Inflammatory cytokines and hypoxia contribute to 18F-FDG uptake by cells involved in pannus formation in rheumatoid arthritis.

UNLABELLED: Assessment of the activity of rheumatoid arthritis (RA) is important for the prediction of future articular destruction. (18)F-FDG PET is known to represent the metabolic activity of inflammatory disease, which correlates with the pannus volume measured by MRI or ultrasonography. To evaluate the correlation between (18)F-FDG accumulation and RA pathology, we assessed (18)F-FDG accumulation in vivo using collagen-induced arthritis (CIA) animal models and (3)H-FDG uptake in vitro using various cells involved in arthritis. METHODS: (18)F-FDG PET images of rats with CIA were acquired on days 10, 14, and 17 after arthritis induction. The specimens were subsequently subjected to macroautoradiography, and the (18)F-FDG accumulation was compared with the histologic findings. (3)H-FDG uptake in vitro in inflammatory cells (neutrophils, macrophages, T cells, and fibroblasts) was measured to evaluate the contributions of these cells to (18)F-FDG accumulation. In addition, the influence on (3)H-FDG uptake of inflammatory factors, such as cytokines (tumor necrosis factor alpha [TNFalpha], interleukin 1 [IL-1], and IL-6), and hypoxia was examined. RESULTS: (18)F-FDG PET depicted swollen joints, and (18)F-FDG accumulation increased with the progression of arthritis. Histologically, a higher level of (18)F-FDG accumulation correlated with the pannus rather than the infiltration of inflammatory cells around the joints. In the in vitro (3)H-FDG uptake assay, fibroblasts showed the highest (3)H-FDG uptake, followed by neutrophils. Although only a small amount of (3)H-FDG was incorporated by resting macrophages, a dramatic increase in (3)H-FDG uptake in both fibroblasts and macrophages was observed when these cells were exposed to inflammatory cytokines, such as TNFalpha and IL-1, and hypoxia. Although neutrophils showed relatively high (3)H-FDG uptake without activation, no increase in (3)H-FDG uptake was observed in response to inflammatory cytokines. (3)H-FDG uptake by T cells was much lower than that by other cells. Thus, fibroblasts and activated macrophages contribute to a high level of (18)F-FDG accumulation in the pannus, and hypoxia as well as cytokine stimulation significantly increases (18)F-FDG uptake by these cells. CONCLUSION: (18)F-FDG accumulation in RA reflects proliferating pannus and inflammatory activity enhanced by inflammatory cytokines and hypoxia. (18)F-FDG PET should be effective for quantifying the inflammatory activity of RA.

Evaluation of brain and whole-body pharmacokinetics of 11C-labeled diphenylhydantoin in rats by means of planar positron imaging system.

OBJECTIVE: A planar positron imaging system (PPIS) enables whole-body dynamic imaging of radiopharmaceuticals labeled with positron-emitting nuclides. We evaluated the difference in the brain and whole-body pharmacokinetics of (11)C-diphenylhydantoin ((11)C-DPH) between intravenous and duodenal administration in rats. METHODS: Male Wistar rats (8 weeks old, mean body weight 250 g) were examined under anesthesia. A tracer amount of (11)C-DPH (2 microg or less; about 5 MBq) was injected into the tail vein (n = 3) or duodenum (n = 3). Immediately following the administration, PPIS scans were obtained for 20 min. Regions of interest (ROIs) were set on the brain, heart, liver, intestinal field, and urinary bladder, identified on the integrated images. The relative uptake value (RUV, %) was calculated as the regional count divided by the whole-body count multiplied by 100. Sequential changes in the RUV for each ROI were analyzed for the brain and other organs. RESULTS: Following intravenous injection of (11)C-DPH, the RUV in the brain was 1.59 +/- 0.07%, 1.53 +/- 0.09%, 1.40 +/- 0.09%, and 1.38 +/- 0.08% at 5 min, 10 min, 15 min, and 20 min after the injection, respectively. After duodenal administration, the corresponding values were 0.54 +/- 0.16%, 1.01 +/- 0.12%, 1.43 +/- 0.24%, and 1.52 +/- 0.06%, respectively. The (11)C-DPH distribution was significantly lower at 5 min and 10 min following duodenal administration than after intravenous injection (P < 0.01). Radioactivity in the urinary bladder was identified by 20 min after both intravenous injection and duodenal administration. CONCLUSIONS: The present study demonstrated a difference in the brain distribution of (11)C-DPH between intravenous and duodenal administration in rats. Use of the PPIS is feasible for the evaluation of the pharmacokinetics in both the target organ and the whole body in small animals.

Mutation at the Lmx1a locus provokes aberrant brain development in the rat.

A rat short-tail mutation with neurological defects (named queue courte, qc) was discovered. Histopathology in adult qc/qc rats revealed hypoplasia of the cerebellum and hippocampus, maldevelopment of the choroid plexus and corpus callosum. These abnormalities are strongly reminiscent of the phenotypic abnormalities found in the shaker short-tail or dreher (dr) mouse mutation at the LIM homeobox transcription factor 1 alpha locus (Lmx1a). The qc mutation is an autosomal recessive and has been mapped to the dr homologous region on rat chromosome 13, and Northern blot analysis demonstrated no expression of Lmx1a in qc/qc rats. Narrowing and distortion of the ventricles were observed from embryonic day 17 (E17) in qc/qc rats. From E17, fusion of the opposing neuroepithelium and formation of neuroepithelial rosettes were also found. Arrangements of neuroepithelial cells were disturbed and processes of radial glia were disoriented in the fused lesions. Neuronal migration analysis using BrdU immunohistochemistry revealed defective migration from the neuroepithelium toward the neocortex and mesencephalon in qc/qc rats. These findings suggest that the qc mutation is involved in development of the ventricular system and dorsal migration of neurons.