Shen X-D, Ke B, Zhai Y, Tsuchihashi S-I, Gao F, Duarte S, Coito A, Busuttil R W, Allison A C, Kupiec-Weglinski J W
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
Am J Transplant. 2007 Nov;7(11):2463-71. doi: 10.1111/j.1600-6143.2007.01967.x. Epub 2007 Sep 14.
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.
缺血/再灌注损伤（IRI）仍是临床移植中的一个重要问题。缺血后，磷脂酰丝氨酸（PS）易位至内皮细胞（ECs）表面，促进白细胞/血小板的早期黏附，损害微血管血流。Diannexin是一种73kD的人膜联蛋白V同源二聚体，可与PS结合，阻止白细胞/血小板黏附于EC，并维持肝血窦血流。本研究分析Diannexin治疗能否预防肝移植中的冷IRI。大鼠肝脏在4℃的UW溶液中保存24小时，然后原位移植（OLT）到同基因受体中。Diannexin（200μg/kg）被注入：（i）恢复后再灌注前的供肝，（ii）再灌注时和术后第2天的OLT受体。对照组为未治疗的OLT。两种Diannexin给药方案均将OLT存活率从40%提高到100%，降低了sALT水平，并减轻了肝脏组织学损伤。Diannexin治疗降低了TNF-α、IL-1β、IP-10的表达，减少了P-选择素、内皮细胞ICAM-1的表达，并减轻了巨噬细胞、CD4细胞和中性粒细胞对OLT的浸润。Diannexin增加了HO-1/Bcl-2/Bcl-xl的表达，并减少了Caspase-3/TUNEL+凋亡细胞。因此，通过调节OLT中的白细胞/血小板运输和EC活化，Diannexin抑制了血管炎症反应并减少了细胞凋亡。Diannexin作为一种减轻IRI从而改善OLT功能/增加器官供体库的新型药物值得进一步探索。
