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Delphine L Chen,
Dong Zhou,
Wenhua Chu,
Phillip Herrbrich,
Jacquelyn T Engle,
Elizabeth Griffin,
Lynne A Jones,
Justin M Rothfuss,
Marco Geraci,
Richard S Hotchkiss,
Robert H Mach
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ABSTRACT: Noninvasive imaging methods that can distinguish apoptosis from necrosis may be useful in furthering our understanding of diseases characterized by apoptotic dysregulation as well as aiding drug development targeting apoptotic pathways. We evaluated the ability of radiolabeled isatins to quantify caspase-3 activity induced by the activation of the extrinsic apoptotic pathway by the anti-Fas antibody in mice.
The behavior of three different radiolabeled isatins ([(18)F]WC-II-89, [(18)F]WC-IV-3 and [(11)C]WC-98) was characterized in mice with and without anti-Fas antibody treatment by microPET imaging and biodistribution studies. The activity of [(18)F]WC-II-89 was also compared with [(99m)Tc]mebrofenin. The effect of pan-caspase inhibition with quinolyl-valyl-O-methylaspartyl-[2,6-difluorophenoxy]-methyl ketone (Q-VD-OPh) on [(18)F]WC-II-89 uptake was studied. Caspase-3 activity was confirmed by a fluorometric enzyme assay.
All three tracers behaved similarly in microPET and biodistribution studies. Increased retention of all tracers was observed in the livers of treated animals and several other organs, all of which demonstrated increased caspase-3 enzyme activity; however, impaired hepatobiliary excretion made attribution of these findings to caspase-3 activity difficult. The isatin [(18)F]WC-II-89 was retained at statistically significantly higher levels in the organs after anti-Fas antibody treatment while [(99m)Tc]mebrofenin activity cleared, suggesting specific binding to activated caspase-3, but the magnitude of increased binding was still relatively low. Caspase inhibition with Q-VD-OPh partially blocked [(18)F]WC-II-89 retention but completely blocked caspase-3 enzyme activity in the liver.
The radiolabeled isatins appear to bind specifically to caspase-3 in vivo, but their sensitivity is limited. Further optimization is required for these tracers to be useful for clinical applications.
Nuclear Medicine and Biology 01/2012; 39(1):137-44. · 3.02 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPARγ) transcriptionally modulates fat metabolism and also plays a role in pathological conditions such as cancer, neurodegenerative disease and inflammation. PPARγ imaging agents are potential tools for investigating these diseases.
Four analogs of GW9662, a PPARγ antagonist, with different fluorine-containing substituents at the para-position of the aniline ring were synthesized and evaluated using two different receptor binding assays for measuring PPARγ affinity. Micro-positron emission tomography (PET) imaging studies were performed in a transgenic mouse model having a heart-specific overexpression of PPARγ.
All four analogs were found to have binding affinities that were comparable to or better than the reference antagonist, GW9662, using a scintillation proximity assay (SPA). However, only the chloro-based analogs (compounds 3 and 4) had activity in a whole-cell assay measuring activation of the PPARγ/retinoid X receptor complex. The microPET imaging studies in an MHC-PPARγ transgenic mouse model showed high uptake and PPARγ-specific binding for the irreversible antagonist [(18)F]3, whereas the corresponding reversible methoxy analog ([(18)F]5) displayed only nonspecific uptake in heart.
The results of this preliminary study show that the irreversible antagonist [(18)F]3 may represent a novel strategy for imaging PPARγ in vivo with PET.
Nuclear Medicine and Biology 09/2011; 39(1):77-87. · 3.02 Impact Factor
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ABSTRACT: The continued progression of chronic lung disease despite current treatment options has led to the increasing evaluation of molecular imaging tools for diagnosis, treatment planning, drug discovery, and therapy monitoring. Concurrently the development of multimodality positron emission tomography (PET) / computed tomography (CT), single-photon emission computed tomography (SPECT)/CT, and magnetic resonance imaging (MRI)/PET scanners has opened the potential for more sophisticated imaging biomarker probes. Here we review the potential uses of multimodality imaging tools, the established uses of molecular imaging in nononcologic lung pathophysiology and drug discovery, and some of the technical challenges in multimodality molecular imaging of the lung.
