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THERAPEUTIC POTENTIAL OF TARGETING ANIGIOGENESIS IN CHRONIC REJECTION AND ISCHEMIA-REPERFUSION INJURY IN SMALL BOWEL TRANSPLANTATION

小肠移植中慢性排斥和缺血再灌注损伤中靶向血管生成的治疗潜力

基本信息

批准号：
17591867
负责人：
KANEHIRO Hiromichi
金额：
$ 1.86万
依托单位：
NARA MEDICALUNIVERITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

Vascular endothelial growth factor (VEGF), a major angiogenesis factor, also plays a critical role as a proinflammatory cytokine in various immune responses. Since it is well known to be induced by hypoxia, it may be a critical mediator in the ischemic injury. To date, however, little is known of its role in intestinal ischemia reperfusion (IR) injury. In this study, we investigated the role of VEGF and its receptors (VEGFR-1 and VEGFR-2) during the intestinal IR injury.Intestinal injury was elicited through clamping of the superior mesenteric artery for 45 followed by reperfusion. The local expression of VEGF was significantly upregulated after reperfusion following ischemia compared to controls suggesting that VEGF and VEGFR may play an important role in the initiation of intestinal I/R injury. To confirm the pathophysiological roles of each VEGFR, we utilized specific neutralizing monoclonal antibodies for each VEGFR. Mice were treated with control IgG or anti-VEGFR mAbs 30 minutes before reperfusion. The simultaneous blockade of two VEGFRs significantly prolonged the survival. By histological analysis, mucosal sloughing and villi destruction were observed in control mice, while these mucosal damages were significantly reduced in mice treated with simultaneous VEGFR blockade. Data are suggestive that both VEGFRs are critical and function synergistically in vivo. The protective effect was associated with the downregulation of local expressions of cytokines. Data demonstrates that VEGF and VEGFR are functional in intestinal I/R injury and targeting VEGF/VEGFR pathway may represent a novel therapy for the protection of the posttransplant intestinal I/R injury.We also found that targeting angiogenesis has significant protective effect on the prevention of chronic rejection using MHC class II-mismatched cardiac transplantation model.

血管内皮生长因子（VEGF）是一种主要的血管生成因子，也是一种促炎细胞因子，在各种免疫反应中发挥关键作用。由于已知它是由缺氧诱导的，因此它可能是缺血性损伤的关键介质。然而，迄今为止，很少有人知道它在肠缺血再灌注（IR）损伤中的作用。本研究通过阻断肠系膜上级动脉45 min后再灌注，观察血管内皮生长因子（VEGF）及其受体（VEGFR-1和VEGFR-2）在肠缺血再灌注损伤中的作用。与对照组相比，缺血再灌注后VEGF的局部表达显著上调，表明VEGF和VEGFR可能在肠I/R损伤的启动中起重要作用。为了确认每种VEGFR的病理生理作用，我们使用了每种VEGFR的特异性中和单克隆抗体。在再灌注前30分钟用对照IgG或抗VEGFR mAb处理小鼠。同时阻断两种VEGF受体可显著延长存活时间。通过组织学分析，在对照小鼠中观察到粘膜脱落和绒毛破坏，而在同时给予VEGFR阻断剂的小鼠中，这些粘膜损伤显著减轻。数据表明，两种VEGF都是关键的，并且在体内协同作用。保护作用与下调局部细胞因子的表达有关。研究结果表明，VEGF和VEGFR在肠I/R损伤中发挥重要作用，靶向VEGF/VEGFR通路可能成为保护移植后肠I/R损伤的新途径，我们还发现靶向血管生成对预防MHC II类不匹配心脏移植模型的慢性排斥反应具有显著的保护作用。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

アポトーシス能動的促進による免疫寛容の誘導

通过积极促进细胞凋亡诱导免疫耐受

DOI：
发表时间：
2006
期刊：
移植 41・2
影响因子：
0
作者：
庄雅之;金廣裕道;中島祥介
通讯作者：
中島祥介

A novel CCR5/CXCR3 antagonist protects intestinal ischemia/reperfusion injury

DOI：
10.1016/j.transproceed.2006.10.115
发表时间：
2006-12-01
期刊：
TRANSPLANTATION PROCEEDINGS
影响因子：
0.9
作者：
Akahori, T.;Sho, M.;Nakajima, Y.
通讯作者：
Nakajima, Y.

Dual Role of Vascular Endothelial Growth Factor in Hepatic Ischemia-Reperfusion Injury

DOI：
10.1097/01.tp.0000161627.84481.5e
发表时间：
2005-05
期刊：
Transplantation
影响因子：
6.2
作者：
Y. Tsurui;M. Sho;Y. Kuzumoto;K. Hamada;S. Akashi;H. Kashizuka;N. Ikeda;T. Nomi;T. Mizuno;H. Kanehiro;Y. Nakajima
通讯作者：
Y. Tsurui;M. Sho;Y. Kuzumoto;K. Hamada;S. Akashi;H. Kashizuka;N. Ikeda;T. Nomi;T. Mizuno;H. Kanehiro;Y. Nakajima

Function of the vascular endothelial growth factor receptors fit-1 and flk-1/KDR in the alloimmune response in vivo.

血管内皮生长因子受体 fit-1 和 flk-1/KDR 在体内同种免疫反应中的功能。