18F-fluorodeoxyglucose positron emission tomography/computed tomography enables the detection of recurrent same-site deep vein thrombosis by illuminating recently formed, neutrophil-rich thrombus.

BACKGROUND: Accurate detection of recurrent same-site deep vein thrombosis (DVT) is a challenging clinical problem. Because DVT formation and resolution are associated with a preponderance of inflammatory cells, we investigated whether noninvasive (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging could identify inflamed, recently formed thrombi and thereby improve the diagnosis of recurrent DVT. METHODS AND RESULTS: We established a stasis-induced DVT model in murine jugular veins and also a novel model of recurrent stasis DVT in mice. C57BL/6 mice (n=35) underwent ligation of the jugular vein to induce stasis DVT. FDG-PET/computed tomography (CT) was performed at DVT time points of day 2, 4, 7, 14, or 2+16 (same-site recurrent DVT at day 2 overlying a primary DVT at day 16). Antibody-based neutrophil depletion was performed in a subset of mice before DVT formation and FDG-PET/CT. In a clinical study, 38 patients with lower extremity DVT or controls undergoing FDG-PET were analyzed. Stasis DVT demonstrated that the highest FDG signal occurred at day 2, followed by a time-dependent decrease (P<0.05). Histological analyses demonstrated that thrombus neutrophils (P<0.01), but not macrophages, correlated with thrombus PET signal intensity. Neutrophil depletion decreased FDG signals in day 2 DVT in comparison with controls (P=0.03). Recurrent DVT demonstrated significantly higher FDG uptake than organized day 14 DVT (P=0.03). The FDG DVT signal in patients also exhibited a time-dependent decrease (P<0.01). CONCLUSIONS: Noninvasive FDG-PET/CT identifies neutrophil-dependent thrombus inflammation in murine DVT, and demonstrates a time-dependent signal decrease in both murine and clinical DVT. FDG-PET/CT may offer a molecular imaging strategy to accurately diagnose recurrent DVT.

Pulmonary retention of primed neutrophils: a novel protective host response, which is impaired in the acute respiratory distress syndrome.

RATIONALE: Acute respiratory distress syndrome (ARDS) affects over 200000 people annually in the USA. Despite causing severe, and often refractory, hypoxaemia, the high mortality and long-term morbidity of ARDS results mainly from extra-pulmonary organ failure; however the mechanism for this organ crosstalk has not been determined. METHODS: Using autologous radiolabelled neutrophils we investigated the pulmonary transit of primed and unprimed neutrophils in humans. Flow cytometry of whole blood samples was used to assess transpulmonary neutrophil priming gradients in patients with ARDS, sepsis and perioperative controls. MAIN RESULTS: Unprimed neutrophils passed through the lungs with a transit time of 14.2 s, only 2.3 s slower than erythrocytes, and with <5% first-pass retention. Over 97% of neutrophils primed ex vivo with granulocyte macrophage colony-stimulating factor were retained on first pass, with 48% still remaining in the lungs at 40 min. Neutrophils exposed to platelet-activating factor were initially retained but subsequently released such that only 14% remained in the lungs at 40 min. Significant transpulmonary gradients of neutrophil CD62L cell surface expression were observed in ARDS compared with perioperative controls and patients with sepsis. CONCLUSIONS: We demonstrated minimal delay and retention of unprimed neutrophils transiting the healthy human pulmonary vasculature, but marked retention of primed neutrophils; these latter cells then 'deprime' and are re-released into the systemic circulation. Further, we show that this physiological depriming mechanism may fail in patients with ARDS, resulting in increased numbers of primed neutrophils within the systemic circulation. This identifies a potential mechanism for the remote organ damage observed in patients with ARDS.

Assay of therapeutic ultrasound induced-antinociception in experimental trigeminal neuropathic pain.

