Angiopoietin‐2 Inhibition Prevents Transplant Ischemia‐Reperfusion Injury and Chronic Rejection in Rat Cardiac Allografts
Angiopoietin‐2 Inhibition Prevents Transplant Ischemia‐Reperfusion Injury and Chronic Rejection in Rat Cardiac Allografts
复制标题
DOI：
10.1111/ajt.12672
复制
发表时间：
2014-05
影响因子：
8.8
通讯作者：
S. Syrjälä;R. Tuuminen;A. Nykänen;A. Raissadati;A. Dashkevich;M. Keränen;R. Arnaudova;R. Krebs;C. C. Leow-C.;P. Saharinen;K. Alitalo;K. Lemström
中科院分区：
文献类型：
--
作者：
S. Syrjälä;R. Tuuminen;A. Nykänen;A. Raissadati;A. Dashkevich;M. Keränen;R. Arnaudova;R. Krebs;C. C. Leow-C.;P. Saharinen;K. Alitalo;K. Lemström
移植物缺血再灌注损伤（Tx‐IRI）和同种异体移植物功能障碍仍然是心脏移植后的两个主要临床挑战。我们研究了血管生成素-2（Ang 2）在Tx‐IRI和排斥反应中的作用，使用完全MHC-不匹配的大鼠心脏同种异体移植物。我们报告说，血浆血管生成素2水平显着提高，在人类和大鼠心脏移植受体，但不是在大鼠受体的同系移植，在IRI。在4 h冷保存前用抗Ang 2抗体对大鼠心脏同种异体移植物进行离体冠状动脉内处理，可预防微血管功能障碍、内皮细胞（EC）粘附分子表达和白细胞浸润、心肌损伤以及心脏纤维化和同种异体移植物血管病变的发生。在术前和术后使用抗Ang 2抗体治疗产生了类似的效果，而不会影响微血管功能障碍，并且在其他实验中延长了同种异体移植物存活。单纯的术前治疗不能产生这些效果。此外，用重组Ang 2离体冠状动脉内治疗同种异体移植物增强了Tx-IRI，并且在加回实验中，消除了抗体的有益作用。我们证明，Ang 2的中和防止EC活化、白细胞浸润、Tx‐IRI和大鼠心脏同种异体移植物中慢性排斥反应的发展。我们的研究结果表明，阻断Ang 2通路是一种新的，临床可行的，T细胞非依赖性的策略，以保护心脏移植物。
Transplant ischemia‐reperfusion injury (Tx‐IRI) and allograft dysfunction remain as two of the major clinical challenges after heart transplantation. We investigated the role of angiopoietin‐2 (Ang2) in Tx‐IRI and rejection using fully MHC‐mismatched rat cardiac allografts. We report that plasma levels of Ang2 were significantly enhanced in the human and rat recipients of cardiac allografts, but not in the rat recipients of syngrafts, during IRI. Ex vivo intracoronary treatment of rat cardiac allografts with anti‐Ang2 antibody before 4‐h cold preservation prevented microvascular dysfunction, endothelial cell (EC) adhesion molecule expression and leukocyte infiltration, myocardial injury and the development of cardiac fibrosis and allograft vasculopathy. Recipient preoperative and postoperative treatment with anti‐Ang2 antibody produced otherwise similar effects without effecting microvascular dysfunction, and in additional experiments prolonged allograft survival. Recipient preoperative treatment alone failed to produce these effects. Moreover, ex vivo intracoronary treatment of allografts with recombinant Ang2 enhanced Tx‐IRI and, in an add‐back experiment, abolished the beneficial effect of the antibody. We demonstrate that neutralization of Ang2 prevents EC activation, leukocyte infiltration, Tx‐IRI and the development of chronic rejection in rat cardiac allografts. Our results suggest that blocking Ang2 pathway is a novel, clinically feasible, T cell–independent strategy to protect cardiac allografts.