Transfusion and Lung Injury

输血和肺损伤

• 批准号: 7128530
• 负责人: Pearl T Toy
• 金额: $ 248.61万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7128530
• 关键词: blood transfusion; clinical research; lung injury

DESCRIPTION (provided by applicant): Transfusion Related Acute Lung Injury (TRALI) is acute lung injury that occurs during or shortly after transfusion, and is the leading cause of mortality associated with transfusion. According to our preliminary data, TRALI may occur in 1:500 high-risk patients who are transfused. This Transfusion Biology and Medicine SCCOR will determine the incidence, epidemiology, and mechanisms of TRALI, in order to provide scientific data to support strategies that will effectively limit this potentially life-threatening syndrome. We propose four interrelated clinical and basic projects that will elucidate the pathogenesis of TRALI, and translate science into practice. Project 1 will determine the incidence of TRALI through implementation of a novel surveillance system that will capture all TRALI cases that occur after transfusion of almost one million units at two large university hospitals. This project will also determine the clinical risk factors associated with TRALI through a large, prospective case-control study at two major university hospitals. Project 2 will determine whether various blood products induce mild to moderate alterations of lung function in healthy, moderately ill, and severely ill patients, and whether the changes are associated with antibody, cytokines or neutrophil priming activity in the blood product. Project 3 will determine the mechanisms of lung injury in mice transfused with monoclonal or polyclonal anti-MHCI and MCHII antibodies, or with plasma from stored blood. In addition, this project will determine the roles of adhesion receptors, chemoattractant receptors, neutrophils and alveolar macrophages in TRALI, and will test a strategy to hasten recovery from TRALI. Project 4 will determine the basic mechanisms of neutrophil adhesion signaling and will study activation of such signaling by plasma from units and recipients with TRALI. The projects are supported by four cores, including a Clinical Skills Development Core to train young investigators in this rich environment. Through these bench-to-bedside collaborations, this SCCOR will develop strategies to limit or even prevent TRALI. (End of Abstract) INDIVIDUAL PROJECTS AND CORE UNITS PROJECT 1: Transfusion-Related Acute Lung Injury: Incidence and Mechanisms (Toy, Pearl) DESCRIPTION (provided by applicant): Project 1 proposes to obtain scientific data to develop strategies that will prevent or reduce transfusion-related acute lung injury (TRALI), the leading reported cause of transfusion-associated mortality. To achieve this goal, we aim to determine the incidence and mechanisms for the syndrome. The incidence of TRALI is underestimated due to lack of a standard definition and lack of an effective surveillance system of large number of transfusions. Our preliminary data indicate the incidence is as high as 1:500 transfusions in high risk patients. Using the new NHLBI Working Group definition, we will determine the actual incidence of clinical TRALI by a novel surveillance system of almost one million transfusions at two university hospitals. The surveillance system will capture all cases. The mechanisms of TRALI are unclear because previous case series did not include appropriate controls. The proposed large, prospective study will enroll concurrent control patients who were transfused but did not develop TRALI. The association of clinical factors will be tested in TRALI cases and controls. We will determine whether patient conditions such as surgery or inflammation predispose patients to developing TRALI. We will correlate the transfusion of anti-HLA, anti-neutrophil and proinflammatory agents in donor blood products with the development of TRALI. We will also determine if there is a correlation between the titer and specificities of anti-HLA and neutrophil antibodies and the development of TRALI. We will determine whether acute neutropenia is pathognomic of antibody-mediated TRALI. The presence of genetic predispositions in TRALI patients will be identified. We will also determine whether leukoreduction removes any risk associated with transfusion of older cellular blood products, by abrogation of cytokines and neutrophil priming activity. Thus, through a large prospective case-control study, we will be able to determine the mechanisms of TRALI. Once this study clarifies the incidence and mechanisms, rational strategies can be developed to limit this potentially life-threatening syndrome. (End of Abstract)

描述（由申请人提供）： 输血相关的急性肺损伤（TRALI）是在输血后或不久内发生的急性肺损伤，是与输血相关的死亡率的主要原因。根据我们的初步数据，Trali可能发生在1：500名被输血的高危患者中。该输血生物学和医学SCCOR将确定Trali的发病率，流行病学和机制，以提供科学数据来支持将有效限制这种潜在的威胁生命综合征的策略。我们提出了四个相互关联的临床和基本项目，这些项目将阐明Trali的发病机理，并将科学转化为实践。项目1将通过实施一种新型的监视系统来确定Trali的发生率，该系统将捕获所有在两家大型大学医院输血后发生的所有Trali案件。该项目还将通过在两家大型大学医院进行大型的前瞻性病例对照研究来确定与Trali相关的临床风险因素。项目2将确定各种血液产物在健康，适度疾病和严重患者中诱导肺功能的轻度至中度改变，以及这些变化是否与抗体，细胞因子或中性粒细胞启动活性有关。项目3将确定带有单克隆或多克隆抗MHCI和MCHII抗体的小鼠中肺损伤的机制，或储存血液中的血浆。此外，该项目将确定Trali中粘附受体，趋化受体，中性粒细胞和肺泡巨噬细胞的作用，并将测试一种策略，以加快从Trali中恢复。项目4将确定中性粒细胞粘附信号传导的基本机制，并将研究来自TRALI单位和受体的血浆对这种信号的激活。这些项目得到了四个核心的支持，其中包括在这个丰富的环境中培训年轻调查员的临床技能发展核心。通过这些基准与床边的合作，该SCCOR将制定限制甚至防止Trali的策略。 （抽象的结尾） 个别项目和核心单位 项目1：输血相关的急性肺损伤：发病率和机制 （玩具，珍珠） 描述（由申请人提供）： 项目1提议获得科学数据，以制定将预防或减少输血相关的急性肺损伤（TRALI）的策略，这是主要报道的输血相关死亡率的主要原因。为了实现这一目标，我们旨在确定综合征的发病率和机制。由于缺乏标准定义和缺乏大量输血的有效监视系统，Trali的发生率被低估了。我们的初步数据表明，高风险患者的发病率高达1：500。使用新的NHLBI工作组定义，我们将通过在两家大学医院进行近一百万个输血的新型监视系统来确定临床Trali的实际发生率。监视系统将捕获所有情况。 Trali的机制尚不清楚，因为先前的病例系列不包括适当的对照。拟议的大型前瞻性研究将招募并发的对照患者，这些患者被输血但没有发展。临床因素的关联将在TRALI病例和对照组中进行测试。我们将确定患者状况（例如手术或炎症）是否会易孕症患者发展。我们将将抗HLA，抗独立噬细胞和供体血液产物中的抗炎性剂与Trali的发展相关联。我们还将确定抗HLA和中性粒细胞抗体的滴度和特异性与Trali的发展之间是否存在相关性。我们将确定急性中性粒细胞减少症是否是抗体介导的TRALI的病理认知。将发现TRALI患者中遗传易感性的存在。我们还将通过废除细胞因子和嗜中性粒细胞启动活性来确定白细胞是否消除了与旧细胞血产品相关的任何风险。因此，通过一项大量的前瞻性病例对照研究，我们将能够确定Trali的机制。一旦这项研究阐明了发生率和机制，就可以制定理性策略来限制这种潜在的威胁生命的综合征。 （抽象的结尾）