The amyloid precursor protein protects against acute lung injury

项目总结 中性粒细胞对感染的反应是一把双刃剑，既可以杀死入侵的病原体 和/或造成组织损伤。因此，中性粒细胞难以定义先天免疫反应是否对 感染对宿主是有益的也是有害的。中性粒细胞脱颗粒与释放的相互依赖 细胞外陷阱(Nets)在急性和慢性炎症中发挥着重要作用。这款新的R21 这一提议是基于一项意想不到的发现，即淀粉样前体蛋白(APP)调节 肺部铜绿假单胞菌感染中性粒细胞脱颗粒和网织红细胞增多。 虽然已知APP通过产生神经毒性β-淀粉样蛋白来推动阿尔茨海默病的病理 肽，越来越多的证据强调了APP、β-淀粉样蛋白和先天性免疫之间的相互作用。老鼠 缺乏APP的人更容易患细菌性脑膜炎，而β-淀粉样蛋白是一种抗菌肽。初步 提供的数据支持App基因敲除小鼠表现出死亡率和肺损伤增加的假设 与野生型对照相比，对铜绿假单胞菌感染的反应。令人惊讶的是，感染铜绿假单胞菌的App 与野生型对照相比，基因敲除小鼠也表现出中性粒细胞流入的增加。此外，体外研究 证明从App基因敲除小鼠分离的骨髓来源的中性粒细胞增加 脱颗粒和网状沉着。总而言之，这些公布的和初步的数据支持概念上的创新 两个特定目标的技术上可行的方法，将测试APP调节的假设 限制铜绿假单胞菌感染期间肺损伤的中性粒细胞脱颗粒和网织红细胞增多。目标1将 阐明APP在铜绿假单胞菌致肺损伤中的保护作用。AIM 2将测试APP的实用性 和β-淀粉样多肽作为危重患者预后的预测因子。 我们发现APP在铜绿假单胞菌肺部感染期间保护宿主，这是一个非常重要的发现 在肺生物学和神经生物学领域具有广泛影响的概念进展。铜绿假单胞菌是 引起慢性肺部疾病患者肺炎的最常见的革兰氏阴性病原菌(例如 阻塞性肺疾病和囊性纤维化)，在合并呼吸衰竭的危重患者中很常见 在重症监护室。在最严重的病例中，肺炎发展为急性肺损伤、败血症和 多器官衰竭。重要的是，幸存者经常遭受长期后遗症，如重症监护后综合症。 (图片)和神经认知功能障碍，降低整体生活质量。因此，我们提议的研究可能会揭示 病原体介导的中性粒细胞功能障碍的APP反应与中性粒细胞之间潜在的变革性联系 器官功能障碍和神经认知后遗症。

PROJECT SUMMARY Neutrophil activation in response to infection is a double-edged sword that can either kill invading pathogens and/or inflict tissue damage. Thus, neutrophils inextricably define whether the innate immune response to infection is beneficial or deleterious to the host. The interdependence of neutrophil degranulation and release of extracellular traps (NETs) has emerged as an important player in acute and chronic inflammation. This new R21 proposal is based on the unexpected discovery that the amyloid precursor protein (APP) regulates neutrophil degranulation and NETosis during Pseudomonas aeruginosa infection in the lung. While APP is known to drive the pathology of Alzheimer's disease via production of neurotoxic β-amyloid peptides, a growing body of evidence highlights an interplay between APP, β-amyloid, and innate immunity. Mice lacking APP are more susceptible to bacterial meningitis, and β-amyloid is an antimicrobial peptide. Preliminary data are presented to support the premise that App knockout mice show increased mortality and lung injury compared to wild type controls in response to P. aeruginosa infection. Surprisingly, P. aeruginosa-infected App knockout mice also exhibit increased neutrophil influx compared to wild type controls. In addition, in vitro studies demonstrate that isolated bone marrow-derived neutrophils from App knockout mice display increased degranulation and NETosis. Together, these published and preliminary data support a conceptually innovative and technically feasible approach for two Specific Aims that will test the HYPOTHESIS that APP modulates neutrophil degranulation and NETosis to limit lung injury during P. aeruginosa infection. Aim 1 will elucidate the protective role of APP during P. aeruginosa-induced lung injury. Aim 2 will test the utility of APP and β-amyloid peptides as predictors of outcome in critically ill patients. Our discovery that APP protects the host during P. aeruginosa lung infection is a highly significant conceptual advance with broad impact across the fields of lung biology and neurobiology. P. aeruginosa is the most frequent Gram-negative pathogen causing pneumonia in patients with chronic lung disease (e.g., chronic obstructive pulmonary disease and cystic fibrosis), and is prevalent in critically ill patients with respiratory failure in the intensive care unit. In the most severe cases, pneumonia progresses to acute lung injury, sepsis, and multi-organ failure. Importantly, survivors often suffer long-term sequelae such as post-intensive care syndrome (PICS) and neurocognitive dysfunction that reduce overall quality of life. Thus, our proposed studies may reveal potentially transformative links between a pathogen-mediated dysfunctional APP response in neutrophils and organ dysfunction and neurocognitive sequelae.