Macrophage Plasticity in Inflammatory Lung Injury

炎症性肺损伤中的巨噬细胞可塑性

• 批准号: 10491049
• 负责人: Asrar B. Malik
• 金额: $ 239.96万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491049
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Admission activity; Alveolar; Anti-Inflammatory Agents; Automobile Driving; Biology; Bone Marrow; COVID-19 pandemic; CREB1 gene; Cells; Characteristics; Clinical; Complement; Critical Illness; Development; Disease; Endothelial Cells; Endothelium; Environment; Epithelial; Equilibrium; Face; Foundations; Functional disorder; Future; Generations; Genetic; Genetic Transcription; Genomics; Homeostasis; Host Defense; Image; Immune; Immune response; Immune system; Infection; Inflammation; Inflammatory; Injury; Instruction; Intensive Care Units; Intervention; Ion Channel; Lung; Measures; Mediating; Microbe; Mus; Patients; Phagocytosis; Phenotype; Population; Potassium; Process; Pulmonary Inflammation; Purinoceptor; Reporter; Research; Resolution; Role; Sampling; Sentinel; Signal Pathway; Signal Transduction; Structure of parenchyma of lung; Supportive care; Testing; Therapeutic; Tissues; WNT Signaling Pathway; acute care; beta catenin; cytokine; innovation; insight; interstitial; intravital imaging; lung injury; lung repair; macrophage; monocyte; mortality; new therapeutic target; novel; novel strategies; novel therapeutic intervention; optogenetics; pathogen; postnatal; prevent; programs; recruit; repair function; repaired; success; synthetic biology; tissue repair; tool; transcription factor; transcriptomics

RESEARCH SUMMARY/ABSTRACT OF PROGRAM The fundamental challenge in treating the hyper-inflammatory state underlying Acute Lung Injury/Acute Respiratory Distress Disorder (ALI/ARDS) is that broad anti-inflammatory interventions could compromise host defense and potentially exacerbate the underlying infectious process that triggered ALI/ARDS. Novel targeted approaches to treat ALI/ARDS thus require an in-depth understanding of the intricate inflammatory mechanisms to reduce the extent of injury and promote the resolution of inflammation as well as the initiation of lung repair without compromising host defense. It is now recognized that macrophages (Mφ) in lungs represent diverse multi-functional cell populations. They have the ability to sense pathogens and danger signals, and their plasticity and diversity allows them to respond in specialized manners to specific niche environments. They are able to change their phenotypes in a chameleon-like manner by activation of specialized transcriptional programs. Thus, they have the remarkable ability to amplify inflammation and also to coordinate resolution of lung inflammatory lung injury and restore homeostasis. Mφ carry out these functions through the release of an array of cytokines, phagocytosis of microbes, efferocytosis of dead cells, and provide the essential inflammatory or reparative signals to nearby cells. The central focus of this program will be to precisely define the roles of distinct macrophage subpopulations in inflammatory lung injury and signaling nodes to harness the plasticity of macrophages and thereby bring about the resolution of lung injury. Project 1 will test the hypothesis that two specific specific ion channels, P2RX7 (Purinergic Receptor 2 subtype X7) and the potassium (K+) efflux channel TWIK2 regulate the plasticity to either promote lung injury or to activate the repair program. Project 2 will test the hypothesis that the transcription factor CREB and its downstream targets are critical regulators of the anti- inflammatory and reparative function of alveolar Mφ. Project 3 will test the hypothesis that endothelial cells lining all lung vessels direct the plasticity of Mφ via modulation of Wnt signaling in Mφ. Project 4 will test the hypothesis that circulating postnatal CX3CR1+ monocytes replenish lung interstitial Mφ during inflammatory injury and can direct the lung tissue repair program. These four Projects are supported and complemented by highly innovative scientific Cores which will provide important optogenetic tools (Synthetic Biology and Optogenetics Core B), super-resolution and intravital imaging (Advanced Imaging Core C), and access to clinical samples as well as single cell transcriptomic analysis of macrophages (Clinical Sampling and Genomics Core D) to unravel the complexities of macrophage biology in lung injury, thus paving the way for much-needed novel therapeutic approaches in ALI/ARDS.

研究摘要/程序摘要 治疗急性肺部损伤/急性的高炎性状态的基本挑战 呼吸窘迫障碍（ALI/ARDS）是广泛的抗炎干预措施可能损害宿主 国防并可能加剧触发ALI/ARDS的基本传染过程。针对性的新颖 因此，治疗ALI/ARD的方法需要深入了解复杂的炎症机制 降低受伤程度并促进感染的分辨率以及肺修复的倡议 没有折衷的主持人防御。现在已经认识到肺中的巨噬细胞（Mφ）代表潜水员 多功能细胞群。他们具有感知病原体和危险信号的能力，并且它们的可塑性 多样性使他们能够以专门的方式对特定的利基环境做出回应。他们能够 通过激活专业的转录程序以变色龙状的方式更改其表型。那， 它们具有扩增感染并协调肺部感染分辨率的显着能力 肺部受伤并恢复体内平衡。 Mφ通过释放一系列细胞因子来执行这些功能， 微生物的吞噬作用，死细胞的吞噬作用，并提供必需的炎症或修复 信号到附近的细胞。该计划的主要重点是精确定义不同的角色 炎症性肺损伤和信号淋巴结中的巨噬细胞亚群，以利用可塑性 巨噬细胞，从而带来肺损伤的分辨率。项目1将检验两个假设 特定的特定离子通道P2RX7（嘌呤能受体2亚型X7）和钾（K+）外排通道 TWIK2调节可塑性以促进肺损伤或激活修复程序。项目2将测试 转录因子CREB及其下游靶标是抗 - 的关键调节因子的假设 肺泡Mφ的炎症和修复功能。项目3将测试内皮细胞内壁的假设 所有肺部容器通过Mφ的Wnt信号调制来指导Mφ的可塑性。项目4将测试 假设炎症期间循环产后CX3CR1+单核细胞复制肺间隙mφ 受伤，可以指导肺组织修复程序。这四个项目得到了支持和完成 高度创新的科学核心将提供重要的光遗传学工具（合成生物学和 光遗传学核心b），超分辨率和插入式成像（高级成像核C），并访问 临床样本以及巨噬细胞的单细胞转录组分析（临床采样和 基因组学核心d）阐明肺损伤中巨噬细胞生物学的复杂性，从而为 在ALI/ARDS中急需的新型治疗方法。