IMAGING MACROPHAGE ACTIVATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

慢性阻塞性肺疾病中巨噬细胞激活的成像

• 批准号: 8688054
• 负责人: Delphine L Chen
• 金额: $ 37.24万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-25 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8688054
• 关键词: Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Benzodiazepine Receptor; Binding; Bronchoalveolar Lavage; Cells; Chronic Obstructive Airway Disease; Clinical; Clinical Trials; Data; Deoxyglucose; Development; Diagnostic Trial; Dichloromethylene Diphosphonate; Disease; Disease Progression; Excision; Flow Cytometry; GLUT-1 protein; Glucose Transporter; Human; Image; Imaging Techniques; Immune; Immunofluorescence Microscopy; Immunohistochemistry; Immunologic Monitoring; In Situ; Individual; Inflammation; Inflammatory; Interferons; Interleukin-13; Liposomes; Lung; Lung Inflammation; Lung diseases; Macrophage Activation; Measures; Methods; Modeling; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mus; Neutrophil Activation; Pathogenesis; Patients; Peripheral; Phenotype; Pilot Projects; Positron-Emission Tomography; Proteins; Relative (related person); Research Personnel; Sampling; Sendai virus; Severities; Specificity; Sputum; Staining method; Stains; Structure of parenchyma of lung; Techniques; Testing; Therapeutic Intervention; Time; Tissue Sample; Tissue Stains; Tracer; Transplant Recipients; Tumor Necrosis Factor-alpha; Virus; Virus Diseases; abstracting; cell type; cohort; effective therapy; efficacy testing; fluorodeoxyglucose; glucose uptake; healthy volunteer; in vivo; in vivo imaging; macrophage; methionyl-leucyl-phenylalanine; monocyte; mortality; mouse model; neutrophil; novel; peripheral blood; protein expression; public health relevance; research study; response; tool; treatment response; uptake

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is a prevalent inflammatory lung disease for which new tools to quantify lung inflammation are needed to aid the development of effective anti-inflammatory treatments. Macrophage activation is critical to disease progression, so a technique that can track macrophage recruitment and activation in the lungs would be valuable for delineating inflammatory phenotypes in patients with COPD and for assessing anti-inflammatory treatment responses. Positron emission tomography (PET) is a noninvasive technique that can quantify lung inflammation using [18F]fluorodeoxyglucose ([18F]FDG), a commonly used clinical tracer. The novel PET tracer [11C]PBR28 targets the translocator protein (TSPO), which is present at high levels in activated macrophages. This project will test the overall hypothesis that [11C]PBR28 binding and [18F]FDG uptake measured by PET can be used to differentiate macrophage-dominant inflammation from neutrophil-dominant inflammation in patients with COPD. We will accomplish this by first conducting studies of TSPO expression and glucose uptake in ex vivo mouse models of macrophage activation along with microPET imaging and tissue staining to determine the specificity of [11C]PBR28 and [18F]FDG for macrophages and neutrophils in mice following virus infection- induced chronic obstructive lung disease (Aim 1). We will then study TSPO expression and glucose uptake in polarized human peripheral blood monocytes to parallel the mouse experiments and in lung tissue samples donated at the time of transplant by patients with COPD or at the time of lung resection by healthy donors and patients with milder severity COPD. Finally, we will conduct a small pilot imaging study to obtain preliminary characterization of [11C]PBR28 binding and [18F]FDG uptake in cohorts of individuals with COPD and healthy volunteers as a prelude to a formal clinical trial testing the efficacy of [11C]PBR28 and [18F]FDG in discriminating between macrophage-dominant and neutrophil-dominant inflammation in patients with COPD (Aim 2).

描述（由申请人提供）：慢性阻塞性肺病（COPD）是一种流行的炎症性肺部疾病，需要量化肺部炎症的新工具来帮助开发有效的抗炎治疗。巨噬细胞激活对于疾病进展至关重要，因此能够追踪肺部巨噬细胞招募和激活的技术对于描绘 COPD 患者的炎症表型和评估抗炎治疗反应非常有价值。正电子发射断层扫描 (PET) 是一种无创技术，可以使用常用的临床示踪剂 [18F] 氟脱氧葡萄糖 ([18F]FDG) 来量化肺部炎症。新型 PET 示踪剂 [11C]PBR28 靶向易位蛋白 (TSPO)，该蛋白在活化的巨噬细胞中高水平存在。该项目将测试总体假设，即通过 PET 测量的 [11C]PBR28 结合和 [18F]FDG 摄取可用于区分 COPD 患者中巨噬细胞主导的炎症与中性粒细胞主导的炎症。我们将首先在巨噬细胞激活的离体小鼠模型中进行 TSPO 表达和葡萄糖摄取研究，并结合 microPET 成像和组织染色来实现这一目标，以确定 [11C]PBR28 和 [18F]FDG 对小鼠巨噬细胞和中性粒细胞的特异性病毒感染引起的慢性阻塞性肺病（目标 1）。然后，我们将研究极化人外周血单核细胞中的 TSPO 表达和葡萄糖摄取，以平行于小鼠实验，以及 COPD 患者移植时或健康供体和病情较轻患者肺切除时捐献的肺组织样本中的 TSPO 表达和葡萄糖摄取慢性阻塞性肺病。最后，我们将进行一项小型试点成像研究，以获得 COPD 患者和健康志愿者队列中 [11C]PBR28 结合和 [18F]FDG 摄取的初步特征，作为测试 [11C] 功效的正式临床试验的前奏。 PBR28 和 [18F]FDG 区分 COPD 患者巨噬细胞主导型炎症和中性粒细胞主导型炎症（目标 2）。