Lung Macrophage Programming in Acute Lung Injury

急性肺损伤中的肺巨噬细胞编程

• 批准号: 10553701
• 负责人: William Janssen
• 金额: $ 95.05万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553701
• 关键词: Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Affect; Alveolar; Alveolar Cell; Alveolar Macrophages; Apoptosis; Binding; Biology; Blood capillaries; Bronchoscopy; Calibration; Cells; Citric Acid Cycle; Clinical Research; Data; Development; Embryonic Development; Endothelial Cells; Endothelium; Energy-Generating Resources; Epithelial Cells; Epithelium; Fibrosis; Glycolysis; Goals; Health; Heart; Human; Human Volunteers; Inflammation; Inflammatory; Inflammatory Response; Life; Link; Lung; Macrophage; Metabolic; Metabolism; Mucins; Pathologic; Patients; Persons; Play; Pneumonia; Proteins; Recovery; Research Personnel; Resolution; Role; Sialic Acids; Specimen; Stable Populations; System; Technology; Testing; Tissues; Transgenic Animals; alveolar epithelium; cell injury; inflammatory lung disease; injured; lung injury; lung repair; monocyte; multidisciplinary; neutrophil; novel; programs; receptor binding; recruit; repair function; repaired; self-renewal; sialic acid binding Ig-like lectin; tissue repair

PROJECT SUMMARY Acute inflammatory lung diseases affect over 450 million people worldwide each year. Pathologic hallmarks include neutrophil accumulation, alveolar epithelial and endothelial cell injury, and loss of epithelial-capillary integrity. For alveolar repair to occur, inflammation must be halted, debris and inflammatory cells removed, injured tissue cells replaced, and capillary barrier function re-established. Macrophages are key players in all of these. The primary objective of this proposal is to create a Program in Lung Macrophage Biology that will determine how lung macrophages are programmed to halt inflammation and promote alveolar repair. A concept at the heart of the proposal is that of macrophage subsets. During health, the airspaces are occupied by a stable population of resident alveolar macrophages (RAM) that arise during embryogenesis and self-renew throughout life. RAMs remain during inflammation but are joined by recruited macrophages (RecM) that mature from circulating monocytes. These RecM remain in the lungs until alveolar function is restored, and then in most cases undergo apoptosis. However, in certain situations RecM escape apoptosis. We have shown that this is associated with the development of fibrosis. The precise roles played by RAMs vs RecM in the resolution of inflammation and promotion of tissue repair remain largely unknown. However, our data suggest that their respective roles are very different. In this context, the Program in Lung Macrophage Biology will explore 3 complementary themes. Theme 1 tests the hypothesis that RecM apoptosis is essential for the resolution of inflammation and that delayed apoptosis leads to fibrosis. The mechanisms that regulate the extrinsic apoptosis pathway and the intracellular proteins that block it will be studied. Theme 2 tests the hypothesis that binding of airway-derived mucins to Siglecs (a class of sialic acid-binding receptors with immunoinhibitory function) expressed on macrophages calibrates macrophage inflammatory responses. Theme 3 provides a tight link with the other themes and explores how cellular metabolism regulates macrophage inflammatory and pro-reparative functions and how it regulates survival of macrophage subsets. In this context, we propose that RecM preferentially use glycolysis as an energy source, whereas RAMs have increased utilization of the TCA cycle. HIF-1a is stabilized in RecM and is viewed as a central metabolic regulator. The 3 themes are further linked by their focus on differential functions of RAM vs RecM, the utilization of fresh human macrophages and shared use of cutting edge technologies. The Program leverages a multidisciplinary team of highly accomplished investigators, novel transgenic animal systems that we have developed, and a strong clinical research component. The latter includes whole human lungs obtained from donors that died with ARDS, bronchoscopy specimens from patients with ARDS, and LPS exposure studies with healthy human volunteers.

项目摘要 急性炎症性肺部疾病每年影响全球超过4.5亿人。病理标志 包括嗜中性粒细胞的积累，肺泡上皮和内皮细胞损伤以及上皮毛细管的损失 正直。为了进行肺泡修复，必须停止炎症，去除碎屑和炎症细胞， 损伤的组织细胞更换，毛细管屏障功能重新建立。巨噬细胞是所有的关键参与者 这些。该提案的主要目的是在肺巨噬细胞生物学中创建一个计划 确定如何编程肺巨噬细胞以阻止炎症并促进肺泡修复。 该提案的核心是巨噬细胞子集的概念。在健康期间，空间是 在胚胎发生和 一生的自我更新。公羊在炎症期间保留，但被招募的巨噬细胞（RECM）加入 从循环的单核细胞中成熟。这些RECM保留在肺中，直到恢复肺泡功能为止，并且 然后，在大多数情况下会经历凋亡。但是，在某些情况下，REC逃脱了凋亡。我们已经显示了 这与纤维化的发展有关。 RAMS vs RECM在炎症和促进组织修复中扮演的精确作用 在很大程度上未知。但是，我们的数据表明它们各自的角色大不相同。在这个 上下文，肺巨噬细胞生物学中的程序将探讨3个互补主题。主题1测试 假设RECM凋亡对于炎症的分辨至关重要，并且延迟凋亡是导致的 进行纤维化。调节外部凋亡途径和细胞内蛋白的机制 将其研究将被研究。主题2检验了以下假设：气道衍生的粘蛋白与Siglecs结合（一个类别） 在巨噬细胞上表达的具有免疫抑制功能的唾液酸结合受体的校准 巨噬细胞炎症反应。主题3提供了与其他主题的紧密联系，并探讨了如何 细胞代谢调节巨噬细胞的炎症和促育功能以及它如何调节 巨噬细胞子集的存活率。在这种情况下，我们建议RECM优先使用糖酵解作为 能源，而公羊的使用率增加了TCA周期。 HIF-1A在RECM中稳定，IS 被视为中央代谢调节剂。这三个主题通过关注差异功能进一步联系在一起 RAM与RECM的利用，新鲜的人类巨噬细胞以及尖端技术的共同使用。 该计划利用了一支由高度成就的研究者，新型转基因动物组成的多学科团队 我们开发的系统和强大的临床研究组成部分。后者包括整个人 从死于ARD的供体，ARDS患者的支气管镜标本的供体获得的肺部和LPS 与健康的人类志愿者的暴露研究。