Hepatic ischemia/reperfusion injury is prevented by a novel matrix metalloproteinase inhibitor, ONO-4817

Background. 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-481 7 (oral inhibitor of MMPs) in rats. Methods. Hepatic ischemia/reperfusion zoos 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 RATA (mRNA) levels, and, mRNA and serum levels of tumor necrosis factor alpha (TATF alpha) and intarleukin 1 beta (IL-1 beta) were measured in both groups. Results. 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-481 7 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. TNF alpha mRNA showed no downregulation, but IL-1 beta mRNA was down-regulated in the liver of the ONO-4817 group to 3 hours after reperfusion. Serum levels of TNF alpha and IL-1 beta showed a significant decrease in the ONO-481 7 group, compared with the vehicle group after reperfusion. Conclusions. 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.