Lung Macrophage Programming in Acute Lung Injury

急性肺损伤中的肺巨噬细胞编程

• 批准号: 10335239
• 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/10335239
• 关键词: Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Affect; Alveolar; Alveolar Macrophages; Apoptosis; Binding; Biology; Blood capillaries; Bronchoscopy; Cells; Citric Acid Cycle; Clinical Research; Data; Development; Embryonic Development; Endothelial Cells; Endothelium; Energy-Generating Resources; Epithelial; Epithelial Cells; Fibrosis; Glycolysis; Goals; Health; Heart; Human; Human Volunteers; Inflammation; Inflammatory; Inflammatory Response; Life; Link; Lung; 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; macrophage; 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.

项目总结 全球每年有超过4.5亿人感染急性炎症性肺病。病理特征 包括中性粒细胞聚集，肺泡上皮和内皮细胞损伤，上皮毛细血管丢失 正直。要进行肺泡修复，必须停止炎症，清除碎片和炎症细胞， 损伤的组织细胞被替换，毛细血管屏障功能重建。巨噬细胞是所有 这些。这项提议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被编程来抑制炎症和促进肺泡修复。 该提案的核心概念是巨噬细胞亚群。在健康期间，空域是 由稳定的常驻肺泡巨噬细胞(RAM)种群占据，这些RAM在胚胎发育和 在一生中自我更新。RAM在炎症期间仍然存在，但会被招募的巨噬细胞(RecM)加入 从循环中的单核细胞中成熟。这些RECM保留在肺内，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逃脱了细胞凋亡。我们已经展示了 这与纤维化的发展有关。 RAMS和RECM在消退炎症和促进组织修复中的确切作用 在很大程度上仍然不为人知。然而，我们的数据表明，他们各自的角色非常不同。在这 在此背景下，肺巨噬细胞生物学计划将探索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是必不可少的，并且延迟的细胞凋亡导致 到纤维化症。调控外源性细胞凋亡途径和细胞内蛋白的机制 我们将对其进行研究。主题2测试了呼吸道来源的粘蛋白与Siglecs(一类)结合的假设 具有免疫抑制功能的唾液酸结合受体)在巨噬细胞上表达 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 细胞代谢调节巨噬细胞炎症和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一种 能源，而公羊则增加了对三氯乙烷循环的利用。HIF-1a在RECM和IS中稳定 被视为中枢新陈代谢调节剂。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的对比，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度成功的研究人员组成的多学科团队，新型转基因动物 我们开发的系统和强大的临床研究组成部分。后者包括全人类 取自死于ARDS的供者的肺，ARDS患者的支气管镜标本，以及内毒素 对健康的人类志愿者进行暴露研究。