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.

项目摘要 急性炎症性肺病每年影响全世界超过4.5亿人。病理特征 包括中性粒细胞积聚、肺泡上皮和内皮细胞损伤以及上皮-毛细血管损失 完整为了进行肺泡修复，必须停止炎症，清除碎片和炎性细胞， 修复受损组织细胞，重建毛细血管屏障功能。宏观经济是所有这些领域的关键参与者， 这些.该提案的主要目标是创建一个肺巨噬细胞生物学项目， 确定肺巨噬细胞如何编程以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， 由胚胎发生过程中出现的稳定的肺泡巨噬细胞（RAM）群体占据， 终生自我更新。RAM在炎症期间保留，但被招募的巨噬细胞（RecM）加入 由循环单核细胞成熟。这些RecM保留在肺中，直到肺泡功能恢复， 然后在大多数情况下经历细胞凋亡。然而，在某些情况下，RecM逃避凋亡。我们已经表明 这与纤维化的发展有关。 RAMs与RecM在缓解炎症和促进组织修复中发挥的确切作用 但基本上仍不为人所知。然而，我们的数据表明，它们各自的作用非常不同。在这 在这种情况下，在肺巨噬细胞生物学计划将探讨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 到纤维化调节外源性凋亡途径和细胞内蛋白质的机制， 块将被研究。主题2检验了气道来源的粘蛋白与Siglecs（一类 具有免疫抑制功能的唾液酸结合受体） 巨噬细胞炎症反应。主题3提供了与其他主题的紧密联系，并探讨如何 细胞代谢调节巨噬细胞炎症和促修复功能，以及它如何调节 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代谢途径。 能源，而RAM增加了TCA循环的利用率。HIF-1a在RecM中稳定， 被认为是一个重要的代谢调节器。这三个主题通过它们对微分函数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享使用。 该计划利用了一个多学科团队的高度成就的研究人员，新的转基因动物， 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的供体获得的肺，从患有ARDS的患者获得的支气管镜检查标本，以及LPS 健康志愿者的暴露研究。