Roles for interstitial and airspace macrophages in resolution of pulmonary inflammation

间质和气腔巨噬细胞在解决肺部炎症中的作用

• 批准号: 10655327
• 负责人: PETER M HENSON
• 金额: $ 72.98万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10655327
• 关键词: Apoptosis; Behavior; Bleomycin; Blood; Categories; Cells; Complex; Effectiveness; Elements; Event; Excision; Exhibits; Exposure to; Fibrosis; Homeostasis; Hydrochloric Acid; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza A Virus, H1N1 Subtype; Influenza A virus; Injury; Lipopolysaccharides; Location; Lung; Lung diseases; Macrophage; Modeling; Mus; Outcome; Participant; Phase; Play; Population; Process; Property; Pulmonary Inflammation; Resistance; Resolution; Role; Sentinel; Skin; Stimulus; Structure; Subgroup; Testing; Therapeutic; Time; Tissues; cell injury; falls; influenza infection; interstitial; monocyte; neutrophil; novel strategies; novel therapeutics; prevent; recruit; repaired; response; restoration; tissue repair; wound

Project Summary/Abstract Inflammation is is a highly complex process that is a component of most forms of pulmonary disease. It represents a response to tissue insult and normally (ideally) leads to return of tissue homeostasis, although, depending on the initating stimulus, the repair process may also involve a transient fibrotic response (akin to “wound heaing” in the skin). Macrophages are essential cells in these events, playing key roles in all steps in the processes, orchestrating many elements of the repair/resolution and return to homeostasis; the understaning of which is the primary focus of this proposal. Macropahges in the lung fall into two general categories: 1) resident macrophages involved in maintaining the homeostasis and serving as sentinels to detect the initial stimulus or injury and 2) recruited macrophages maturing from incoming monocytes. We and others have recently identified unique macrophage subtypes (resident and recruited) within the pulmonary interstitium in addition to those in the airspaces, but at this point, their specific responses to, or participation in, the inflammatory responses and their resolution have not been determined. Accordingly, during this project we will elucidate the roles for individual macrophage subsets in the resolution phase of the inflammatory response, with the ultimate objective of devising therapeutic approaches for its enhancement. Using novel approaches to target, lineage trace and manipulate the different macrophage populations we will determine their numbers, functional programing state, and critically their specific location within the lungs over the course of inflammation induced by four unrelated stimuli – two that lead to early resolution (bacterial lipopolysaccharide and H1N1 influenza infection) and two that include a transient fibrotic response during a more prolonged resolution (bleomycin or HCl, the latter mimicking exposure to gastic contents). During inflammation, the resident macrophages within the normal lung interstitium and airspaces increase in numbers but also are joined by large numbers of recruited macrophages. In the processes of resolution, these excess macrophages are removed and a major focus of the proposal will be determination of the modes of removal and the effects of deliberately enhancing (or delaying) this removal on the desired return to homeostatic lung structure and function. Key hypotheses to be explored include: 1) Unique macrophage properties during both iniation of inflammation and especially its resolution, for subsets of interstitial macrophages (vs. those in the airspaces) relating to their precise localization, for example within the bronchovascular bundles or in the subpleural region). 2) Macrophages are recruited to inflamed lungs in waves, exhibiting unique programing properties, with later recruited cells playing the key roles in inflammation resolution, including both the induction and resolution of the transient fibrotic response. 3) The recruited macrophages themselves, in both the transient and extended inflammatory circumstances are removed after undergoing extrinsic apoptosis.

