Determinants of Resolution in Acute Lung Injury

急性肺损伤消退的决定因素

基本信息

批准号：
7790614
负责人：
LANDON S KING
金额：
$ 41万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7790614
关键词：
Acute Acute Lung Injury Adoptive Cell Transfers Adoptive Transfer Adult Respiratory Distress Syndrome Allergic Alveolar Animals Anti-Inflammatory Agents Anti-inflammatory Apoptosis Appearance Area Attention Autoimmune Process Bleomycin Cells Cessation of life Clinical Coculture Techniques Communicable Diseases Disease Effectiveness Event Exhibits Exposure to Fluorescence-Activated Cell Sorting Health Healthcare Systems Histologic Human Immune response In Vitro Inflammation Inflammatory Injury Integrins Investigation Knockout Mice Lipopolysaccharides Lipoxins Lung Lymphocyte Lymphocyte Subset Mediating Mediator of activation protein Modeling Molecular Profiling Morbidity - disease rate Mouse Strains Mus Nitric Oxide Pathogenesis Patients Pattern Phagocytosis Phenotype Play Process Production Proteins Pseudomonas aeruginosa Recovery Recruitment Activity Regulation Regulatory T-Lymphocyte Resolution Role Source Specificity Spleen Syndrome Testing Translating Translations Wild Type Mouse cytokine effective therapy insight lipid mediator lung injury macrophage mortality mouse model neutrophil novel reconstitution response

项目摘要

DESCRIPTION (provided by applicant): Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) impose a substantial health burden, with nearly 200,000 cases and 75,000 deaths per year. Investigation of disease pathogenesis has focused largely on determinants of injury, however to date the focus on early events has not translated into clinically useful therapies. Using a mouse model of direct lung injury with intratracheal lipopolysaccharide (IT LPS), we identified lymphocyte influx into the alveolar compartment that correlated with resolution of injury. To test a potential role for lymphocytes in this process, we examined the response to IT LPS in lymphocyte-deficient Rag-1 null mice. Wild type (WT) and Rag-1 null mice exhibited similar injury patterns up to four days after LPS, however Rag-1 null mouse had profoundly impaired resolution, while WT mice completely recovered by day 10. In particular, inflammation persisted through day 10 in the Rag-1 null mice. Adoptive transfer of CD4+CD25+ regulatory T cells (Tregs) into Rag-1 null mice mediated resolution of injury, with clearance of inflammation and normalization of histologic changes. Preliminary studies indicate that Tregs likely mediate resolution of lung injury after bleomycin exposure as well, suggesting a general role for Tregs in resolution of lung injury. In vitro studies demonstrated that Tregs alter macrophage function, including altered cytokine expression profiles and phagocytosis, and enhance neutrophil apoptosis, consistent with facilitation of the transition from a pro-inflammatory microenvironment to one of recovery. We hypothesize that Tregs mediate resolution of acute lung injury by altering macrophage and neutrophil function in the alveolar compartment. We propose three aims to examine this hypothesis: 1) To examine the effectiveness of Tregs in mediating resolution of injury in distinct models of lung injury; 2) To examine mechanisms by which Tregs mediate resolution of alveolar inflammation; and 3) To identify mechanisms intrinsic to Tregs that contribute to their function. We believe these studies will provide insights into resolution of lung injury, and will provide the impetus for identification of novel therapies to accelerate resolution in humans with ALI/ARDS. The focus on T regulatory cells or their products as mediators of resolution in lung injury is novel, and may provide new insights into a syndrome for which available therapies are extremely limited. PROJECT NARRATIVE. Acute lung injury is a potentially devastating clinical condition for which few therapies are available. We have identified an important role for a distinct subset of lymphocytes that are critical to achieve resolution of injury. These findings indicate new areas in which potential targets for therapy can be sought.

描述（由申请人提供）：急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）施加了实质性的健康负担，每年近20万例和75,000例死亡。疾病发病机理的研究主要集中在损伤的决定因素上，但是迄今为止，对早期事件的关注尚未转化为临床上有用的疗法。使用气管内脂多糖（IT LPS）的直接肺损伤的小鼠模型，我们将淋巴细胞涌入与损伤分辨率相关的肺泡室中。为了测试淋巴细胞在此过程中的潜在作用，我们检查了淋巴细胞缺陷型rag-1 null小鼠中对IT LPS的反应。野生型（WT）和RAG-1 NULL小鼠在LPS后长达四天表现出相似的损伤模式，但是RAG-1 NULL小鼠的分辨率严重受损，而WT小鼠在第10天之前完全恢复了WT小鼠。尤其是在RAG-1 NULL小鼠中，炎症一直持续到第10天。 CD4+ CD25+调节T细胞（Tregs）的过继转移到RAG-1无效小鼠中介导的损伤分辨率，并清除炎症和组织学变化的归一化。初步研究表明，TREG也可能介导博来霉素暴露后的肺损伤分辨率，这表明TREG在肺损伤的分辨率中起了一般作用。体外研究表明，Tregs改变了巨噬细胞功能，包括改变细胞因子表达谱和吞噬作用，并增强中性粒细胞凋亡，这与从促炎性微环境促进过渡到一种恢复。我们假设Tregs通过改变肺泡室中的巨噬细胞和中性粒细胞功能来介导急性肺损伤的分辨率。我们提出三个旨在检查这一假设的目的：1）检查Tregs在不同的肺损伤模型中介导损伤解决方案的有效性； 2）检查Treg介导牙槽炎症的分辨率的机制； 3）确定对其功能有助于其功能的固有的机制。我们认为，这些研究将为解决肺损伤的分辨率提供见解，并将为鉴定新型疗法加速ALI/ARDS分辨率的新疗法提供动力。对T调节细胞或其产物作为肺损伤介体的产品的重点是新颖的，可以为可用疗法极为有限的综合征提供新的见解。项目叙述。急性肺损伤是一种潜在的破坏性临床状况，几乎没有疗法。我们已经确定了对实现损伤至关重要的不同淋巴细胞子集的重要作用。这些发现表明可以寻求潜在的治疗靶标的新领域。