kure Medical Center, Hiroshima, Japan.
Hepatol Res. 2019 Jun;49(6):663-675. doi: 10.1111/hepr.13317. Epub 2019 Feb 15.
Rho-kinase (ROCK) inhibitor could ameliorate liver fibrosis by suppressing hepatic stellate cell (HSC) activation. However, because systemic administration of ROCK inhibitor causes serious adverse effects, we developed a drug delivery system selectively delivering ROCK inhibitor to HSCs. Here, we examined whether our developed vitamin A (VA)-coupled liposomal ROCK inhibitor reduced liver fibrosis in rats without causing systemic adverse effects.
LX-2 HSCs were analyzed for morphological changes and the expression of profibrotic proteins. The inhibitory effects of VA-coupled liposomal ROCK inhibitor on liver fibrosis were confirmed in a rat model of liver fibrosis induced by i.p. injection of carbon tetrachloride. The degree of liver fibrosis, biochemical changes, and survival rates were also investigated.
Vitamin A-coupled liposomal ROCK inhibitor had an effect at approximately 1/100 the amount of the free ROCK inhibitor for inhibiting the activation of LX-2 cells and caused significant decreases in the expression levels of α-smooth muscle actin (SMA) and transforming growth factor (TGF)-β1. The degree of liver fibrosis was suppressed by treatment with VA-coupled liposomal ROCK inhibitor, and the expression of α-SMA and TGF-β1 in liver tissues was also significantly suppressed. In addition, serum levels of alanine aminotransferase and hyaluronic acid were significantly reduced, and there was no decline in kidney function, which has been noted as a systemic adverse effect of ROCK inhibitor. Furthermore, VA-coupled liposomal ROCK inhibitor improved survival rates in rats with liver fibrosis.
Vitamin A-coupled liposomal ROCK inhibitor efficiently suppressed liver fibrosis without causing systemic adverse effects.
Rho激酶（ROCK）抑制剂可通过抑制肝星状细胞（HSC）激活来改善肝纤维化。然而，由于全身性给予ROCK抑制剂会引起严重的不良反应，我们开发了一种将ROCK抑制剂选择性递送至肝星状细胞的药物递送系统。在此，我们研究了我们开发的维生素A（VA）偶联脂质体ROCK抑制剂是否能在不引起全身性不良反应的情况下减轻大鼠肝纤维化。
分析LX-2肝星状细胞的形态变化和促纤维化蛋白的表达。通过腹腔注射四氯化碳诱导大鼠肝纤维化模型，证实VA偶联脂质体ROCK抑制剂对肝纤维化的抑制作用。还研究了肝纤维化程度、生化变化和存活率。
维生素A偶联脂质体ROCK抑制剂在抑制LX-2细胞激活方面的效果约为游离ROCK抑制剂的1/100，并且显著降低了α-平滑肌肌动蛋白（SMA）和转化生长因子（TGF）-β1的表达水平。VA偶联脂质体ROCK抑制剂治疗可抑制肝纤维化程度，肝组织中α-SMA和TGF-β1的表达也显著受到抑制。此外，血清丙氨酸转氨酶和透明质酸水平显著降低，且肾功能未下降，而肾功能下降曾被视为ROCK抑制剂的全身性不良反应。此外，VA偶联脂质体ROCK抑制剂提高了肝纤维化大鼠的存活率。
维生素A偶联脂质体ROCK抑制剂能有效抑制肝纤维化，且不引起全身性不良反应。