Journal of Magnetic Resonance Imaging 12/2010; 32(6):1409-20. · 2.70 Impact Factor
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ABSTRACT: Caspase-3 is one of the executioner caspases activated as a result of apoptosis. Radiolabeled isatins bind to caspase-3 with high affinity and are potential tracers for use with positron emission tomography to image apoptosis. We compared the ability of two novel radiolabeled isatins, [18F]WC-IV-3 and [11C]WC-98, to detect caspase-3 activation in a rat model of cycloheximide-induced liver injury.
Male Sprague-Dawley rats were treated with cycloheximide and then imaged with microPET 3 h later with [18F]WC-IV-3 and [11C]WC-98. Biodistribution studies were also performed simultaneously, with caspase-3 activation verified by fluorometric enzyme assay and Western blots.
MicroPET imaging studies demonstrated similar behavior of both tracers but with a lower maximum peak with [11C]WC-98 than with [18F]WC-IV-3. Biodistribution studies demonstrated increased uptake of both tracers in the liver and spleen, but this was statistically significant only in the liver with both compounds. The level of [18F]WC-IV-3 uptake appeared to correlate roughly with rates of caspase-3 activation by the enzyme assay, but the magnitude of difference between treated and control groups was lower than that observed in previously published data with [18F]WC-II-89, another radiolabeled isatin analog. Activation was also confirmed in the liver and spleen but not in fat by Western blot.
[18F]WC-IV-3 uptake appears to correlate with increased caspase-3 enzyme activity, but the dynamic range of uptake of these two tracers appears to be less than that seen with [18F]WC-II-89. Studies are ongoing to verify these results in other animal models of apoptosis.
Nuclear Medicine and Biology 09/2009; 36(6):651-8. · 3.02 Impact Factor
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ABSTRACT: 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.
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.
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.
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).
American Journal of Respiratory and Critical Care Medicine 08/2009; 180(6):533-9. · 11.08 Impact Factor
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ABSTRACT: The radiolabeled isatin sulfonamide caspase-3 inhibitor, [18F] 2 (WC-II-89), is a potential PET radiotracer for noninvasive imaging of apoptosis. The radiolabeling mechanism was studied by 13C NMR, ESI/MS, and computational calculations. It was found that the high electrophilicity of the C3 carbonyl group in the isatin ring, which served as a trap for [18F]fluoride, was responsible for the failure of the radiolabeling via nucleophilic substitution of the mesylate group in 7a by [18F]fluoride. Once treated with a strong base, 7a opened the isatin ring completely to form an isatinate intermediate 16, which lost the ability to trap [18F]fluoride, thereby allowing the displacement of the mesylate group to afford the 18F-labeled isatinate 17. [18F] 17 can be converted to isatin [18F] 2 efficiently under acidic conditions. The ring-opening and re-closure of the isatin ring under basic and acidic conditions were confirmed by reversed phase HPLC analysis, ESI/MS and 13C NMR studies. Computational studies of model compounds also support the above proposed mechanism. Similarly, the ring-opening and re-closure method was used successfully in the synthesis of the 11C labeled isatin sulfonamide analogue [11C] 4 (WC-98). A microPET imaging study using [11C] 4 in the Fas liver apoptosis model demonstrated retained activity in the target organ (liver) of the treated mice. Increased caspase-3 activation in the liver was verified by the fluorometric caspase-3 enzyme assay. Therefore, this study provides a useful method for radio-synthesis of isatin derivative radiotracers for PET and SPECT studies, and [11C] 4 is a potential PET radiotracer for noninvasive imaging of apoptosis.
