This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The overall objective of this project is to show that non-invasive imaging with [18F] fluorodeoxyglucose (FDG) and positron emission tomography (PET) can be used to improve the efficiency with which potential new anti-inflammatory drugs are screened for possible use in patients with lung disease characterized by neutrophilic inflammation (e.g., cystic fibrosis (CF), acute respiratory distress syndrome, and others). The project is motivated and quantify inflammatory responses in the lungs. This deficiency seriously hampers the development and testing of novel drugs for these diseases.It is already clear that FDG-PET imaging can detect inflammatory lesions in the lungs. However, as our recently published data show, the signal obtained by FDG-PET imaging is also quantitatively related to the influx of activated neutrophils into the lungs. Recent preliminary data provide additional support for this conclusion. For instance, using CF as a human model of inflammatory lung disease, we found that the pulmonary uptake of [18F]FDG correlates positively with the number of neutrophils present in bronchoalveolar lavage (BAL) fluid, and that the in vitro uptake of another glucose analog, H-deoxyglucose ([18F]DG), is limited to neutrophils harvested from BAL. Of potential clinical importance, the imaging signal was highest in CF patients with the most rapid decline in pulmonary function. In addition, we have recently shown that FDG-PET imaging can quantify focal inflammatory responses to experimentally-induced airway inflammation in normal human volunteers (specifically, after the direct intra-bronchial instillation of low-dose endotoxin). Finally, this clinical work has been supplemented by recent animal studies showing that FDG-PET imaging can quantify the anti-inflammatory effects of novel drugs.The results lead us to propose the hypothesis that FDG-PET imaging will be able to quantify drug-induced suppression of pulmonary inflammation. We plan to support this hypothesis by pursuing the following specific aims:
Specific Aim 1. In normal volunteers, demonstrate that the recombinant form of activated protein C (rhAPC, drotrecogin [alpha], Xigris ), and separately, the hydroxymethylglutaryl co-A reductase inhibitor lovastatin (Mevacor ), will significantly suppress experimentally-induced focal lung inflammation as measured by FDG-PET imaging. East of the test drugs is commercially available and FDA-approved. The study will be prospective, triple-blinded, randomized, and placebo-controlled. rhAPC has already been shown by other, using fluid obtained via BAL, to reduce lung inflammation in this same model of endotocin-induced inflammation in normal human volunteers. Statin drugs have been shown in animal models, but not yet in humans, to reduce endotoxin-induced airway inflammation. The primary outcome measure will be a quantitative measure of [18F]FDG uptake by the lungs, namely the net uptake rate constant, Ki.
Specific Aim 2. Compare anti-inflammatory drug effects on Ki with their effects on alternative measures of lung inflammation. The FDG-PET measurements will be compared with neutrophil concentrations in BAL fluid and with xray computed tomography (CT) measures of inflammation lung density.The study will produce a unique set of data about potential biomarkers of pulmonary inflammatory responses which could prove useful as surrogate end-points in early developmental trials of new anti-inflammatory drugs. Since rhAPC has already been shown to reduce endotoxin-induced inflammation, data from this study will serve as a positive control. The data from the lovastatin arms will serve as a test of a new paradigm for studying anti-inflammatory drugs in patients with lung diseases characterized by neutrophilic inflammation, in which drugs are first screened with FDG-PET imaging in normal human volunteers after bronchial instillation of endotoxin, followed by a similar screening study in a small group of actual patients. Positive results for anti-inflammatory efficacy would provide justification for further testing in large Phase III studies to demonstrate improvements in functional or clinical outcomes. Overall, the proposed studies will help establish the role of FDG-PET imaging as a new and useful biomarker of pulmonary inflammatory responses.
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