Original communication| Volume 139, ISSUE 5, P653-664, May 2006

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


      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 α (TNFα) and interleukin 1β (IL-1β) 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. 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.


      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.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Farhood A.
        • McGuire G.M.
        • Manning A.M.
        • et al.
        Intercellular adhesion molecule 1 (ICAM-1) expression and its role in neutrophil-induced ischemia-reperfusion injury in rat liver.
        Journal of Leukoce Biol. 1995; 57: 368-374
        • Lentsch A.B.
        • Yoshidome H.
        • Cheadle W.G.
        • et al.
        Chemokine involvement in hepatic ischemia/reperfusion injury in mice.
        Hepatology. 1998; 27 ([republished from Hepatology 1998;27:507-12]): 1172-1177
        • Jaeschke H.
        • Smith C.W.
        Mechanisms of neutrophil-induced parenchymal cell injury.
        J Leukoc Biol. 1997; 61: 647-653
        • Birkedal-Hansen H.
        • Moore W.G.
        • Bodden M.K.
        • et al.
        Matrix metalloproteinases.
        Crit Rev Oral Biol Med. 1993; 4: 197-250
        • Soccal P.M.
        • Gasche Y.
        • Pache J.C.
        • et al.
        Matrix metalloproteinases correlate with alveolar-capillary permeability alteration in lung ischemia-reperfusion injury.
        Transplantation. 2000; 70: 998-1005
        • Cheung P.Y.
        • Sawicki G.
        • Wozniak M.
        • et al.
        Matrix metalloproteinase-2 contributes to ischemia-reperfusion injury in the heart.
        Circulation. 2000; 101: 1833-1839
        • Romanic A.M.
        • White R.F.
        • Arleth A.J.
        • et al.
        Matrix metalloproteinase expression increases after cerebral focal ischemia in rats.
        Stroke. 1998; 29: 1020-1030
        • Planas A.M.
        • Sole S.
        • Justicia C.
        • et al.
        Estimation of gelatinase content in rat brain.
        Biochem Biophys Res Commun. 2000; 278: 803-807
        • Rosenberg G.A.
        • Estrada E.Y.
        • Dencoff J.E.
        • et al.
        Tumor necrosis factor-alpha-induced gelatinase B causes delayed opening of the blood-brain barrier.
        Brain Res. 1995; 703: 151-155
        • Rosenberg G.A.
        • Estrada E.Y.
        • Dencoff J.E.
        Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain.
        Stroke. 1998; 29: 2189-2195
        • Fukuda S.
        • Fini C.A.
        • Mabuchi T.
        • et al.
        Focal cerebral ischemia induces active proteases that degrade microvascular matrix.
        Stroke. 2004; 35: 998-1004
        • Pfefferkorn T.
        • Rosenberg G.A.
        Closure of the blood-brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion.
        Stroke. 2003; 34: 2025-2030
        • Liotta L.A.
        Cancer cell invasion and metastasis.
        Sci Am. 1992; 266 (62-3): 54-59
        • MacDougall J.R.
        • Matrisian L.M.
        Contributions of tumor and stromal matrix metalloproteinases to tumor progression, invasion and metastasis.
        Cancer Metastasis Rev. 1995; 14: 351-362
        • Jiang W.G.
        • Puntis M.C.
        • Hallett M.B.
        Molecular and cellular basis of cancer invasion and metastasis.
        Br J Surg. 1994; 81: 1576-1590
        • Folkman J.
        Angiogenesis in psoriasis.
        J Invest Dermatol. 1972; 59: 40-43
        • Cursio R.
        • Mari B.
        • Louis K.
        • Rostagno P.
        • et al.
        Rat liver injury after normothermic ischemia is prevented by a phosphinic matrix metalloproteinase inhibitor.
        Faseb J. 2002; 16: 93-95
        • Yamada A.
        • Uegaki A.
        • Nakamura T.
        • et al.
        ONO-4817, an orally active matrix metalloproteinase inhibitor, prevents lipopolysaccharide-induced proteoglycan release from the joint cartilage in guinea pigs.
        Inflamm Res. 2000; 49: 144-146
        • Hariya A.
        • Takazawa K.
        • Yamamoto T.
        • et al.
        ONO-4817, a novel matrix metalloproteinase inhibitor, attenuates allograft vasculopathy in a rat cardiac transplant.
        J Heart Lung Transplant. 2004; 23: 1163-1169
        • Deryckere F.
        • Gannon F.
        A one-hour minipreparation technique for extraction of DNA-binding proteins from animal tissues.
        Biotechniques. 1994; 16: 405
        • Morrison T.B.
        • Weis J.J.
        • Wittwer C.T.
        Quantification of low-copy transcripts by continuous SYBR Green I monitoring during amplification.
        Biotechniques. 1998; 24 (960, 962): 954-958
