ANIMAL MODEL OF TRANSFUSION RELATED ACUTE LUNG INJURY

细胞因子IL-1 β、IL-6、IL-8和TNF α以及脂质溶血磷脂酰胆碱（lyso-PC）在血液储存过程中产生，可能对输血宿主造成有害影响。这些危及生命的并发症之一是输血相关急性肺损伤（TRALI）。 先前的研究表明，在常规血液储存过程中产生的脂质参与TRALI的发病机制。 Lyso-PC在体外快速引发中性粒细胞（PMN），以获得最大的细胞毒性潜力并增加对血管内皮（EC）的粘附。 此外，IL-6、IL-8和TNF α也在体外致敏PMN。 因此，血液储存过程中产生的脂质和细胞因子可能会引发输血宿主的PMN，使其易于TRALI。 中性粒细胞引发涉及扩增的脱粒和呼吸爆发响应于第二激动剂，以及增加粘附的中性粒细胞EC，这导致在不分青红皂白地坚持EC的中性粒细胞的最大细胞毒性潜力。 预激剂在动物模型中引起急性肺损伤;然而，必须施用两种药剂。 此外，在这些动物模型中使用的许多试剂也激活EC，引起粘附分子的上调。 我们假设TRALI存在类似的两事件模型，每例患者都有潜在的临床状况，这可能是第一个事件，随后在储存的血液成分中输注脂质和细胞因子代表第二个事件。 我们将通过完成以下具体目标来检验这一假设。 具体目标1：我们已经开发了TRALI的动物模型，以研究来自储存血液的细胞因子和脂质的作用，作为TRALI发病机理中所需的两种损伤中的第二种。 具体目标2将检查与这两个事件模型的第一个事件相关的临床实体，包括近期手术、大量输血和细胞因子治疗。 此外，将测试与这些临床实体相关的介质激活肺内皮和改变PMN：EC生理学的能力。 这些具体目标的完成将为临床干预的目标区域提供信息，以使输血更安全。

Cytokines, IL-1beta, IL-6, IL-8, and TNFalpha, and lipids, lysophosphatidy1cholines (lyso-PCs), are generated during blood storage and may cause deleterious effects in the transfused host. One of these life-threatening complications is transfusion related acute lung injury (TRALI). Previous work has shown that lipids generated during routine blood storage are involved in the pathogenesis of TRALI. Lyso-PCs rapidly prime neutrophils (PMNs) in vitro for maximal cytotoxic potential and increased adherence to vascular endothelium (EC). Moreover, IL-6, IL-8 and TNFalpha also prime PMNs in vitro. Therefore, lipids and cytokines produced during blood storage may prime the PMNs of transfused hosts predisposing them to TRALI. PMN priming involves augmentation of both degranulation and the respiratory burst in response to a second agonist as well as increased adhesion of PMNs to EC, which results in the indiscriminate adherence to EC of PMNs with maximal cytotoxic potential. Priming agents cause acute lung injury in animal models; however, two agents must be administered. Furthermore, many of the agents used in these animal models also activate EC causing upregulation of adhesion molecules. We have hypothesized that a similar two event model exists for TRALI with each patient having an underlying clinical condition, which could act as the first event, followed by the infusion of lipids and cytokines in stored blood components representing the second event. We will test this hypothesis in by completing the following specific aims. Specific Aim 1: we have developed an animal model of TRALI to investigate the role of cytokines and lipids from stored blood as the second, of the two insults required in the pathogenesis of TRALI. Specific Aim 2 will examine the clinical entities associated with the first event of this two event model including recent surgery, massive transfusion and cytokine therapy. In addition, the ability of the mediators involved with these clinical entities to activate pulmonary endothelium and to alter the PMN:EC physiology will be tested. Completion of these specific aims will provide information to target areas for clinical intervention to make transfusions safer.