Experimental transfusion-related acute lung injury

马克·R·鲁尼是加州大学旧金山分校的肺部和重症监护内科医生， 对急性肺损伤及其基本机制有明确的兴趣。鲁尼博士在这项申请中建议 建立三种不同的输血相关急性肺损伤(TRALI)小鼠体内模型 人类输血相关死亡的主要原因。TRALI的发病机制尚不清楚 缺乏临床相关的活体动物模型。鲁尼博士建议开发一种 (1)MHC-I和MHC-II单抗对小鼠TRALI模型的影响 抗原，(2)来自同种免疫小鼠的针对不匹配菌株的多克隆抗体，以及(3)较老的血液 对基因相同的小鼠具有中性粒细胞启动活性的产品。此外，他还将使用与临床相关的 启动机制(内毒素、正压通风)潜在地增强对小鼠的反应 TRALI的模型。三种鼠标模型的通用性，以及个体的潜在组合 模型，将允许解剖导致急性肺损伤的致病机制。鲁尼医生 假设中性粒细胞将是小鼠TRALI的关键细胞介质，因此他将测试 中性粒细胞和内皮细胞黏附分子、免疫复合体受体的作用及激活 补体受体基因敲除小鼠和细胞耗尽/重建实验。他也 假设肺泡巨噬细胞将在小鼠TRALI中发挥作用，并将用 肺泡巨噬细胞耗竭与重建实验。最后，组织的潜在贡献 在选定的实验性TRALI模型中，将使用肥大细胞缺陷小鼠来测试肥大细胞。通过 开发相关的TRALI动物模型并仔细确定其致病机制，他将 为这一严重的输血治疗并发症提供了新的线索。鲁尼博士召集了一位专家 科学顾问委员会将监督他的研究并帮助实施一项教育计划，该计划将 丰富了他的技术和智力发展。心血管研究所和大学 致力于发展鲁尼博士的学术生涯，并在最后 在授权期内，鲁尼博士将做好充分准备，开始作为一名独立人士的成功职业生涯 急性肺损伤领域的调查员。

Mark R. Looney is a pulmonary and critical care physician at the University of California, San Francisco with a well-defined interest in acute lung injury and its basic mechanisms. Dr. Looney proposes in this application to develop three different in vivo mouse models of transfusion-related acute lung injury (TRALI), which is the leading cause of transfusion-related mortality in humans. The pathogenesis of TRALI is poorly understood and suffers from the lack of a clinically relevant in vivo animal model. Dr. Looney proposes to develop mouse models of TRALI by transfusing (1) monoclonal antibodies to mice with corresponding MHC I and II antigens, (2) polyclonal antibodies from alloimmunized mice to mismatched strains, and (3) older blood products with neutrophil priming activity to genetically identical mice. Also, he will use clinically relevant priming mechanisms (LPS, positive pressure ventilation) to potentially augment the response to the mouse models of TRALI. The versatility of three mouse models, and also the potential combination of individual models, will allow dissection of the pathogenic mechanisms responsible for acute lung injury. Dr. Looney postulates that the neutrophil will be a key cellular mediator of mouse TRALI and accordingly he will test the role of neutrophil and endothelial adhesion molecules, immune complex receptors, and activated complement receptors using gene knockout mice and cell depletion/reconstitution experiments. He also hypothesizes that the alveolar macrophage will play a role in mouse TRALI and will test this hypothesis with alveolar macrophage depletion and reconstitution experiments. Finally, the potential contribution of tissue mast cells will be tested by using mast cell deficient mice in selected models of experimental TRALI. By developing a relevant animal model of TRALI and carefully determining its pathogenic mechanisms, he will shed new light on this serious compliction of transfusion therapy. Dr. Looney has assembled an expert scientific advisory committee who will oversee his research and help implement an educational plan that will enrich his technical and intellectual development. The Cardiovascular Research Institute and the University of California, San Francisco are committed to developing the academic career of Dr. Looney, and at the end of the grant period, Dr. Looney will be well equipped to embark on a successful career as an independent investigator in the field of acute lung injury.