Organic & Biomolecular Chemistry 05/2009; 7(7):1337-48. · 3.70 Impact Factor
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ABSTRACT: A series of position-6 substituted 2-amino-4-methylpyridine analogues was synthesized and compounds 9, 18, and 20 were identified as the inhibitors with the greatest potential to serve as PET tracers for imaging inducible nitric oxide synthase (iNOS). [(18)F]9 was synthesized and evaluated in a mouse model of lipopolysaccharide (LPS)-induced iNOS activation. In vivo biodistribution studies of [(18)F]9 indicate higher tracer uptake in the lungs of the LPS-treated mice when compared to control mice. Tracer uptake at 60 min postinjection was reduced in a blocking study using a known inhibitor of iNOS. The expression of iNOS was confirmed by Western blot analysis of lung samples from the LPS-treated mice. MicroPET studies also demonstrated accumulation of radiotracer in the lungs of the LPS-treated mice. Taken collectively, these data suggest that [(18)F]9 shows favorable properties as a PET tracer to image iNOS activation with PET.
Journal of Medicinal Chemistry 04/2009; 52(8):2443-53. · 4.80 Impact Factor
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ABSTRACT: A series of fluorine-containing benzamide analogs was synthesized and evaluated as candidate ligands for positron emission tomography (PET) imaging of the sigma-2 (sigma2) receptor status of solid tumors. Four compounds having a moderate to high affinity for sigma2 receptors and a moderate to low affinity for sigma-1 (sigma1) receptors were radiolabeled with fluorine-18 via displacement of the corresponding mesylate precursor with [18F]fluoride. Biodistribution studies in female Balb/c mice bearing EMT-6 tumor allografts demonstrated that all four F-18-labeled compounds had a high tumor uptake (2.5-3.7% ID/g) and acceptable tumor/normal tissue ratios at 1 and 2 h post-i.v. injection. An analysis of the chemistry and biodistribution data suggested that N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-[18F]-fluoroethoxy)-5-methylbenzamide ([18F]3c) and N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-[18F]-fluoroethoxy)-5-iodo-3-methoxybenzamide ([18F]3f) are acceptable compounds for imaging the sigma2 receptor status of solid tumors.
Journal of Medicinal Chemistry 08/2007; 50(14):3194-204. · 5.25 Impact Factor
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ABSTRACT: Recent studies indicate that a focal, limited, inflammatory response can be safely elicited after direct bronchial instillation of small doses of endotoxin into a single lung segment. Because the radiotracer [18F]fluorodeoxyglucose ([18F]FDG) is taken up at accelerated rates within inflamed tissues, we hypothesized that we could detect and quantify this regional inflammatory response with positron emission tomography (PET). We imaged 18 normal volunteers in a dose-escalation study with 3 endotoxin dosing groups (n = 6 in each group): 1 ng/kg, 2 ng/kg, and 4 ng/kg. Endotoxin was instilled by bronchoscopy into a segment of the right middle lobe, with imaging performed approximately 24 h later, followed by bronchoalveolar lavage (BAL). A "subtraction imaging analysis" was performed in the highest dose cohort to identify the area of inflammation, using the preendotoxin scan as a baseline. BAL neutrophil counts were significantly higher in the highest dose group compared with the other two groups (1,413 +/- 625 vs. 511 +/- 396 and 395 +/- 400 cells/mm3; P < 0.05). Autoradiography performed on cells harvested by BAL showed specific [3H]deoxyglucose ([3H]DG) uptake limited to neutrophils. In vitro [3H]DG uptake in BAL neutrophils in the 4 ng/kg dose group (but not in the 2 ng/kg group) was statistically greater than in peripheral blood neutrophils obtained before endotoxin instillation. The rate of [18F]FDG uptake was greatest in the 4 ng/kg group, with a consistent, statistically significant increase in the rate of uptake after endotoxin instillation compared with baseline. We conclude that the inflammatory response to low-dose endotoxin in a single lung segment can be visualized and quantified by imaging with FDG-PET.
