Role of coagulation and pulmonary xenograft injury

描述(申请人提供)：我们的目的是确定肺移植中凝血系统的激活和调节不足对内皮细胞激活、炎症增强和肺移植损伤的作用。凝血系统的启动与急性肺损伤相吻合，急性肺损伤是由a)缺血-再灌流，b)补体激活，c)可能是抗体结合，d)肺巨噬细胞的促凝和抗纤溶作用引起的。凝血系统失调使凝血不受控制地加速，对内皮细胞和炎症系统产生级联作用。减少导致凝血系统激活的启动事件的策略是我们关注的重点。我们计划1)通过重复静脉注射脂质体氯屈磷酸钠来耗尽肺巨噬细胞，以确定它们在启动弥漫性血管内凝血、内皮细胞激活和肺移植损伤中的作用。2)在没有补体激活的情况下，通过使用α-半乳糖-聚乙二醇偶联物去除抗体，结合使用C1-抑制剂和抗-C5a抑制补体，来确定异种抗体与Gala1-3Gal表位结合在肺移植损伤中的重要性；以及3)通过使用TFPI或ASIS抑制组织因子依赖的因子IX和X的激活来抑制和调节凝血系统。用活化蛋白C抑制Villa和Va因子，评价其对内皮细胞功能、炎症系统激活和异种移植功能的影响。

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.