[18F]fluorodeoxyglucose positron emission tomography for lung antiinflammatory response evaluation

Abstract

Rationale: Few noninvasive biomarkers for pulmonary inflammation are currently available that can assess the lung-specific response to antiinflammatory treatments. Positron emission tomography with [(18)F]fluorodeoxyglucose (FDG-PET) is a promising new method that can be used to quantify pulmonary neutrophilic inflammation.

Objectives: To evaluate the ability of FDG-PET to measure the pulmonary antiinflammatory effects of hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) and recombinant human activated protein C (rhAPC) in a human model of experimentally-induced lung inflammation.

Methods: Eighteen healthy volunteers were randomized to receive placebo, lovastatin, or rhAPC before intrabronchial segmental endotoxin challenge. FDG-PET imaging was performed before and after endotoxin instillation. The rate of [(18)F]FDG uptake was calculated as the influx constant K(i) by Patlak graphical analysis. Bronchoalveolar lavage (BAL) was performed to determine leukocyte concentrations for correlation with the PET imaging results.

Measurements and main results: There was a statistically significant decrease in K(i) in the lovastatin-treated group that was not seen in the placebo-treated group, suggesting attenuation of inflammation by lovastatin treatment despite a small decrease in BAL total leukocyte and neutrophil counts that was not statistically significant. No significant decrease in K(i) was observed in the rhAPC-treated group, correlating with a lack of change in BAL parameters and indicating no significant antiinflammatory effect with rhAPC.

Conclusions: FDG-PET imaging is a sensitive method for quantifying the lung-specific response to antiinflammatory therapies and may serve as an attractive platform for assessing the efficacy of novel antiinflammatory therapies at early phases in the drug development process. Clinical trial registered with www.clinicaltrials.gov (NCT00741013).

Figures

Figure 1.

Study procedures and participant flow diagram: schedule of study procedures with associated volunteer participation flow. *Lovastatin or placebo was administered beginning on the evening of Day 1 every 4 hours, while recombinant human activated protein C (rhAPC) or placebo was administered as a continuous infusion beginning the morning of Day 2, 2 hours before endotoxin instillation. All drug treatments were stopped 2 hours before bronchoalveolar lavage on Day 3. §One volunteer had a drop in pulmonary function tests of greater than 20%. ‡One volunteer was excluded for elevated liver function tests, the other for subsequent discovery of recent epidural placement. †Five screened volunteers declined to participate, and six did not meet inclusion criteria. **One volunteer withdrew consent before the second positron emission tomography with [18F]fluorodeoxyglucose (FDG-PET) scan. BAL = bronchoalveolar lavage.

Figure 2.

Summed images from the last 20 minutes of dynamically acquired positron emission tomography (PET) images after injection of [18F]fluorodeoxyglucose ([18F]FDG), before and after bronchoscopic instillation of endotoxin (Etx), and subtraction images in a representative subject from each treatment group. Arrows point to location of maximal difference in the region of the Etx instillation in the right middle lobe. The greatest difference is seen in the placebo subject and easily visualized on the subtraction images, whereas this difference is not visualized in the lovastatin-treated subject and attenuated in the recombinant human activated protein C (rhAPC) subject. In addition, these differences are not readily apparent on the FDG-PET images alone. Lung fields are illustrated by the white regions of interest. The PET Scale represents pixel values in the Before and After Etx images (μCi/cm3). The Difference Scale represents difference between Before and After Etx pixel values (μCi/cm3). Black areas in the mediastinum (between lung fields) indicate overflow of counts in those pixels in the region of the heart. Gray arrowheads in the rhAPC subject indicate a change in position of breast tissue between the two scans, leading to an apparent difference in uptake on the subtraction images.

Figure 3.

Quantification of endotoxin-dependent [18F]fluorodeoxyglucose ([18F]FDG) uptake. Representative Patlak plots of the right lobe region before (open circles) and after endotoxin (closed circles) for the placebo (A), lovastatin (B), and rhAPC (C) cohorts. The plots demonstrate a higher rate of uptake of [18F]FDG as measured by the influx constant Ki (the slope of the linear regression line of the Patlak plots; solid line) in the subject treated with placebo compared with the subjects treated with lovastatin and rhAPC. Dashed lines represent the 95% confidence interval of the linear regression line.

Figure 4.

Effect of pharmacologic intervention on positron emission tomography (PET)-measured [18F]fluorodeoxyglucose ([18F]FDG) uptake as an indicator of inflammation. (A–C) Changes in PET-measured the influx constant Ki before and after treatment with placebo, lovastatin, or recombinant human activated protein C (rhAPC), respectively, in both the right and left lungs. n = 6 for each group. Increases in Ki were noted in all groups after endotoxin treatment. Although Ki was lower in both treatment groups compared with placebo, the decrease was statistically significant only in the lovastatin group (*P < 0.05). (D) Mean change in Ki in both right and left lungs. Open columns = placebo; closed columns = lovastatin; gray columns = rhAPC. *P < 0.05 when compared with placebo. No changes in Ki were noted in the left lung in any treatment group.