        • Galis Z.S.
        • Sukhova G.K.
        • Libby P.
        Microscopic localization of active proteases by in situ zymography.
        Faseb J. 1995; 9: 974-980
        • Knox J.B.
        • Sukhova G.K.
        • Whittemore A.D.
        • et al.
        Evidence for altered balance between matrix metalloproteinases and their inhibitors in human aortic diseases.
        Circulation. 1997; 95: 205-212
        • Mungall B.A.
        • Pollitt C.C.
        • Collins R.
        Localisation of gelatinase activity in epidermal hoof lamellae by in situ zymography.
        Histochem Cell Biol. 1998; 110: 535-540
        • Krejci-Papa N.C.
        • Paus R.
        A novel in situ-zymography technique localizes gelatinolytic activity in human skin to mast cells.
        Exp Dermatol. 1998; 7: 321-326
        • Nakamura H.
        • Ueno H.
        • Yamashita K.
        • et al.
        Enhanced production and activation of progelatinase A mediated by membrane-type 1 matrix metalloproteinase in human papillary thyroid carcinomas.
        Cancer Res. 1999; 59: 467-473
        • Ikeda M.
        • Maekawa R.
        • Tanaka H.
        • et al.
        Inhibition of gelatinolytic activity in tumor tissues by synthetic matrix metalloproteinase inhibitor.
        Clin Cancer Res. 2000; 6: 3290-3296
        • Wang X.
        • Barone F.C.
        • White R.F.
        • et al.
        Subtractive cloning identifies tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) increased gene expression following focal stroke.
        Stroke. 1998; 29: 516-520
        • Malinin N.L.
        • Boldin M.P.
        • Kovalenko A.V.
        • et al.
        MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1.
        Nature. 1997; 385: 540-544
        • Bradham C.A.
        • Schemmer P.
        • Stachlewitz R.F.
        • et al.
        Activation of nuclear factor-kappaB during orthotopic liver transplantation in rats is protective and does not require Kupffer cells.
        Liver Transpl Surg. 1999; 5: 282-293
        • Yoshidome H.
        • Kato A.
        • Edwards M.J.
        • et al.
        Interleukin-10 suppresses hepatic ischemia/reperfusion injury in mice.
        Hepatology. 1999; 30: 203-208
        • Takeuchi D.
        • Yoshidome H.
        • Kato A.
        • et al.
        Interleukin 18 causes hepatic ischemia/reperfusion injury by suppressing anti-inflammatory cytokine expression in mice.
        Hepatology. 2004; 39: 699-710
        • Miyagi S.
        • Ohkohchi N.
        • Oikawa K.
        • et al.
        Effects of anti-inflammatory cytokine agent (FR167653) and serine protease inhibitor on warm ischemia-reperfusion injury of the liver graft.
        Transplantation. 2004; 77: 1487-1493
        • Tsuchihashi S.
        • Tamaki T.
        • Tanaka M.
        • et al.
        Pyrrolidine dithiocarbamate provides protection against hypothermic preservation and transplantation injury in the rat liver.
        Surgery. 2003; 133: 556-567
        • Muller C.
        • Dunschede F.
        • Koch E.
        • et al.
        Alpha-lipoic acid preconditioning reduces ischemia-reperfusion injury of the rat liver via the PI3-kinase/Akt pathway.
        Am J Physiol Gastrointest Liver Physiol. 2003; 285: G769-G778
        • Glanemann M.
        • Strenziok R.
        • Kuntze R.
        • et al.
        Ischemic preconditioning and methylprednisolone both equally reduce hepatic ischemia/reperfusion injury.
        Surgery. 2004; 135: 203-214
        • Zhong Z.
        • Froh M.
        • Connor H.D.
        • et al.
        Prevention of hepatic ischemia-reperfusion injury by green tea extract.
        Am J Physiol Gastrointest Liver Physiol. 2002; 283: G957-G964
        • Gearing A.J.
        • Beckett P.
        • Christodoulou M.
        • et al.
        Processing of tumour necrosis factor-alpha precursor by metalloproteinases.
        Nature. 1994; 370: 555-557
        • McGeehan G.M.
        • Becherer J.D.
        • Bast Jr, R.C.
        • et al.
        Regulation of tumour necrosis factor-alpha processing by a metalloproteinase inhibitor.
        Nature. 1994; 370: 558-561
        • Naito Y.
        • Takagi T.
        • Kuroda M.
        • et al.
        An orally active matrix metalloproteinase inhibitor, ONO-4817, reduces dextran sulfate sodium-induced colitis in mice.
        Inflamm Res. 2004; 53: 462-468
        • Lee K.S.
        • Jin S.M.
        • Kim H.J.
        • et al.
        Matrix metalloproteinase inhibitor regulates inflammatory cell migration by reducing ICAM-1 and VCAM-1 expression in a murine model of toluene diisocyanate-induced asthma.
        J Allergy Clin Immunol. 2003; 111: 1278-1284