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

Abstract

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 alpha (TNFalpha) and interleukin 1beta (IL-1beta) 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. 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.

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.

• Authors: Kengo Shirahane, Koji Yamaguchi, Kenichiro Koga, Masato Watanabe, Syoji Kuroki, Masao Tanaka
• Journal: Surgery (Surgery) Vol. 139 Issue 5 Pg. 653-64 (May 2006) ISSN: 0039-6060 [Print] United States
• PMID: 16701099 (Publication Type: Journal Article)

Chemical References

• DNA Primers
• Matrix Metalloproteinase Inhibitors
• N-hydroxy-5-ethoxymethyloxy-2-methyl-4-(4-phenoxybenzoyl)aminopentanamide
• Phenyl Ethers
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• Tissue Inhibitor of Metalloproteinase-2
• Matrix Metalloproteinase 2

Topics

• Animals
• DNA Primers
• Disease Models, Animal
• Kinetics
• Liver Circulation
• Male
• Matrix Metalloproteinase 2 (genetics)
• Matrix Metalloproteinase Inhibitors
• Phenyl Ethers (therapeutic use)
• RNA, Messenger (drug effects, genetics)
• Rats
• Rats, Wistar
• Reperfusion Injury (prevention & control)
• Reverse Transcriptase Polymerase Chain Reaction
• Time Factors
• Tissue Inhibitor of Metalloproteinase-2 (genetics)
• Tumor Necrosis Factor-alpha (genetics)