title: Diannexin, a novel annexin V homodimer, protects rat liver transplants against cold ischemia-reperfusion injury.
abstract: Ischemia/reperfusion injury (IRI) remains an important problem in clinical transplantation. Following ischemia, phosphatidylserine (PS) translocates to surfaces of endothelial cells (ECs) and promotes the early attachment of leukocytes/platelets, impairing microvascular blood flow. Diannexin, a 73 KD homodimer of human annexin V, binds to PS, prevents attachment of leukocytes/platelets to EC, and maintains sinusoidal blood flow. This study analyzes whether Diannexin treatment can prevent cold IRI in liver transplantation. Rat livers were stored at 4 degrees C in UW solution for 24 h, and then transplanted orthotopically (OLT) into syngeneic recipients. Diannexin (200 microg/kg) was infused into: (i) donor livers after recovering and before reperfusion, (ii) OLT recipients at reperfusion and day +2. Controls consisted of untreated OLTs. Both Diannexin regimens increased OLT survival from 40% to 100%, depressed sALT levels, and decreased hepatic histological injury. Diannexin treatment decreased TNF-alpha, IL-1beta, IP-10 expression, diminished expression of P-selectin, endothelial ICAM-1, and attenuated OLT infiltration by macrophages, CD4 cells and PMNs. Diannexin increased expression of HO-1/Bcl-2/Bcl-xl, and reduced Caspase-3/TUNEL+ apoptotic cells. Thus, by modulating leukocyte/platelet trafficking and EC activation in OLTs, Diannexin suppressed vascular inflammatory responses and decreased apoptosis. Diannexin deserves further exploration as a novel agent to attenuate IRI, and thereby improve OLT function/increase organ donor pool.
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: X-D
authors.initials: XD
authors.lastname: Shen
authors.forename: B
authors.initials: B
authors.lastname: Ke
authors.forename: Y
authors.initials: Y
authors.lastname: Zhai
authors.forename: S-I
authors.initials: SI
authors.lastname: Tsuchihashi
authors.forename: F
authors.initials: F
authors.lastname: Gao
authors.forename: S
authors.initials: S
authors.lastname: Duarte
authors.forename: A
authors.initials: A
authors.lastname: Coito
authors.forename: R W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: A C
authors.initials: AC
authors.lastname: Allison
authors.forename: J W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017304:Annexin A5 / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D016031:Liver Transplantation / Q000009:adverse effects / Q000502:physiology*; D008297:Male; D009195:Peroxidase / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*
chemical_list: D017304:Annexin A5; C519264:diannexin, human; D009195:Peroxidase; D051547:Heme Oxygenase-1; D000410:Alanine Transaminase; D053148:Caspase 3