Journal
GASTROENTEROLOGY
Volume 133, Issue 2, Pages 632-646Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2007.05.027
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Funding
- NIAAA NIH HHS [R01 AA12436] Funding Source: Medline
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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 mu g/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 recrititment (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.
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