Journal of Applied Physiology 06/2006; 100(5):1602-9. · 3.75 Impact Factor
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ABSTRACT: Although infection contributes to morbidity in patients with cystic fibrosis (CF), the host inflammatory response is also an important cause of progressive pulmonary function deterioration. Quantifying the inflammatory burden in these patients is challenging and often requires invasive procedures. Positron emission tomographic imaging with [18F]fluorodeoxyglucose ([18FDG]) could be used as a noninvasive alternative to quantify lung inflammation.
To determine the relationships among lung [18F]FDG uptake, bronchoalveolar lavage (BAL) neutrophil concentrations, and pulmonary function in patients with CF.
Twenty patients and seven healthy volunteers were studied. A subset of seven patients also consented to undergo BAL. The uptake of [18F]FDG by the lungs was measured as the net influx rate constant Ki. Patients were stratified by rate of decline in pulmonary function into stable, intermediate, and rapidly declining groups. Ki was compared among groups and was correlated against neutrophil concentrations in BAL fluid.
Ki was significantly elevated (p<0.05) among patients with CF as a whole compared with healthy control subjects (0.0015+/-0.0009 versus 0.0007+/-0.0002 ml blood/ml lung/min) but especially in patients with rapidly declining pulmonary function (0.0022+/-0.0011 ml blood/ml lung/min). Ki correlated positively with the number of neutrophils present in BAL fluid.
Imaging with [18F]fluorodeoxyglucose and positron emission tomography can be used to assess inflammatory burden in patients with CF. Elevations in Ki may be able to identify patients with more aggressive disease and may be useful in monitoring changes in inflammatory burden in response to novel treatments.
American Journal of Respiratory and Critical Care Medicine 06/2006; 173(12):1363-9. · 11.08 Impact Factor
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ABSTRACT: 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.
AJP Lung Cellular and Molecular Physiology 12/2005; 289(5):L760-8. · 3.66 Impact Factor
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ABSTRACT: Positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) has been established as a useful tool in the management of patients with non-small cell lung cancer and promises to be as valuable in the clinical management of other cancers. PET imaging with FDG allows the assessment of tumor glucose metabolism in vivo; however, a number of other PET tracers are being used in oncologic research to assess changes in other cellular processes associated with malignant transformation of the cell. [11C]-Labeled methionine and choline are being used to assess changes in cell membrane synthesis; however, small studies have not shown the added information from these tracers to be clinically useful. DNA synthesis can be assessed by measuring the uptake of the thymidine analog 3'-deoxy-3'-[18F]fluorothymidine, which may be more specific for evaluating malignancy without the problem of false-positive results from inflammatory lesions, as seen with FDG. Tumor hypoxia imaging with copper-labeled diacetyl-bis(N(4)-methylthiosemicarbazone) or [18F]fluoromisonidazole may provide a better method of predicting which tumors will respond best to conventional therapy. The role of PET will continue to evolve with further clinical studies using these and other new tracers.
Proceedings of the American Thoracic Society 02/2005; 2(6):541-4, 512.
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ABSTRACT: PET with 18F-FDG may be useful for quantifying neutrophilic activation. We previously demonstrated that pulmonary neutrophil sequestration could be detected during acute lung injury (ALI), even without migration into the alveolar compartment. Using the influx constant Ki as the method to quantify lung 18F-FDG uptake, we also showed that Ki correlated positively with in vitro assays of 3H-deoxyglucose (3H-DG) uptake in cells harvested via bronchoalveolar lavage. In the present study, we have reanalyzed data from that study to determine if simpler nonkinetic methods of quantifying the pulmonary uptake of 18F-FDG could be as powerful as calculating Ki.
18F-FDG uptake was quantified as Ki, calculated by 3-compartmental model analysis (used as the gold standard) and Patlak graphical analysis, with and without normalization for initial volume of tracer distribution; the standardized uptake value; and the tissue-to-plasma activity ratio (TPR).
