Fine-tuning the Neutrophilic Response to Pneumonia

项目总结/摘要 肺是多种病原体的入口，这些病原体可能导致肺炎甚至急性呼吸道疾病。 呼吸窘迫综合征（ARDS），这是一种危及生命的综合征，没有具体的治疗方法 除了提供温和的机械通气和支持性护理。中性粒细胞是一个关键的 病原性肺部感染早期免疫反应的细胞介质，但过度旺盛 中性粒细胞反应可引起肺的附带损伤并导致急性肺损伤。在本申请中， 中性粒细胞的一种新功能，即释放中性粒细胞胞外陷阱（NETs），将在小鼠中进行研究 急性肺部感染模型。NET由细胞外染色质组成， 颗粒蛋白，并已被提出在捕获和杀死细菌中起重要作用， 其他病原体。然而，我们认为NET对邻近细胞是有毒的，并且在平衡状态下， 肺炎和急性肺损伤中的适应不良和非必要的宿主反应。本申请的目标1将 使用新技术研究NET在细菌和病毒性肺炎小鼠模型中的作用， 可视化和量化NET。我们还将测试脂氧素介导剂通过Fpr 2信号传导在 中性粒细胞在调节NET生产和急性肺损伤的进展。目标2将测试 DNase 1在调节NETs在肺中的降解中的作用以及DNase 1治疗的重要作用 控制感染和保护肺屏障。在翻译研究中，Aim 2还将使用 来自严重感染的危重患者的生物样品，以测试NET和DNase 1生物活性（a） 预测进展为ARDS或（B）与ARDS的不良临床结局相关。的因素 确定局部肺部感染是否进展为急性肺损伤尚不清楚，但这种应用 建议，NET的关键调解人在这一过程中，有针对性的。我们的研究使用活的细菌和 病毒感染，急性肺部炎症和损伤可视化的新方法，NET，药理学 中和NET的遗传学方法，以及补充我们小鼠模型的翻译研究， 很好地定位于提供关于NET的体内意义的明确证据，并将NET定位为 治疗病原体诱导的肺损伤的新靶点。

Project Summary/Abstract The lung is a portal of entry for a variety of pathogenic organisms that may cause pneumonia or even the acute respiratory distress syndrome (ARDS), which is a life-threatening syndrome that has no specific treatments except for the provision of gentle mechanical ventilation and supportive care. The neutrophil is a critical cellular mediator of the early immune response to pathogenic lung infections, but an overly exuberant neutrophil response may cause collateral damage to the lung and lead to acute lung injury. In this application, a new function of neutrophils, the release of neutrophil extracellular traps (NETs), will be investigated in mouse models of acute lung infection. NETs are composed of extracellular chromatin decorated with neutrophil granular proteins and have been proposed to serve an important role in the trapping and killing of bacteria and other pathogens. However, we propose that NETs are toxic to adjacent cells and are on balance a maladaptive and dispensible host response in pneumonia and acute lung injury. Aim 1 of this application will investigate the role of NETs in mouse models of bacterial and viral pneumonia using novel techniques to visualize and quantify NETs. We will also test the role of lipoxin mediators signaling through Fpr2 on neutrophils in regulating NET production and the progression to acute lung injury. Aim 2 will test the role of DNase1 in regulating the degradation of NETs in the lung and the important effects of DNase1 treatment on the containment of infection and preservation of the lung barrier. In translational studies, Aim 2 will also use biological samples from critically ill patients with severe infections to test if NETs and DNase1 bioactivity (a) predict the progression to ARDS or (b) are associated with poor clinical outcomes in ARDS. The factors that determine whether a localized lung infection progresses to acute lung injury are not known, but this application proposes that NETs are critical mediators in this process and targetable. Our studies using live bacterial and viral infections, novel approaches to visualize acute lung inflammation and injury, and NETs, pharmacologic and genetic approaches to neutralize NETs, and translational studies to complement our mouse models, are well-positioned to provide definitive evidence on the in vivo significance of NETs, and to position NETs as a novel target for the treatment of pathogen-induced lung injury.