Influence of Acute Respiratory Distress Syndrome on Human Alveolar Macrophage Polarity

项目摘要 急性呼吸窘迫综合征（ARDS）是危重病常见而又严重的并发症， 在美国，每年有多达75,000人死亡。肺泡巨噬细胞（AM）是最 大量的白细胞在休息的人肺，并由于其假定的功能异质性， 表型可塑性可能在人类ARDS的诱导和消退中起关键作用。电流 在动物和体外人单核细胞衍生的巨噬细胞（MDM）中的知识表明， 巨噬细胞具有响应其局部微环境而改变其结构和功能的能力。 然而，一个有待回答的主要问题是，人类AM在多大程度上 如果有的话，在ARDS中重新编程。鉴定AM的亚群，这些亚群在治疗过程中进化， ARDS可能导致靶向治疗策略的发展，重点是操纵AM的方法 结构和功能。 总体研究目标是确定人类AM在ARDS各阶段中的作用。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）识别深层免疫- 通过利用质谱细胞术在取自患有ARDS的人类患者的AM中的表型谱;以及2） 确定ARDS微环境是否影响AM极化和功能，通过研究正常 将人AM与取自不同临床条件下的患者的支气管肺泡灌洗液一起孵育 ARDS的阶段。阐明AM在人类ARDS中的作用对于进一步研究该综合征至关重要。 迄今为止，还没有针对ARDS致病机制的特异性药物治疗。这 项目也将直接增加申请人成为独立的成功概率 专注于ARDS和人类巨噬细胞生物学的翻译医师科学家。

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.