Molecular imaging of lung glucose uptake after endotoxin in mice.
Positron emission tomographic imaging after administration of the glucose analog fluorine-18 fluorodeoxyglucose ([18F]FDG) may be useful to study neutrophilic inflammation of the lungs. In this study, we sought to determine the specificity of the increase in lung [18F]FDG uptake after intraperitoneal endotoxin (Etx) for neutrophil influx into mouse lungs and to determine the regulation of glucose uptake after Etx by Toll-like receptors (TLRs) and TNF-alpha. Lung tissue radioactivity measurements by imaging were validated against counts in a gamma well counter. Glucose uptake was quantified as the [18F]FDG tissue-to-blood radioactivity ratio (TBR) after validating this measure against the "gold standard" measure of glucose uptake, the "net influx rate constant." TBR measurements were made in a control group (no intervention), a group administered Etx, and a group administered Etx plus an additional agent (e.g., vinblastine) or Etx administered to a mutant mouse strain. The glucose uptake measurements were compared with measurements of myeloperoxidase. Increases in TBR after Etx were significantly but not completely eliminated by neutrophil depletion with vinblastine. Increases in TBR after Etx were consistent with signaling via either TLR-4 or TLR-2 (the latter probably secondary to peptidoglycan contaminants in Etx preparation) and were decreased by drug inhibition of TLR-4 but not by inhibition of TNF-alpha. Thus molecular imaging can be used to noninvasively monitor biological effects of Etx on lungs in mice, and changes in lung glucose uptake can be used to monitor effects of anti-inflammatory agents. Such imaging capacity provides a powerful new paradigm for translational "mouse-to-human" pulmonary research.
Departments of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Zhaohui
Z
Zhou
James
J
Kozlowski
Andrea L
AL
Goodrich
Nathaniel
N
Markman
Delphine L
DL
Chen
Daniel P
DP
Schuster
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D004731:Endotoxins / Q000633:toxicity*; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism*; D007700:Kinetics; D008168:Lung / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009195:Peroxidase / Q000378:metabolism; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014057:Tomography, X-Ray Computed
D004731:Endotoxins; D019275:Radiopharmaceuticals; D018124:Receptors, Tumor Necrosis Factor; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019788:Fluorodeoxyglucose F18; D009195:Peroxidase; D005947:Glucose