Diannexin, a Novel Annexin V Homodimer, Provides Prolonged Protection Against Hepatic Ischemia-Reperfusion Injury in Mice

Narci C. Teoh, Yoshiya Ito, Jacqueline Field, Nancy W. Bethea, Deama Amr, Margaret K. McCuskey, Robert S. McCuskey, Geoffrey C. Farrell*, Anthony C. Allison

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    65 Citations (Scopus)

    Abstract

    Background & Aims: Ischemia-reperfusion injury (IRI) remains an important cause of liver failure after hepatic surgery or transplantation. The mechanism seems to originate within the hepatic sinusoid, with damage to endothelial cells, an early, reproducible finding. Sinusoidal endothelial cells (SECs), damaged during reperfusion, activate and recruit inflammatory cells and platelets. We hypothesized that a recombinant human annexin V homodimer, Diannexin, would protect SECs from reperfusion injury. Methods: We tested this proposal in a well-characterized in vivo murine partial hepatic IRI model. Results: Whether administered 5 minutes or 24 hours before or 1 hour after ischemia-reperfusion, Diannexin (100-1000 μg/kg) almost completely protected against liver injury. The protective efficacy conferred by Diannexin was highly visible at the microcirculatory level. Thus, although IR in this model is associated with early swelling and gap formation in SECs, Diannexin ameliorated these effects as shown by >80% reduction in alanine aminotransferase values during the early phase of reperfusion injury (2 hours) and near normalization of liver necrosis and inflammation in the late phase of inflammatory recruitment (24 hours). Consistent with the proposed role of SEC injury in hepatic IRI, Diannexin also decreased hepatic expression of proinflammatory molecules (MIP-2, ICAM-1, VCAM), abolished leukocyte and platelet adherence to damaged SECs, and, by in vivo microscopy, Diannexin preserved microcirculatory blood flow and hepatocyte integrity during reperfusion. Conclusions: Diannexin is an apparently safe therapeutic protein that provides prolonged protection against hepatic IRI via cytoprotection of SECs, thereby interrupting secondary microcirculatory inflammation and coagulation.

    Original languageEnglish
    Pages (from-to)632-646
    Number of pages15
    JournalGastroenterology
    Volume133
    Issue number2
    DOIs
    Publication statusPublished - Aug 2007

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