Modulation of Steroid Suppression by Alveolar Macrophage Efferocytosis

肺泡巨噬细胞胞吞作用对类固醇抑制的调节

• 批准号: 9205175
• 负责人: JEFFREY Louis CURTIS
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9205175
• 关键词: Acute; Adoptive Transfer; Adrenal Cortex Hormones; Adverse effects; Alveolar Macrophages; Anti-Bacterial Agents; Antibacterial Response; Ants; Apoptosis; Apoptotic; Bacteria; Biological Assay; Breathing; Cause of Death; Cell Count; Cell physiology; Cells; Cessation of life; Chronic Disease; Chronic Obstructive Airway Disease; Clinical; Communities; Data; Defect; Dose; Down-Regulation; Eating; Gene Expression; Gene Targeting; Genes; Global Change; Glucocorticoids; Goals; Histology; Host Defense; Human; Human Volunteers; Immune; Immune response; Immunosuppression; Impairment; In Vitro; Infection; Inflammation Mediators; Inflammatory; Investigation; Laboratories; Lead; Leukocytes; Lung; Mediator of activation protein; Messenger RNA; MicroRNAs; Molecular; Molecular Profiling; Mus; Nucleotides; Organ; Organism; Outcome; Patients; Phenotype; Pneumococcal Infections; Pneumococcal Pneumonia; Pneumonia; Predisposition; Process; Production; Proteins; Protocols documentation; Pulmonary Emphysema; Recruitment Activity; Risk; Severities; Signal Transduction; Smoke; Smoker; Smoking; Steroids; Stimulus; Streptococcus pneumoniae; Survival Analysis; Testing; Untranslated RNA; Veterans; Work; bactericide; base; chemokine; cigarette smoking; clinically relevant; cytokine; fighting; fluticasone; immune function; immunoregulation; improved outcome; in vivo; killings; macrophage; monocyte; mouse model; neutrophil; never smoker; novel; overexpression; personalized medicine; public health relevance; response; transcriptome; uptake

 DESCRIPTION (provided by applicant): Treating chronic obstructive pulmonary disease (COPD) patients with inhaled glucocorticosteroids has been convincingly shown to increase their risk of pneumonia, but the responsible mechanisms are undefined. Work from this laboratory suggests a possible mechanism, related to the increased numbers of cells dying by apoptosis in the lungs in COPD, especially in emphysema. Uptake of apoptotic cells ("efferocytosis") suppresses the ability of alveolar macrophages (AMØ) to fight infections. By markedly increasing AMØ efferocytosis, glucocorticoids plus apoptotic cells cause greater immune defects than either stimulus alone. This effect is called glucocorticoid-augmented efferocytosis (GCAE). MicroRNAs (miRNAs) are 19-25 nucleotide-long non-coding RNAs that coordinately target large numbers of genes and reduce their protein products. Preliminary data imply that defective AMØ function is caused by down-regulation of specific miRNAs by GCAE (but not by apoptotic cells alone or glucocorticosteroids alone). The long-term goal of this project is to develop novel, inhalational treatments, based on transient over-expression of these specifically decreased miRNAs, to reverse defective AMØ immune function when COPD patients taking inhaled glucocorticoids present with community-acquired pneumonia. This project will use ex vivo investigation of AMØ from both smoke-exposed mice and human volunteers (including active smokers and patients with COPD), and an established murine model of pneumococcal pneumonia. Its immediate goals are to: (a) confirm that GCAE increases pneumococcal pneumonia risk and severity, and in the process, validate a murine model for testing strategies to reverse those defects; (b) define GCAE-induced defects in human AMØ functionally and by whole- transcriptome analysis, identifying genes uniquely regulated by the GCAE x pneumococcus interaction; (c) validate and optimize miRNA-over-expression to reverse the adverse effects of GCAE on AMØ defensive functions. Successful completion of this project could lead to more precisely personalized therapies and better outcomes in COPD, currently the third leading cause of death in the USA, and the most expensive-to-treat chronic disease on a per-case basis among Veterans.

 描述（由申请人提供）： 吸入糖皮质激素治疗慢性阻塞性肺疾病（COPD）患者已被令人信服地证明会增加他们患肺炎的风险，但其机制尚不明确。该实验室的工作提出了一种可能的机制，与COPD，特别是肺气肿中肺细胞凋亡死亡的细胞数量增加有关。凋亡细胞的摄取（“细胞增多症”）抑制肺泡巨噬细胞（AMH）抵抗感染的能力。糖皮质激素和凋亡细胞通过显著增加巨噬细胞增多，比单独刺激引起更大的免疫缺陷。这种效应被称为糖皮质激素增强的红细胞增多症（GCAE）。microRNA（miRNAs）是一种长度为19-25个核苷酸的非编码RNA，其协同靶向大量基因并减少其蛋白质产物。初步数据表明，AMPDs功能缺陷是由GCAE下调特异性miRNA引起的（但不是由单独的凋亡细胞或单独的糖皮质激素引起的）。该项目的长期目标是开发新的吸入治疗方法，基于这些特异性降低的miRNAs的短暂过表达，以逆转COPD患者吸入糖皮质激素后出现社区获得性肺炎时的AMPDs免疫功能缺陷。该项目将使用来自烟雾暴露小鼠和人类志愿者（包括主动吸烟者和COPD患者）的AMP 19的体外研究，以及已建立的肺炎球菌肺炎小鼠模型。其近期目标是：（a）确认GCAE增加肺炎球菌性肺炎的风险和严重程度，并在此过程中，验证用于测试逆转这些缺陷的策略的鼠模型;（B）定义 通过全转录组分析，鉴定由GCAE X肺炎球菌相互作用独特调节的基因;（c）验证和优化miRNA过表达以逆转GCAE对AMP 12防御功能的不利影响。该项目的成功完成可能会导致COPD更精确的个性化治疗和更好的结果，COPD目前是美国第三大死亡原因，也是退伍军人中每例治疗费用最高的慢性病。