ANIMAL MODEL OF TRANSFUSION RELATED ACUTE LUNG INJURY

细胞因子il -1 β、IL-6、IL-8和TNFalpha以及脂质溶血磷脂酰胆碱（lyso-PCs）在血液储存过程中产生，并可能对输入的宿主产生有害影响。这些危及生命的并发症之一是输血相关的急性肺损伤（TRALI）。先前的研究表明，常规血液储存过程中产生的脂质参与了TRALI的发病机制。Lyso-PCs快速启动中性粒细胞（PMNs）体外最大的细胞毒性潜能和增加粘附血管内皮（EC）。此外，IL-6、IL-8和TNFalpha也能在体外激活PMNs。因此，血液储存过程中产生的脂质和细胞因子可能会激活输入宿主的pmn，使其易患TRALI。PMN启动包括对第二种激动剂的脱颗粒和呼吸爆发的增强，以及PMN对EC的粘附性增加，这导致PMN以最大的细胞毒性潜势不加区分地粘附在EC上。启动剂引起动物模型急性肺损伤；然而，必须使用两种药物。此外，在这些动物模型中使用的许多药物也会激活EC，导致粘附分子的上调。我们假设TRALI存在类似的两个事件模型，每个患者都有潜在的临床状况，这可能是第一个事件，其次是储存血液成分中的脂质和细胞因子的输注，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：我们已经建立了TRALI动物模型，以研究细胞因子和储存血液中的脂质在TRALI发病机制中所起的第二种作用。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，包括最近的手术，大量输血和细胞因子治疗。此外，与这些临床实体相关的介质激活肺内皮和改变PMN:EC生理学的能力将被测试。这些具体目标的完成将为临床干预的目标地区提供信息，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.