Diannexin, a novel annexin V homodimer, provides prolonged protection against hepatic ischemia-reperfusion injury in mice.
OBJECTIVE
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 microg/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.
Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, NSW, Australia.
Narci C
NC
Teoh
Yoshiya
Y
Ito
Jacqueline
J
Field
Nancy W
NW
Bethea
Deama
D
Amr
Margaret K
MK
McCuskey
Robert S
RS
McCuskey
Geoffrey C
GC
Farrell
Anthony C
AC
Allison
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017304:Annexin A5 / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D048429:Cell Size / Q000187:drug effects; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D019281:Dimerization; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006505:Hepatitis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007511:Ischemia / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008102:Liver Circulation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects; D009336:Necrosis; D010718:Phosphatidylserines / Q000378:metabolism; D020011:Protective Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D017304:Annexin A5; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D010718:Phosphatidylserines; D020011:Protective Agents; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; C519264:diannexin, human; D018799:Intercellular Adhesion Molecule-1; D000410:Alanine Transaminase