Trigeminal neuralgia is considered one of the most painful conditions, and pharmacological treatment can be as debilitating as the pathology itself. The aim of this work was to evaluate the effectiveness of pulsed therapeutic ultrasound (TU) on an experimental rat model of trigeminal neuropathic nociception (chronic constriction injury-infraorbital nerve; CCI-ION). To evaluate facial thermonociception, an apparatus that measured the reaction time for head withdrawal was constructed. After surgery, a gradual reduction in reaction time was observed until day 15 post-CCI, when the values became constant. Three ipsilateral applications of TU to post-CCI rats promoted an increase in latency time. This antinociceptive effect was evident even after the first TU application, reaching maximal values at 24 hr. The magnitude of this effect was proportional to ultrasonic wave intensity (0.3 and 0.4 W/cm(2)). Posttreatment with naltrexone (5 mg/kg, s.c.) completely blocked the hypoalgesic effect of TU. Pretreatment with an opioid antagonist was unable to block the antinociceptive effect during the first 8 hr, suggesting that opioids are involved only in the latter phase of the TU effects. Myeloperoxidase (MPO) levels in the infraorbital nerve were not increased by TU use, indicating that TU causes no injury or is at least insufficient to induce neutrophil migration. In conclusion, TU is an effective resource in a model of trigeminal neuropathic pain, with a mechanism involving opioid receptor activation, confirming its potential usefulness in the treatment of trigeminal neuralgia.

Quantification of neutrophil migration into the lungs of patients with chronic obstructive pulmonary disease.

OBJECTIVE: To quantify neutrophil migration into the lungs of patients with chronic pulmonary obstructive disease (COPD). METHODS: Neutrophil loss via airways was assessed by dedicated whole-body counting 45 min, 24 h and 2, 4, 7 and 10 days after injection of very small activities of (111)In-labelled neutrophils in 12 healthy nonsmokers, 5 healthy smokers, 16 patients with COPD (of whom 7 were ex-smokers) and 10 patients with bronchiectasis. Lung accumulation of (99m)Tc-labelled neutrophils was assessed by sequential SPECT and Patlak analysis in six COPD patients and three healthy nonsmoking subjects. RESULTS: Whole body (111)In counts, expressed as percentages of 24 h counts, decreased in all subjects. Losses at 7 days (mean ± SD) were similar in healthy nonsmoking subjects (5.5 ± 1.5%), smoking subjects (6.5 ± 4.4%) and ex-smoking COPD patients (5.8 ± 1.5%). In contrast, currently smoking COPD patients showed higher losses (8.0 ± 3.0%) than healthy nonsmokers (p = 0.03). Two bronchiectatic patients lost 25% and 26%, indicating active disease; mean loss in the remaining eight was 6.9 ± 2.5%. The rate of accumulation of (99m)Tc-neutrophils in the lungs, determined by sequential SPECT, was increased in COPD patients (0.030-0.073 min(-1)) compared with healthy nonsmokers (0-0.002 min(-1); p = 0.02). CONCLUSION: In patients with COPD, sequential SPECT showed increased lung accumulation of (99m)Tc-labelled neutrophils, while whole-body counting demonstrated subsequent higher losses of (111)In-labelled neutrophils in patients who continued to smoke. Sequential SPECT as a means of quantifying neutrophil migration deserves further evaluation.

A novel neutrophil-specific PET imaging agent: cFLFLFK-PEG-64Cu.