Values for Ki, determined either from a 3-compartmental model analysis of the time-activity data or by Patlak graphical analysis, were highly correlated (R2 = 0.97). The correlation was worse if these variables were normalized for the initial volume of tracer distribution. TPR was highly correlated with Ki determined by the compartmental model (R2 = 0.96) and with in vitro measurements of 3H-DG uptake (R2 = 0.63).
The TPR is a simple and equally effective alternative to dynamic imaging in determining net 18F-FDG uptake during ALI. Normalization of the kinetic data for differences in the initial volume of tracer distribution does not contribute significantly to signal interpretation during ALI.
Journal of Nuclear Medicine 10/2004; 45(9):1583-90. · 6.38 Impact Factor
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ABSTRACT: Molecular imaging is a rapidly developing multidisciplinary field that combines advances in contrast agent development, instrumentation, and molecular/cell biology to follow cellular and sub-cellular events in intact organisms. Platforms for molecular imaging include radionuclide-based methods, optical methods, and magnetic resonance. To date, molecular imaging studies of the lungs have been used to monitor the effectiveness of gene transfer, neutrophilic inflammation, and cell trafficking. Eventually, the goal will be to translate these new techniques to clinical settings such as cystic fibrosis.
Pediatric Pulmonology 05/2004; 37(4):286-96. · 2.53 Impact Factor
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ABSTRACT: PET imaging represents a promising approach for noninvasive monitoring of reporter gene expression in living subjects. We evaluated the relationship between various methods of quantifying the imaging signal and in vitro assays of the expression of a PET reporter gene (a mutant Herpes simplex virus-1 thymidine kinase (mHSV1-tk); 9-(4-(18)F-fluoro-3-hydroxymethylbutyl)guanine ((18)F-FHBG) was used as the PET reporter probe.
In 14 rats, pulmonary gene transfer was performed by intratracheal administration of various amounts of an adenovector containing a fusion gene encoding for mHSV1-tk and an enhanced green fluorescent protein. Three days later, the animals were divided into 2 groups. One group (n = 7) did not receive any other interventions. The other group was treated with alpha-naphthylthiourea (ANTU) to increase pulmonary vascular permeability. All rats were injected intravenously with (18)F-FHBG. Two additional rats in both groups received a null adenovector and served as controls. In the normal rats, repetitive blood samples were obtained and PET imaging was performed simultaneously using a dynamic imaging protocol. Rate constants estimating (18)F-FHBG transport (K(1)) or trapping (k(3)) within target cells were generated by compartmental modeling. After euthanasia, pulmonary uptake of (18)F-FHBG was determined using a gamma-counter in all rats, and in vitro assays of transgene expression were performed on lung tissue.
In normal rats, pulmonary uptake of (18)F-FHBG increased as thymidine kinase (TK) activity increased only at low levels of mHSV1-tk expression and then plateaued as TK activity continued to increase. Compartmental modeling failed to improve the correlation with in vitro assays of transgene expression. However, a linear relationship was obtained between the pulmonary uptake of (18)F-FHBG and in vitro assays of TK activity in rats treated with ANTU.
In rodent lungs, (18)F-FHBG uptake appears to be a function of both transport into tissues expressing the transgene as well as the level of transgene expression itself.
Journal of Nuclear Medicine 05/2004; 45(4):644-54. · 6.38 Impact Factor
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ABSTRACT: 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.
