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

Abstract

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.