UNLABELLED: The synthesis and validation of a new, highly potent (64)Cu-labeled peptide, cFLFLFK-PEG-(64)Cu, that targets the formyl peptide receptor (FPR) on leukocytes is described. The peptide ligand is an antagonist of the FPR, designed not to elicit a chemotactic response resulting in neutropenia. Evidence for the selective binding of this synthesized ligand to neutrophils is provided. PET properties of the compound were evaluated in a mouse model of lung inflammation. METHODS: The FPR-specific peptide, cinnamoyl-F-(D)L-F-(D)L-FK (cFLFLF), was sequentially conjugated with a bifunctional polyethylene glycol moiety (PEG, 3.4 kD) and a 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) through a lysine (K) spacer and finally labeled with (64)Cu-CuCl(2) to form cFLFLFK-PEG-(64)Cu. The binding affinity and stimulation potency of the ligand toward human neutrophils were assessed in vitro. Blood kinetic and organ biodistribution properties of the peptide were studied in the mouse. Ten male C57BL/6 mice were used in this study; 4 control mice and 6 administered Klebsiella pneumonia. PET/CT scans were performed to assess the localization properties of the labeled peptide in lungs 18 h after tracer administration. Lung standardized uptake values (SUVs) were correlated with lung neutrophil activity as measured by myeloperoxidase assays. Immunohistochemistry was performed to confirm that neutrophils constitute the majority of infiltrating leukocytes in lung tissue 24 h after Klebsiella exposure. RESULTS: In vitro binding assays of the compound cFLFLFK-PEG-(64)Cu to the neutrophil FPR yielded a dissociation constant of 17.7 nM. The functional superoxide stimulation assay exhibited negligible agonist activity of the ligand with respect to neutrophil superoxide production. The pegylated peptide ligand exhibited a blood clearance half-life of 55 +/- 8 min. PET 18 h after tracer administration revealed mean lung SUVs and lung myeloperoxidase activities for Klebsiella-infected mice that were 5- and 6-fold higher, respectively, than those for control mice. Immunohistochemistry staining confirmed that the cellular infiltrate in lungs of Klebsiella-infected mice was almost exclusively neutrophils at the time of imaging. CONCLUSION: This new radiolabeled peptide targeting the FPR binds to neutrophils in vitro and accumulates at sites of inflammation in vivo. This modified peptide may prove to be a useful tool to probe inflammation or injury.

Ultrasound radiation force modulates ligand availability on targeted contrast agents.

Radiation force produced by low-amplitude ultrasound at clinically relevant frequencies remotely translates freely flowing microbubble ultrasound contrast agents over distances up to centimeters from the luminal space to the vessel wall in order to enhance ligand-receptor contact in targeting applications. The question arises as to how the microbubble shell might be designed at the molecular level to fully take advantage of such physical forces in targeted adhesion for molecular imaging and controlled therapeutic release. Herein, we report on a novel surface architecture in which the tethered ligand is buried in a polymeric overbrush. Our results, with biotin-avidin as the model ligand-receptor pair, show that the overbrush conceals the ligand, thereby reducing immune cell binding and increasing circulation persistence. Targeted adhesion is achieved through application of ultrasound radiation force to instantly reveal the ligand within a well-defined focal zone and simultaneously bind the ligand and receptor. Our data illustrate how the adhesive properties of the contrast agent surface can be reversibly changed, from stealth to sticky, through the physical effects of ultrasound. This technique can be combined with any ligand-receptor pair to optimize targeted adhesion for ultrasonic molecular imaging.

99mTc-Fanolesomab: affinity, pharmacokinetics and preliminary evaluation.

Localization of infection is critical for both diagnosis and treatment. Several radioactive compounds such as (67)Gallium citrate, (111I)ndium and (99m)Technetium-labeled leukocytes, peptides and antibodies have been used to localize sites of bacterial infection and phlegmons when anatomical imaging techniques failed. With labeled leukocytes the major concern besides the cost, was the in vitro procedure requiring more than 2 h and trained personnel to handle blood samples. Such limitations paved the way for the emergence of new agents like human immunoglobulin, interleukin-1, peptides and monoclonal antibodies. Following the intensive study of 10 monoclonal antibodies the anti SSEA-1 antibody specific for CD15 antigen was found to have a high Kd value of 1.6x10(-11) M for human neutrophils. Labeling of anti CD15 antibody (NeutroSpec) with (99m)Tc and its FDA approval was a boon to diagnostic imaging as it promised to eliminate many of the well known drawbacks of the in vitro WBC labeling. This antibody has a large number of antigenic binding sites: 5.1x10(5) per circulating human neutrophil. It has been established that very little CD15 antigen is expressed on the other blood cell lines. Upon intravenous administration to patients there was no adverse reaction except in those with underlying cardiovascular compromise or chronic pulmonary obstructive disease. Another advantage is that, this particular monoclonal antibody has not produced significant human antimouse antibody in research volunteers and patients. Twenty-four hour imaging, SPECT or planar was not required. The following pages describe the various stages of the research activity carried out towards NeutroSpec.

