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.

项目概要 急性炎症性肺病每年影响全球超过 4.5 亿人。病理标志 包括中性粒细胞积聚、肺泡上皮细胞和内皮细胞损伤以及上皮毛细血管丧失 正直。为了发生肺泡修复，必须停止炎症，清除碎片和炎症细胞， 受损的组织细胞被替换，毛细血管屏障功能重新建立。巨噬细胞是所有这些过程中的关键角色 这些。该提案的主要目标是创建一个肺巨噬细胞生物学计划，该计划将 确定肺巨噬细胞如何编程来阻止炎症并促进肺泡修复。 该提案的核心概念是巨噬细胞亚群。在健康期间，空域是 被胚胎发生过程中产生的稳定的常驻肺泡巨噬细胞（RAM）群占据 终生自我更新。 RAM 在炎症期间保留，但由招募的巨噬细胞 (RecM) 加入 由循环单核细胞成熟。这些 RecM 保留在肺部，直到肺泡功能恢复，并且 然后在大多数情况下会发生细胞凋亡。然而，在某些情况下，RecM 会逃避细胞凋亡。我们已经展示了 这与纤维化的发展有关。 RAM 与 RecM 在解决炎症和促进组织修复中所发挥的精确作用 仍然很大程度上不为人所知。然而，我们的数据表明他们各自的角色非常不同。在这个 在此背景下，肺巨噬细胞生物学项目将探索 3 个互补的主题。主题 1 测试 假设 RecM 细胞凋亡对于炎症的消退至关重要，并且延迟的细胞凋亡导致 至纤维化。调节外源性细胞凋亡途径的机制和细胞内蛋白质 阻止它将被研究。主题 2 检验以下假设：气道来源的粘蛋白与 Siglecs（一类 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炎症和促修复功能及其调节方式 巨噬细胞亚群的存活。在这种情况下，我们建议 RecM 优先使用糖酵解作为 能源，而 RAM 增加了 TCA 循环的利用率。 HIF-1a 在 RecM 中稳定，并且 被视为中央代谢调节剂。这三个主题通过对不同功能的关注而进一步联系在一起 RAM 与 RecM 的比较，新鲜人类巨噬细胞的利用以及尖端技术的共同使用。 该计划利用了一支由高水平研究人员、新型转基因动物组成的多学科团队 我们开发的系统以及强大的临床研究组成部分。后者包括整个人类 从死于 ARDS 的捐献者身上获取的肺部、ARDS 患者的支气管镜检查标本和 LPS 对健康人类志愿者进行的暴露研究。