Miyaoka Yuta, Jin Denan, Tashiro Keitaro, Komeda Koji, Masubuchi Shinsuke, Hirokawa Fumitoshi, Hayashi Michihiro, Takai Shinji, Uchiyama Kazuhisa
Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki 569-8686, Japan.
Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical College, Takatsuki 569-8686, Japan.
J Pharmacol Sci. 2017 Jul;134(3):139-146. doi: 10.1016/j.jphs.2017.04.005. Epub 2017 Jun 20.
The effect of the chymase inhibitor TY-51469 on the development and progression of non-alcoholic steatohepatitis (NASH) was evaluated in rats fed a high-fat and high-cholesterol (HFC) diet. To evaluate the preventive effect of TY-51469 on the development of NASH, stroke-prone spontaneously hypertensive rat 5 (SHRSP5)/Dmcr rats were fed either a normal or HFC diet for 8 weeks, and concurrently administered either placebo or TY-51469 (1 mg/kg per day). To evaluate the effect of TY-51469 on the survival rate, TY-51469 was administered either concurrently with HFC diet (pretreated group) or 8 weeks after HFC diet at which point NASH had developed (posttreated group). Eight weeks after HFC diet, significant increases of steatosis, fibrosis and chymase-positive cells were observed in liver from the placebo-treated rats. Significant increases of myeloperoxidase, transforming growth factor-β, matrix metalloproteinase-9, and collagen I mRNA levels were also observed. However, all parameters were significantly attenuated in the TY-51469-treated group. A survival rate of the placebo-treated group fed the HFC diet was 0% at 14 weeks. In comparison, the rates of TY-51469-pretreated and TY-51469-posttreated groups were 100% and 50% at 14 weeks, respectively. Chymase inhibitor may be applicable to preventing the development and progression of NASH.
在喂食高脂高胆固醇（HFC）饮食的大鼠中评估了糜酶抑制剂TY - 51469对非酒精性脂肪性肝炎（NASH）发生和发展的影响。为了评估TY - 51469对NASH发生的预防作用，将易中风自发性高血压大鼠5（SHRSP5）/Dmcr大鼠喂食正常或HFC饮食8周，并同时给予安慰剂或TY - 51469（每天1毫克/千克）。为了评估TY - 51469对存活率的影响，在给予HFC饮食的同时给予TY - 51469（预处理组）或在HFC饮食8周后NASH已经发生时给予TY - 51469（后处理组）。在给予HFC饮食8周后，观察到安慰剂处理大鼠肝脏中的脂肪变性、纤维化和糜酶阳性细胞显著增加。还观察到髓过氧化物酶、转化生长因子-β、基质金属蛋白酶-9和I型胶原mRNA水平显著增加。然而，在TY - 51469处理组中所有参数均显著减轻。喂食HFC饮食的安慰剂处理组在14周时的存活率为0%。相比之下，TY - 51469预处理组和TY - 51469后处理组在14周时的存活率分别为100%和50%。糜酶抑制剂可能适用于预防NASH的发生和发展。