Imaging of infection and inflammation with 99mTc-Fanolesomab.

(99m)Tc-fanolesomab, a murine M class antigranulocyte antibody, is injected directly into patients, avoiding in vitro leukocyte labeling. Normal distribution includes reticuloendothelial system, genitourinary tract, and blood pool. Small bowel activity appears within 4 h, colonic activity by 24 h. Accumulation in infection is via two mechanisms: binding to circulating neutrophils that migrate to the infection and binding to neutrophils and neutrophil debris containing CD-15 receptors already sequestered in the infection. (99m)Tc-fanolesomab is valuable in atypical appendicitis. Its sensitivity, specificity, and accuracy, in 200 patients were 91%, 86%, and 87%, respectively. This agent is comparable to (111)In- labeled leukocytes for diagnosing osteomyelitis in the appendicular skeleton in general and in diabetic patients with pedal ulcers. Preliminary experience suggests (99m)Tc-fanolesomab might replace in vitro labeled leukocytes for other indications as well. Initial clinical investigations found the agent was safe. A transient decrease in circulating leukocytes within 20 min after injection occurred, but with no associated clinical complaints. Recovery averaged about 20 min. One study found no statistically significant HAMA titer elevation and no adverse reactions following injection. In another investigation 5 out of 30 subjects who received two separate antibody injections, exhibited HAMA induction with no serious or severe adverse events. Forty-nine adverse events, including 4 severe ones, were reported among 523 subjects in clinical trials. In 2004, (99m)Tc-falosomab was approved in the United States for use in patients with equivocal presentation of appendicitis. However, following postmarketing reports of serious adverse events, including two fatalities, the agent was withdrawn in late 2005, and its future is uncertain.

PMA-enhanced neutrophil [18F]FDG uptake is independent of integrin occupancy but requires PI3K activity.

OBJECTIVE: While respiratory burst enhances neutrophil glucose utilization, many neutrophil functions are critically influenced by extracellular matrix interaction and phosphoinositide-3-OH kinase (PI3K) signaling. We thus evaluated the role of RGD integrin occupancy and PI3K inhibition on respiratory burst and [(18)F]fluorodeoxyglucose ([(18)F]FDG) uptake of stimulated neutrophils. METHODS: Human neutrophils were stimulated by 100 ng/ml phorbol-myristate-acetate (PMA), and respiratory burst was measured by cumulative luminescence with lucigenin. [(18)F]FDG uptake and total hexokinase activity was measured 20 min after PMA stimulation in the presence or absence of soluble RGD peptides (200 microg/ml) and/or the PI3K inhibitor wortmannin (200 nM). RESULTS: Phorbol-myristate-acetate induced a 71.7+/-0.9 fold increase in neutrophil oxygen intermediate generation. [(18)F]FDG uptake was increased to 194.6+/-3.7% and hexokinase activity to 145.0+/-2.0% of basal levels (both P<.0005). RGD peptides attenuated respiratory burst activation to 35.6+/-0.2% (P<.005) but did not inhibit stimulated [(18)F]FDG uptake or hexokinase activity. In contrast, without affecting respiratory burst activation, wortmannin inhibited PMA-stimulated [(18)F]FDG uptake to 66.9+/-1.6% and hexokinase activity to 81.0+/-4.2% (both P<.0005), demonstrating its dependence on PI3K activity. Neither RGD nor wortmannin reversed the other's inhibitory effect on stimulated [(18)F]FDG uptake and hexokinase activity or respiratory burst, which suggests the involvement of distinct signaling pathways. CONCLUSION: Neutrophil [(18)F]FDG uptake is enhanced by PMA through a mechanism that requires PI3K activity but is independent of integrin receptor occupancy or respiratory burst activation.

