Role of coagulation and pulmonary xenograft injury

凝血和肺异种移植损伤的作用

• 批准号: 6608785
• 负责人: EDWARD CANTU
• 金额: $ 4.81万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-08 至 2004-07-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6608785
• 关键词: anaphylatoxins; anticoagulants; antigen antibody reaction; baboons; blood coagulation; complement; complement pathway; diphosphonate; genetically modified animals; lung injury; lung transplantation; macrophage; postdoctoral investigator; protein C; swine; transplant rejection; xenotransplantation

DESCRIPTION (provided by applicant): Our purpose is to determine the role of coagulation system activation and inadequate regulation within the pulmonary xenograft on endothelial cell activation, inflammatory augmentation and pulmonary xenograft injury. Initiation of the coagulation system coincides with the acute lung injury that is caused by a) ischemia-reperfusion b) complement activation c) probably antibody binding and d) the pro-coagulant and anti-fibrinolytic actions of pulmonary macrophages. Coagulation system dysregulation allows for uncontrolled acceleration of coagulation with cascading effects on the endothelial cell and the inflammatory system. Strategies to decrease the initiating events leading to activation of the coagulation system are our focus. We plan to 1) deplete the pulmonary macrophages by repetitive administration of intravenous liposomal clodronate to determine their role in initiation of the diffuse intravascular coagulation, endothelial cell activation, and pulmonary xenograft injury 2) determine the importance of xenoreactive antibody binding to Gala1 -3Gal epitopes in pulmonary xenograft injury by depleting antibody in the absence of complement activation using a-gal trisaccharide-PEG conjugates in conjunction with complement inhibition using C1-inhibitor and anti- C5a and 3) inhibit and regulate the coagulation system through the use of inhibition of tissue factor dependent activation of factors IX and X using TFPI or ASIS, and inhibition of factor VIlla and Va by Activated Protein C to assess the effects on endothelial cell function, inflammatory system activation and xenograft function.

描述（由申请人提供）：我们的目的是确定肺异种移植物内凝血系统激活和调节不足对内皮细胞激活、炎症增强和肺异种移植物损伤的作用。凝血系统的启动与急性肺损伤同时发生，急性肺损伤是由a）缺血再灌注b）补体激活c）可能的抗体结合和d）肺巨噬细胞的促凝血和抗纤溶作用引起的。凝血系统失调导致凝血不受控制地加速，对内皮细胞和炎症系统产生级联效应。减少导致凝血系统激活的起始事件的策略是我们的重点。我们计划 1) 通过重复静脉注射氯膦酸脂质体来消耗肺巨噬细胞，以确定它们在引发弥漫性血管内凝血、内皮细胞活化和肺异种移植损伤中的作用 2) 确定异种反应性抗体与 Gala1 -3Gal 表位结合的重要性在没有补体激活的情况下，使用 a-gal 三糖-PEG 缀合物与补体抑制相结合，通过消耗抗体来治疗肺异种移植物损伤C1抑制剂和抗C5a和3)通过使用TFPI或ASIS抑制因子IX和X的组织因子依赖性激活以及通过激活蛋白C抑制因子VIIa和Va来抑制和调节凝血系统以评估凝血系统对内皮细胞功能、炎症系统激活和异种移植功能的影响。

项目成果

Economic evaluation of everolimus vs. azathioprine at one year after de novo heart transplantation.

从头心脏移植后一年依维莫司与硫唑嘌呤的经济评估。

• DOI: 10.1111/j.1399-0012.2004.00312.x
• 发表时间: 2005
• 期刊: Clinical transplantation
• 影响因子: 2.1
• 作者: Radeva,JasminaI;Reed,ShelbyD;Kalo,Zoltan;Kauf,TeresaL;Cantu3rd,Edward;Cretin,Nathalie;Schulman,KevinA
• 通讯作者: Schulman,KevinA