AJP Lung Cellular and Molecular Physiology 04/2004; 286(4):L834-40. · 3.66 Impact Factor
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Methods in Enzymology 02/2004; 385:315-33. · 2.04 Impact Factor
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ABSTRACT: Small-dose endotoxin (Etx) prevents pulmonary perfusion redistribution away from edematous dorsal lung regions after oleic acid (OA)-induced injury in dogs, causing a significant deterioration in oxygenation. We hypothesized that small-dose Etx might mediate this effect via polymorphonuclear neutrophil (PMN) priming with release of inflammatory mediators such as platelet activating factor (PAF) or secretory phospholipase A(2) (sPLA(2)). To test this hypothesis, we administered specific inhibitors directed against each mediator and used two strategies to generate neutropenia. PAF and sPLA(2) inhibitors were administered before OA injury, followed 2 h later by small-dose Etx (n = 4 each group). PMN depletion was achieved by hydroxyurea administration for 5 days before the study to achieve absolute neutrophil counts <1000/mm(3) (n = 4). Inhibition of PMN adherence to lung endothelium was achieved by the administration of an anti-CD18 monoclonal antibody immediately before lung injury (n = 5). Positron emission tomography was used to evaluate pulmonary perfusion distribution and lung water content. We observed no effect of these interventions on the perfusion pattern after Etx + OA. Thus, neither neutrophils nor PAF or sPLA(2) mediate the effects of Etx on the pattern of perfusion in this model of lung injury. IMPLICATIONS: Acute respiratory failure is characterized by severe decreases in blood oxygen. The pattern of blood flow within the lungs can contribute to this problem. This study investigated the potential role of white blood cells and their products in mediating abnormal pulmonary blood flow patterns in an experimental animal model of respiratory failure.
Anesthesia & Analgesia 02/2004; 98(2):452-7, table of contents. · 3.29 Impact Factor
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ABSTRACT: Prevention and control of graft rejection remain essential in the investigation of peripheral nerve allotransplantation. Although use of cyclosporin A (CsA) has been shown to suppress successfully the rejection of nerve allografts, limited information exists concerning use of this drug to arrest rejection in progress, and thereby effect salvage of these grafts. The aim of this study was to determine the efficacy of CsA in the treatment of ongoing acute rejection of peripheral nerve allografts. Buffalo rats received posterior tibial nerve grafts from either Lewis or Buffalo donor animals and were divided into five groups: group 1 received isografts and no CsA treatment (n = 8), group 2 received allografts with continuous CsA therapy (n = 10), group 3 received allografts with no treatment (n = 7), group 4 received allografts with initiation of CsA therapy delayed until 3 weeks after the procedure (n = 11), and group 5 received allografts with an interrupted course of CsA (n = 15). All grafts were harvested at 10 weeks. Histomorphometric analysis demonstrated comparable nerve regeneration in groups 1 and 2 and good regeneration in group 3 animals, despite cellular infiltrate suggestive of rejection. At 3 weeks after surgery, group 4 animals showed early rejection and significantly less neuroregeneration than positive controls at 10 weeks after delayed initiation of CsA therapy. Finally, group 5 animals showed early regeneration at 3 weeks but significantly lesser regeneration by 10 weeks after interruption of therapy. In this experimental protocol, CsA was ineffective in rescuing histologically proven rejection in progress.
Annals of Plastic Surgery 01/2003; 49(6):660-7. · 1.32 Impact Factor
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ABSTRACT: Methods currently used to assess lung and airway inflammation are often poorly quantitative, invasive, nonspecific, or insensitive. Positron emission tomography (PET) with [18F]fluorodeoxyglucose [18F]FDG), on the other hand, is a noninvasive, highly sensitive imaging technique that can be used to quantify pulmonary inflammation. [18F]FDG, an analogue of glucose, is taken up by the same transporters that take up glucose into the cell; therefore, [18F]FDG uptake tracks cellular glucose transport, which is highly correlated to the rate of cellular glucose metabolism. Recent studies in animal models of neutrophilic lung inflammation, as well as in patients with inflammatory lung disease, indicate that increased [18F]FDG uptake by the lungs correlates with the number of activated neutrophils recovered from the lungs. Therefore, the in vivo measurement of pulmonary glucose metabolism is a measure of neutrophil burden within the lungs. We propose that FDG-PET imaging can be used as a measurable biomarker in the development of drug therapies targeting lung inflammation.
Molecular Pharmaceutics 3(5):488-95. · 4.78 Impact Factor
