Determinants of Resolution in Acute Lung Injury

急性肺损伤消退的决定因素

• 批准号: 8249421
• 负责人: LANDON S KING
• 金额: $ 40.59万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/8249421
• 关键词: Acute; Acute Lung Injury; Adoptive Cell Transfers; Adoptive Transfer; Adult Respiratory Distress Syndrome; Allergic Disease; Alveolar; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Appearance; Area; Attention; Autoimmune Diseases; 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; IL2RA gene; 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

PROJECT SUMMARY/ABSTRACT 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. 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.

项目摘要/摘要 急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）施加重大健康负担， 每年有近200,000例和75,000例死亡。疾病发病机理的研究已集中 但是，主要是损伤决定因素，但是迄今为止，对早期事件的重点尚未转化为临床 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 鉴定出与损伤分辨率相关的肺泡室中的淋巴细胞流入。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IT对IT LPS的反应 rag-1 null小鼠。野生型（WT）和RAG-1 NULL小鼠表现出相似的损伤模式，最多四天后 lps，但是rag-1 null小鼠的分辨率严重受损，而WT小鼠完全恢复了 第10天。特别是，在RAG-1 NULL小鼠中，炎症一直持续到第10天。收养的转移 CD4+ CD25+调节T细胞（Tregs）进入rag-1 null小鼠介导的损伤分辨率，并清除 组织学变化的炎症和归一化。初步研究表明Treg可能介导 博来霉素暴露后的肺损伤解决 肺部受伤。体外研究表明Tregs改变了巨噬细胞功能，包括细胞因子改变 表达谱和吞噬作用，并增强中性粒细胞凋亡，与促进 从促炎的微环境过渡到恢复的一种。我们假设Tregs介导 通过改变肺泡室中巨噬细胞和中性粒细胞功能来解决急性肺损伤。我们 提出三个目的旨在检查这一假设：1）检查Tregs在中介中的有效性 在不同的肺损伤模型中损伤的分辨率； 2）检查Treg介导的机制 牙槽炎症的分辨率； 3）确定Treg固有的机制 功能。我们认为这些研究将提供有关解决肺损伤的见解，并将提供 推动鉴定新型疗法以加速ALI/ARDS人类分辨率的动力。关注T 调节细胞或其产品作为肺损伤中分辨率的介体的产品是新颖的，可能会提供新的 对可用疗法极为有限的综合征的见解。急性肺损伤是一种潜在的破坏性临床状况，很少有治疗方法 可用的。我们已经确定了独特的淋巴细胞子集的重要作用 对于解决伤害至关重要。这些发现表明了新领域 可以寻求治疗的潜在靶标。