Dedicated pinhole SPECT of intestinal neutrophil recruitment in a mouse model of dextran sulfate sodium-induced colitis.

UNLABELLED: Evaluating the efficacy of therapy in experimental inflammatory bowel disease (IBD) requires information about inflammatory activity in bowel segments or leukocyte recruitment and about kinetics in the follow-up of treatment. This study evaluated a noninvasive scintigraphic technique able to assess neutrophil trafficking in a mouse model of dextran sulfate sodium (DSS)-induced colitis. METHODS: Groups of 4 BALB/c mice were assessed at baseline and after 1, 3, 5, and 8 d of treatment with DSS. Donor neutrophils were harvested by rinsing of the peritoneal cavity with phosphate-buffered saline 5 h after intraperitoneal injection of proteose peptone contained in phosphate-buffered saline and labeled with freshly prepared (99m)Tc-hexamethylpropylene amine oxime (HMPAO). Pinhole SPECT of the abdomen was performed 1 h after reinjection of 50 MBq of labeled neutrophils. In addition, the severity of inflammation was determined by histologic examination. The possibilities of the technique were illustrated by scintigraphic assessment of neutrophil trafficking with and without blocking of neutrophil migration by a CD97 monoclonal antibody in mice with DSS-induced colitis. RESULTS: Colonic uptake of (99m)Tc-HMPAO neutrophils was determined with dedicated animal pinhole SPECT in mice with DSS-induced colitis and correlated well with histologic findings (R = 0.81) and wet colon weight (R = 0.87) and moderately with clinical weight loss (R = 0.62). The neutrophil uptake ratio was reduced significantly (P < 0.01) by blocking of neutrophil migration capacity with the CD97 antibody. CONCLUSION: Animal pinhole SPECT can be used to study inflammatory activity and neutrophil recruitment in vivo in experimental colitis.

Relative uptake of technetium 99m stannous colloid by neutrophils and monocytes is altered by gram-negative infection.

Gram-negative infection alters phagocytic cell function; hence, it could affect phagocytic uptake of inorganic colloids by these cells. Neutrophil and monocyte uptake of technetium 99m stannous colloid (99mTc SnC) in whole blood was measured in 10 patients with gram-negative infection (Burkholderia pseudomallei) and 7 controls. Mean uptake per individual neutrophil was reduced in infection. Uptake per monocyte was not significantly different. Blood from six normal individuals was incubated with lysed B. pseudomallei and colloid, which showed reduced neutrophil uptake, but increased monocyte uptake. These results indicate that uptake of 99mTc SnC stannous colloid can be used to measure alteration in phagocytic cell function. They suggest that infection with B. pseudomallei is associated with reduced phagocytosis by individual neutrophils, possibly through toxic effects of bacterial products. This could have immunopathogenic consequences for this gram-negative infection and may explain why it responds to granulocyte colony-stimulating factor.

Prosthetic radioiodination of interleukin-8 ([(123/131)I]-IL-8): biological behavior in a mouse infection model.

Numerous molecular entities with diverse structures have been radiolabeled and investigated as potential infection and inflammation detection agents. However, none of these molecules have gained the acceptance of gallium citrate or radiolabeled autologous white blood cells. We have radioiodinated interleukin-8 using two different methods and tested the biological behavior of the products in mice. As expected, the direct radioiodinated material displayed extensive in vivo deiodination. The use of pyridine-based prosthetic label yielded a product with better kinetics than the direct radioiodination method and showed a better target to non-target ratio. Nonetheless, this method is not suited for labeling of bioactive peptides such as the title peptide because of the very high specific activity required to prevent cytotoxic effects in a human application.

Relationship between neutrophil-binding affinity and suitability for infection imaging: comparison of (99m)Tc-labeled NAP-2 (CXCL-7) and 3 C-terminally truncated isoforms.

