Role of coagulation and pulmonary xenograft injury

描述（由申请方提供）：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一致，急性肺损伤由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维蛋白溶解作用引起。凝血系统失调允许不受控制的凝血加速，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、和肺异种移植物损伤2）通过在不存在补体活化的情况下使用α-gal三糖消耗抗体来确定异种反应性抗体与Gala 1 - 3Gal表位结合在肺异种移植物损伤中的重要性。PEG缀合物与使用C1-抑制剂和抗-C5 a的补体抑制结合，和3）通过使用TFPI或ASIS抑制因子IX和X的组织因子依赖性活化，以及通过活化蛋白C抑制因子VIIa和Va来抑制和调节凝血系统，以评估对内皮细胞功能、炎症系统活化和异种移植物功能的影响。

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.