项目总结/摘要 炎症是一个高度复杂的过程，是大多数形式的肺部疾病的组成部分。它 代表对组织损伤的反应，并且通常（理想地）导致组织稳态的恢复，尽管， 取决于起始刺激，修复过程也可能涉及短暂的纤维化反应（类似于 皮肤中的“伤口愈合”）。巨噬细胞是这些事件中必不可少的细胞，在所有步骤中发挥关键作用， 过程，协调修复/解决和恢复稳态的许多要素; 理解这一点是本提案的主要重点。肺巨噬细胞分为两大类， 类别：1）参与维持体内平衡并充当哨兵的常驻巨噬细胞， 检测初始刺激或损伤，以及2）从进入的单核细胞中募集成熟的巨噬细胞。我们和 其他人最近在肺内鉴定出独特的巨噬细胞亚型（驻留和募集）， 除了那些在领空，但在这一点上，他们的具体反应，或参与， 炎症反应及其消退尚未确定。因此，在这个项目中，我们 将阐明单个巨噬细胞亚群在炎症反应消退阶段的作用， 其最终目标是设计治疗方法以增强其效果。使用新的方法， 靶向、谱系追踪和操纵不同的巨噬细胞群体，我们将确定它们的数量， 功能编程状态，以及关键的是它们在炎症过程中在肺内的具体位置 由四种不相关的刺激诱导-其中两种导致早期消退（细菌脂多糖和H1N1 流感感染）和两种包括在更长时间的缓解期间的短暂纤维化反应 （博莱霉素或HCl，后者模拟暴露于胃内容物）。在炎症期间，居民 正常肺组织和肺间隙内的巨噬细胞数量增加，但也加入了 大量募集的巨噬细胞。在分解过程中，这些多余的巨噬细胞 建议的一个主要重点将是确定清除的方式和 有意地增强（或延迟）这种去除，以期望恢复到稳态肺结构， 功能待探索的关键假设包括：1）在两种启动过程中独特的巨噬细胞特性， 炎症，尤其是间质巨噬细胞亚群的炎症消退（与气隙中的巨噬细胞相比） 与其精确定位有关，例如在支气管血管束内或胸膜下 区域）。2)巨噬细胞以波浪状被招募到发炎的肺部，表现出独特的编程特性， 后来募集的细胞在炎症消退中起关键作用，包括诱导和 暂时性纤维化反应的消退。3)募集的巨噬细胞本身，在短暂的 并在经历外源性凋亡后去除扩展的炎症环境。

项目成果

Polyamine import and accumulation causes immunomodulation in macrophages engulfing apoptotic cells.

• DOI: 10.1016/j.celrep.2021.110222
• 发表时间: 2022-01-11
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: McCubbrey AL;McManus SA;McClendon JD;Thomas SM;Chatwin HB;Reisz JA;D'Alessandro A;Mould KJ;Bratton DL;Henson PM;Janssen WJ
• 通讯作者: Janssen WJ

Interstitial Macrophages Mediate Efferocytosis of Alveolar Epithelium during Influenza Infection.

流感感染期间间质巨噬细胞介导肺泡上皮的胞吞作用。

• DOI: 10.1165/rcmb.2023-0217ma
• 发表时间: 2024
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Zuttion,MariliaSanchezSantosRizzo;Parimon,Tanyalak;Yao,Changfu;Stripp,BarryR;Wang,Ying;Soto,ChristopherM;Ortega,Zackary;Li,Xiao;Janssen,WilliamJ;Chen,Peter
• 通讯作者: Chen,Peter

Air-Inflation of Murine Lungs with Vascular Perfusion-Fixation.

• DOI: 10.3791/62215
• 发表时间: 2021-02-02
• 期刊: JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
• 影响因子: 1.2
• 作者: Thomas, Stacey M.;Bednarek, Joseph;Janssen, William J.;Hume, Patrick S.
• 通讯作者: Hume, Patrick S.

Cigarette smoke-induced airspace disease in mice develops independently of HIF-1α signaling in leukocytes.

香烟烟雾引起的小鼠空腔疾病的发展独立于白细胞中的 HIF-1α 信号传导。

• DOI: 10.1152/ajplung.00491.2021
• 发表时间: 2022
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Hume,PatrickS;McClendon,Jazalle;Kopf,KatrinaW;Harral,JulieW;Poczobutt,JoannaM;McCubbrey,AlexandraL;Smith,BradfordJ;Henson,PeterM;Majka,SusanM;Petrache,Irina;Janssen,WilliamJ
• 通讯作者: Janssen,WilliamJ

Application-specific approaches to MicroCT for evaluation of mouse models of pulmonary disease.

• DOI: 10.1371/journal.pone.0281452
• 发表时间: 2023
• 期刊: PloS one
• 影响因子: 3.7