UNLABELLED: The CXC chemokines are a family of closely related chemoattractant cytokines that bind to, attract, and activate neutrophils to variable degrees. In this study, the relationship between neutrophil-binding affinity and suitability for infection imaging was investigated in a selected group of CXC chemokines. Neutrophil-activating peptide-2 (NAP-2, 70 residues; also called CXCL7) binds with high affinity to the CXCR2 receptor on neutrophils. Recently, C-terminally truncated NAP-2-variants have been described that have enhanced neutrophil-binding affinity and neutrophil-stimulating capacity. Here, NAP-2 and its C-terminal shortened variants NAP-2(1-68), NAP-2(1-66), and NAP-2(1-63) were labeled with (99m)Tc via the hydrazinonicotinamide (HYNIC) chelator and their potential for imaging of infection was investigated in a rabbit model of infection. The CXC chemokine interleukin-8 (IL-8) was used for comparison. In addition, a series of (99m)Tc-labeled CXC chemokines were screened for their potential to image infection, including CTAP-III, GCP-2, ENA-78, PF-4, and IP-10. METHODS: The receptor-binding affinity of HYNIC-conjugated NAP-2 and its analogs was compared in competitive binding assays on Jurkat cells transfected with the CXCR2 receptor gene. Biodistribution of labeled NAP-2 (analogs) and other CXC chemokines in rabbits with intramuscular Escherichia coli infections was determined both by gamma-camera imaging and by counting dissected tissues at 6 h after injection. RESULTS: The CXCR2-binding affinity of the HYNIC-conjugated NAP-2 analogs relative to NAP-2 was as follows: NAP-2(1-68), 2.5-fold; NAP-2(1-66), 10-fold; and NAP-2(1-63), 3-fold. In the rabbit model, uptake in the abscess (in percentage injected dose per gram +/- SEM) was 0.084 +/- 0.015 for NAP-2, 0.098 +/- 0.010 for NAP-2(1-68), 0.189 +/- 0.044 for NAP-2(1-66), and 0.114 +/- 0.017 for NAP-2(1-63) at 6 h after injection. In comparison, higher uptake in the abscess was found for labeled IL-8, a modest uptake was found for GCP-2 and ENA-78, and a low uptake was found for CTAP-III, PF-4, and IP-10. CONCLUSION: This study showed a clear relationship between affinity to receptors on neutrophils and suitability for infection imaging. Of the NAP-2 variants, NAP-2(1-66) combined highest affinity to CXCR2 with the best characteristics for imaging. IL-8 binds to both CXCR1 and CXCR2 with high affinity and showed a superior imaging quality. The other CXC chemokines tested bind to neutrophils with lower affinity and were shown to be less suitable for infection imaging in this study.

Neutrophil and platelet dynamics at organ level after cardiopulmonary bypass: an in vivo study in neonatal pigs.

The aim was to investigate if organ dysfunction is a consequence of cell accumulation in the tissue and whether this accumulation is caused by the cardiopulmonary bypass (CPB) procedure. Twenty-six piglets were used in the sham group (sternotomy, n=12) or in the CPB group (sternotomy, CPB, n=14). Isotope-labeled autologous (99m)Tc-neutrophils (PMNs) and (111)In-platelets were infused and dynamically followed at organ level with a gamma camera before, during, and 4 h after termination of CPB. The CPB group showed a 49% increase in (99m) Tc-PMNs in the kidneys in the postoperative period compared to a decrease of 2% in the sham group. A less marked decrease was observed in the lungs and peripheral blood between the two groups. The increased radioactivity at organ level post-CPB could be due to changes in flow, extraction in the organ or accumulation of cells, especially in the kidneys and lungs, and might contribute to temporary organ dysfunction postoperatively.

Imaging of experimental colitis with a radiolabeled leukotriene B4 antagonist.

