IMAGING MACROPHAGE ACTIVATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

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病，需要新的工具来量化肺部炎症，以帮助开发有效的抗炎治疗。巨噬细胞活化对疾病进展至关重要，因此可以跟踪肺中巨噬细胞募集和活化的技术对于描绘COPD患者的炎症表型和评估抗炎治疗反应将是有价值的。正电子发射断层扫描（PET）是一种非侵入性技术，可以使用[18 F]氟脱氧葡萄糖（[18 F]FDG）（一种常用的临床示踪剂）量化肺部炎症。新型PET示踪剂[11 C]PBR28靶向转运蛋白（TSPO），该蛋白在活化的巨噬细胞中以高水平存在。本项目将检验总体假设，即通过PET测量的[11 C]PBR28结合和[18 F]FDG摄取可用于区分COPD患者中的巨噬细胞占主导地位的炎症与嗜中性粒细胞占主导地位的炎症。我们将通过首先在巨噬细胞活化的离体小鼠模型中进行TSPO表达和葡萄糖摄取的研究沿着microPET成像和组织染色来实现这一点，以确定[11 C]PBR28和[18 F]FDG对病毒感染诱导的慢性阻塞性肺病后小鼠中巨噬细胞和中性粒细胞的特异性（目的1）。然后，我们将研究极化的人外周血单核细胞中的TSPO表达和葡萄糖摄取，以平行于小鼠实验和COPD患者在移植时或健康供体和轻度COPD患者在肺切除术时捐献的肺组织样品。最后，我们将进行一项小型初步成像研究，以获得COPD患者和健康志愿者队列中[11 C]PBR28结合和[18 F]FDG摄取的初步特征，作为正式临床试验的前奏，测试[11 C]PBR28和[18 F]FDG在区分COPD患者中巨噬细胞占主导地位的炎症和嗜中性粒细胞占主导地位的炎症方面的疗效（目的2）。

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).