Influence of Acute Respiratory Distress Syndrome on Human Alveolar Macrophage Polarity

急性呼吸窘迫综合征对人肺泡巨噬细胞极性的影响

• 批准号: 9393863
• 负责人: Eric Douglas Morrell
• 金额: $ 7.01万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9393863
• 关键词: Acute Respiratory Distress Syndrome; Alveolar; Alveolar Cell; Alveolar Macrophages; Animals; Award; Biological Assay; Biology; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cells; Cessation of life; Clinical; Complication; Critical Illness; Cytometry; Development; Environment; Flow Cytometry; Foundations; Gene Expression; Gene Expression Profile; Genetic Transcription; Heterogeneity; Human; In Vitro; Incidence; Incubated; Inflammatory; Intervention; Knowledge; Lead; Leukocytes; Link; Lung; Mass Spectrum Analysis; Measures; Mechanics; Methods; Molecular; Mus; Natural History; Pathogenicity; Pathologic; Patients; Phagocytes; Pharmacology; Phase; Phenotype; Physicians; Plasticizers; Play; Probability; Proteins; Research; Research Training; Resolution; Rest; Role; Sampling; Scientist; Statistical Methods; Structure; Supportive care; Syndrome; Techniques; Testing; Therapeutic; Time; Translational Research; United States; Virulence Factors; Work; cell type; experimental study; genomic signature; high dimensionality; human subject; improved outcome; in vivo; macrophage; monocyte; mortality; mouse model; novel; novel therapeutics; response; success; targeted treatment; treatment strategy; ventilator-associated pneumonia

PROJECT SUMMARY Acute respiratory distress syndrome (ARDS) is a common and formidable complication of critical illness, and is associated with up to 75,000 deaths annually in the United States. Alveolar macrophages (AMs) are the most abundant leukocyte in the resting human lung, and due to their presumed functional heterogeneity and phenotypic plasticity, may play a key role in both the induction and resolution of human ARDS. Current knowledge in animals and in human monocyte-derived macrophages (MDMs) in vitro has shown that macrophages have the ability to modify their structure and function in response to their local microenvironment. However, a major question that remains to be answered is what degree do human AMs undergo reprogramming in ARDS, if at all. The identification of subpopulations of AMs that evolve over the course of ARDS could lead to the development of targeted treatment strategies focused on methods to manipulate AM structure and function in this syndrome. The overall study objective is to determine the role that human AMs play in each phase of ARDS. This project accomplishes the overall study objective by pursuing the following two specific aims: 1) Identify deep immuno- phenotypic profiles in AMs taken from human patients with ARDS by utilizing mass cytometry; and 2) Determine whether the ARDS microenvironment influences AM polarization and function by studying normal human AMs that have been incubated with bronchoalveolar lavage fluid taken from patients at various clinical stages of ARDS. Clarifying the role of AMs in human ARDS is essential to further research in this syndrome. To date, there are no specific pharmacologic therapies directed at the pathogenic mechanisms of ARDS. This project will also directly increase the probability of success for the applicant in becoming an independent translational physician scientist focusing on ARDS and human macrophage biology.

项目总结 急性呼吸窘迫综合征(ARDS)是危重病的常见和可怕的并发症， 在美国，每年与多达7.5万人的死亡有关。肺泡巨噬细胞(AM)最多 在静息的人肺中有丰富的白细胞，由于它们假定的功能异质性和 表型可塑性，可能在人类ARDS的诱导和解决中发挥关键作用。当前 在动物和体外培养的人类单核细胞衍生巨噬细胞(MDM)中的知识表明 巨噬细胞具有根据局部微环境改变自身结构和功能的能力。 然而，一个有待回答的主要问题是，人类的AM经历了多大程度的变化 在ARDS中重新编程，如果可以的话。AMS亚群在进化过程中的鉴定 急性呼吸窘迫综合征可能导致开发专注于操纵AM的方法的靶向治疗策略 这种综合征的结构和功能。 总体研究目标是确定人类AM在ARDS各个阶段中所起的作用。这个项目 通过追求以下两个具体目标来实现总体研究目标：1)鉴定深层免疫- 用质量细胞术检测人类ARDS患者AM的表型特征； 通过研究正常来确定ARDS微环境是否影响AM极化和功能 与不同临床患者的支气管肺泡灌洗液孵育的人AM 急性呼吸窘迫综合征的分期。阐明AM在人类ARDS中的作用对于进一步研究这种综合征是至关重要的。 到目前为止，还没有针对ARDS发病机制的特效药物治疗。这 项目还将直接增加申请者成为独立候选人的成功几率 翻译内科科学家，专注于ARDS和人类巨噬细胞生物学。