Fine-tuning the Neutrophilic Response to Pneumonia

项目摘要/摘要 肺是各种病原体进入的门户，这些病原体可能会导致肺炎甚至急性肺炎 呼吸窘迫综合征(ARDS)，这是一种没有特定治疗方法的危及生命的综合征 除了提供温和的机械通风和支持性护理。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，但过度活跃 中性粒细胞反应可能对肺造成附带损害，导致急性肺损伤。在此应用程序中， 中性粒细胞的一项新功能--中性粒细胞胞外陷阱(Nets)的释放将在小鼠身上进行研究 急性肺部感染模型。Net是由细胞外染色质装饰的中性粒细胞组成的 颗粒蛋白，已被认为在捕获和杀死细菌和 其他病原体。然而，我们认为Net对邻近的细胞是有毒的，而且平衡起来是一种 肺炎和急性肺损伤中的不适应和可支配的宿主反应。此应用程序的目标1将 利用新技术研究Net在细菌性和病毒性肺炎小鼠模型中的作用 可视化和量化网络。我们还将测试脂氧素介体通过Fpr2在 中性粒细胞在调节净产量和进展为急性肺损伤中的作用。《目标2》将测试 DNase1在调节肺内Net降解中的作用及DNase1治疗对大鼠肺损伤的重要作用 控制感染和保护肺屏障。在翻译研究中，Aim 2也将使用 重症感染患者的生物样本用于检测NETS和DNase1的生物活性(A) 预测进展为ARDS或(B)与ARDS的不良临床结果相关。这些因素是 确定局部肺部感染是否进展为急性肺损伤尚不清楚，但这一应用 提出网络是这一进程中的关键调解人，并且是有针对性的。我们的研究使用活细菌和 病毒感染，显示急性肺部炎症和损伤的新方法，以及网络，药理学 而中和Net的遗传方法，以及补充我们小鼠模型的翻译研究，都是 处于有利地位，为NETS的活体意义提供明确的证据，并将NETS定位为 治疗病原体所致肺损伤的新靶点。

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.