REVERSIBLE PATHOLOGY OF THE PLATELET STORAGE LESION

在采集和储存过程中，血小板形成了各种结构 以及体外功能异常，包括表面的改变 膜成分，颗粒释放，信号转导，膜 磷脂组成、能量代谢与细胞骨架 组织。这种血小板储存损伤的发展是 血小板活化、调理、高代谢和 衰老。我们还知道，在输注其中一些细胞后， 体外异常逆转；然而，对其定义 异常是很容易逆转的，而不可逆的则不是 很好理解。根据初步数据，我们假设(A) 以前被认为是不可逆转的异常情况可能并非如此，因为 例如，P-选择素在血小板表面的表达；(B)a 激活衍生的和光学电离的很大一部分- 衍生性血小板损伤继发于补体激活 收集和储存；以及(C)代谢的一部分 观察到的异常也与血小板激活直接相关。 通过正常激活事件引起的线粒体功能障碍。我们 已经开发出一种体外全血输血模型，可以 一种是单独分析“输注”的血小板亚群 与天然的血小板同步。此外，我们之前已经 详细调查了特定补体的参与情况 与类似的血小板损伤的发生有关的成分 它与体外循环有关，现在有 初步数据显示，补体参与情况类似 储存性损伤。我们现建议：(A)界定 血小板储存损伤是可逆的，重新引入储存的 使用输血将血小板注入正常的全血环境 模型；和(B)界定特定补体成分在 激活、调理和代谢储存损伤的产生 在不同的收集和储存条件下。我们将使用 特异性阻断分子、多参数流式细胞仪及图像分析 分析技术、细胞骨架和信号转导分析和 新应用的新陈代谢分析。该项目的长期目标， 它结合了几个已建立的 研究人员，是为了提高血小板的临床效果 输血。

During collection and storage, platelets develop a variety of structural and in vitro functional abnormalities, including alterations in surface membrane constituents, granule release, signal transduction, membrane phospholipid composition, energy metabolism and cytoskeletal organization. The development of this platelet storage lesion is the result of platelet activation, opsonization, hypermetabolism and senescence. It is also known that upon transfusion some of these in vitro abnormalities reverse; however, the definition of which abnormalities are readily reversible and which are irreversible is not well understood. Based on preliminary data, we hypothesize that (a) abnormalities previously thought to be irreversible may not be so, for example, P-selectin expression on the platelet surface; (b) a significant portion of both the activation-derived and the opsonization- derived platelet lesion is secondary to complement activation during collection and storage; and (c) that a portion of the metabolic abnormalities observed are also directly linked to platelet activation via mitochondrial dysfunction induced by normal activation events. We have developed an in vitro whole blood model of transfusion that allows one to separately analyze subsets of "transfused" platelets simultaneously with native platelets. In addition, we have previously investigated in detail the participation of specific complement components in the development of the somewhat analogous platelet lesion which is associated with extracorporeal circulation and now have preliminary data to suggest similar complement participation in the storage lesion. We now propose to: (a) define which aspects of the platelet storage lesion are reversible upon reintroduction of the stored platelets into the normal whole blood milieu using the transfusion model; and (b) define the role of specific complement components in the generation of the activation, opsonization and metabolic storage lesion under different conditions of collection and storage. We will use specific blocking molecules, multiparameter flow cytometric and image analysis technology, cytoskeletal and signal transduction analysis and newly applied metabolic assays. The long term goal of the project, which combines the synergistic expertise of several established investigators, is to improve the clinical results of platelet transfusion.