Shirahane Kengo, Yamaguchi Koji, Koga Kenichiro, Watanabe Masato, Kuroki Syoji, Tanaka Masao
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Japan.
Surgery. 2006 May;139(5):653-64. doi: 10.1016/j.surg.2005.10.002.
Matrix metalloproteinases (MMPs) play an important role in inflammation and neoplastic invasion and metastasis. Little is known about the effects of MMP inhibitors on hepatic ischemia/reperfusion injury. The aim of this study is to examine the inhibitory effects of ONO-4817 (oral inhibitor of MMPs) in rats.
Hepatic ischemia/reperfusion was induced in male Wister rats by clamping the portal vein and hepatic artery. The animals were randomized into an ONO-4817 group (300 mg/kg body weight per/day) and a vehicle group by oral gavage of a test substance. Serum alanine aminotransferase, histologic changes, gelatinolytic activity, MMP-2 and MMP-9 activities, tissue inhibitor of metalloproteinase 2 (TIMP-2) messenger RNA (mRNA) levels, and mRNA and serum levels of tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) were measured in both groups.
ONO-4817 prevented ischemia/reperfusion injury to the hepatocytes as shown by significant reductions of serum alanine aminotransferase and less severe histologic changes. Gelatinolytic activity was inhibited markedly in the liver of the ONO-4817 group as demonstrated by film in situ zymography. MMP-9 and MMP-2 activities also were inhibited in the ONO-4817 group as shown by gelatin zymography. TIMP-2 mRNA levels showed no significant differences between the 2 groups. TNFalpha mRNA showed no downregulation, but IL-1beta mRNA was downregulated in the liver of the ONO-4817 group 1 to 3 hours after reperfusion. Serum levels of TNFalpha and IL-1beta showed a significant decrease in the ONO-4817 group, compared with the vehicle group after reperfusion.
Hepatic ischemia/reperfusion injury was improved by a novel MMP inhibitor, ONO-4817, not only by inhibition of gelatinolytic activity but also by a decrease in release of inflammatory cytokines.
基质金属蛋白酶（MMPs）在炎症及肿瘤侵袭和转移过程中发挥重要作用。关于MMP抑制剂对肝缺血/再灌注损伤的影响，目前了解甚少。本研究旨在探讨ONO-4817（一种口服MMP抑制剂）对大鼠的抑制作用。
通过夹闭门静脉和肝动脉，在雄性Wistar大鼠中诱导肝缺血/再灌注。通过口服灌胃给予受试物质，将动物随机分为ONO-4817组（每日300mg/kg体重）和溶剂对照组。检测两组血清丙氨酸氨基转移酶、组织学变化、明胶酶活性、MMP-2和MMP-9活性、金属蛋白酶组织抑制剂2（TIMP-2）信使核糖核酸（mRNA）水平以及肿瘤坏死因子α（TNFα）和白细胞介素1β（IL-1β）的mRNA和血清水平。
ONO-4817可预防肝细胞的缺血/再灌注损伤，表现为血清丙氨酸氨基转移酶显著降低以及组织学变化较轻。如膜原位酶谱分析所示，ONO-4817组肝脏中的明胶酶活性受到明显抑制。如明胶酶谱分析所示，ONO-4817组的MMP-9和MMP-2活性也受到抑制。两组之间TIMP-2 mRNA水平无显著差异。TNFα mRNA未出现下调，但再灌注后1至3小时，ONO-4817组肝脏中的IL-1β mRNA下调。与再灌注后的溶剂对照组相比，ONO-4817组血清TNFα和IL-1β水平显著降低。
新型MMP抑制剂ONO-4817可改善肝缺血/再灌注损伤，不仅通过抑制明胶酶活性，还通过减少炎性细胞因子的释放。