UNLABELLED: The use of radiolabeled leukocytes is considered the gold standard for scintigraphic imaging of inflammatory bowel disease. The disadvantages of (99m)Tc-hexamethylpropyleneamine oxime (HMPAO)-leukocytes, however, encourage the search for new imaging agents with at least similar diagnostic accuracy but without the laborious preparation and subsequent risk of contamination. In this study we investigated the imaging characteristics of a new imaging agent that specifically binds to the leukotriene B(4) (LTB(4)) receptors expressed on neutrophils. Imaging characteristics of the (111)In-labeled LTB(4) antagonist (DPC11870) were compared with those of (18)F-FDG and (99m)Tc-HMPAO-granulocytes in a rabbit model of experimental colitis. METHODS: Acute colitis was induced in New Zealand White (NZW) rabbits by infusion of trinitrobenzene sulfonic acid in the descending colon. Forty-eight hours after induction of colitis, all animals were injected intravenously with (99m)Tc-granulocytes, (18)F-FDG, or (111)In-DPC11870. The pharmacokinetics and biodistribution were studied by serial scintigraphic imaging and by ex vivo counting of dissected tissues. RESULTS: All 3 radiopharmaceuticals showed the inflamed colon as early as 1 h after injection. However, compared with (99m)Tc-granulocytes, both (111)In-DPC11870 and (18)F-FDG were superior in revealing the inflamed lesions. The biodistribution data showed that uptake of (111)In-DPC11870 in the inflamed colon was highest (0.72 +/- 0.18 percentage injected dose per gram [%ID/g]), followed by uptake of (99m)Tc-granulocytes (0.40 +/- 0.11 %ID/g) and of (18)F-FDG (0.16 +/- 0.04 %ID/g). Because of low activity concentrations in the noninflamed colon, the radiolabeled LTB(4) antagonist also revealed the highest ratio of affected colon to unaffected colon (11.6 for (111)In-DPC11870, 5.5 for (99m)Tc-granulocytes, and 4.1 for (18)F-FDG). CONCLUSION: The radiolabeled LTB(4) antagonist DPC11870 clearly delineated acute colitis lesions in NZW rabbits within 1 h after injection. Because of high uptake in the inflamed lesions and a low activity concentration in the noninflamed colon, images acquired with (111)In-DPC11870 were better than those acquired with (99m)Tc-granulocytes or (18)F-FDG.

Positron emission tomography with [18F]fluorodeoxyglucose to evaluate neutrophil kinetics during acute lung injury.

We measured neutrophil glucose uptake with positron emission tomographic imaging and [18F]fluorodeoxyglucose ([18F]FDG-PET) in anesthetized dogs after intravenous oleic acid-induced acute lung injury (ALI; OA group, n = 6) or after low-dose intravenous endotoxin (known to activate neutrophils without causing lung injury) followed by OA (Etx + OA group, n = 7). The following two other groups were studied as controls: one that received no intervention (n = 5) and a group treated with Etx only (n = 6). PET imaging was performed 1.5 h after initiating experimental interventions. The rate of [3H]deoxyglucose ([3H]DG) uptake was also measured in vitro in cells recovered from bronchoalveolar lavage (BAL) performed after PET imaging. Circulating neutrophil counts fell significantly in animals treated with Etx but not in the other two groups. The rate of [18F]FDG uptake, measured by the influx constant Ki, was significantly elevated (P < 0.05) in both Etx-treated groups (7.9 +/- 2.6 x 10(-3) ml blood x ml lung(-1) x min(-1) in the Etx group, 9.3 +/- 4.8 x 10(-3) ml blood x ml lung(-1) x min(-1) in the Etx + OA group) but not in the group treated only with OA (3.4 +/- 0.8 x 10-3 ml blood x ml lung(-1) x min(-1)) when compared with the normal control (1.6 +/- 0.4 x 10(-3) ml blood x ml lung(-1) x min(-1)). [3H]DG uptake was increased (73 +/- 7%) in BAL neutrophils recovered from the Etx + OA group (P < 0.05) but not in the OA group. Ki and [3H]DG uptake rates were linearly correlated (R2 = 0.65). We conclude that the rate of [18F]FDG uptake in the lungs during ALI reflects the state of neutrophil activation. [18F]FDG-PET imaging can detect pulmonary sequestration of activated neutrophils, despite the absence of alveolar neutrophilia. Thus [18F]FDG-PET imaging may be a useful tool to study neutrophil kinetics during ALI.