IMAGING MACROPHAGE ACTIVATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Washington University, Saint Louis MO

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Abstract

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).