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-4817 (oral inhibitor of MMPs) in rats.
Methods
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 α (TNFα) and interleukin
1β (IL-1β) 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-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. TNFα mRNA showed no downregulation, but IL-1β mRNA
was downregulated in the liver of the ONO-4817 group 1 to 3 hours after reperfusion.
Serum levels of TNFα and IL-1β showed a significant decrease in the ONO-4817 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.
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Article info
Publication history
Accepted:
October 11,
2005
Identification
Copyright
© 2006 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
