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Daniel P Schuster

Publications and source records attributed to Daniel P Schuster.

At least 19 recordsLinked to original sources
PubMed2006

Regulation of lipopolysaccharide-induced increases in neutrophil glucose uptake.

The pathogenesis of many lung diseases involves neutrophilic inflammation. Neutrophil functions, in turn, are critically dependent on glucose uptake and glycolysis to supply the necessary energy to meet these functions. In this study, we determined the effects of p38 mitogen-activated protein kinase and hypoxia-inducible factor (HIF)-1, as well as their potential interaction, on the expression of membrane glucose transporters and on glucose uptake in murine neutrophils. Neutrophils were harvested and purified from C57BL/6 mice and stimulated with lipopolysaccharide (LPS) in the presence or absence of specific p38 and HIF-1 inhibitors. Glucose uptake was measured as the rate of [3H]deoxyglucose (DG) uptake. We identified GLUT-1 in mouse neutrophils, but neither GLUT-3 nor GLUT-4 were detected using Western blot analysis, even after LPS stimulation. LPS stimulation did not increase GLUT-1 protein levels but did cause translocation of GLUT-1 from the cell interior to the cell surface, together with a dose-dependent increase in [3H]DG uptake, indicating that glucose uptake is regulated in these cells. LPS also activated both p38 and the HIF-1 pathway. Inhibitors of p38 and HIF-1 blocked GLUT-1 translocation and [3H]DG uptake. These data suggest that LPS-induced increases in neutrophil glucose uptake are mediated by GLUT-1 translocation to the cell surface in response to sequential activation of neutrophil p38 and HIF-1alpha in neutrophils. Given that neutrophil function and glucose metabolism are closely linked, control of the latter may represent a new target to ameliorate the deleterious effects of neutrophils on the lungs.

Animals↗
PubMed2006

Visualizing lung function with positron emission tomography.

Positron emission tomography (PET) provides three-dimensional images of the distributions of radionuclides that have been inhaled or injected into the lungs. By using radionuclides with short half-lives, the radiation exposure of the subject can be kept small. By following the evolution of the distributions of radionuclides in gases or compounds that participate in lung function, information about such diverse lung functions as regional ventilation, perfusion, shunt, gas fraction, capillary permeability, inflammation, and gene expression can be inferred. Thus PET has the potential to provide information about the links between cellular function and whole lung function in vivo. In this paper, recent advancements in PET methodology and techniques and information about lung function that have been obtained with these techniques are reviewed.

Animals↗
PubMed2006

Extravascular lung water measurements and hemodynamic monitoring in the critically ill: bedside alternatives to the pulmonary artery catheter.

The recently completed Fluid and Catheter Treatment Trial conducted by the National Institutes of Health ARDSNetwork casts doubt on the value of routine pulmonary artery catheterization for hemodynamic management of the critically ill. Several alternatives are available, and, in this review, we evaluate the theoretical, validation, and empirical databases for two of these: transpulmonary thermodilution measurements (yielding estimates of cardiac output, intrathoracic blood volume, and extravascular lung water) that do not require a pulmonary artery catheter, and hemodynamic measurements (including estimates of cardiac output and ejection time, a variable sensitive to intravascular volume) obtained by esophageal Doppler analysis of blood flow through the descending aorta. We conclude that both deserve serious consideration as a means of acquiring useful hemodynamic data for managing shock and fluid resuscitation in the critically ill, especially in those with acute lung injury and pulmonary edema, but that additional study, including carefully performed, prospective clinical trials demonstrating outcome benefit, is needed.

Blood Flow Velocity↗
PubMed2006

Quantifying pulmonary inflammation in cystic fibrosis with positron emission tomography.

RATIONALE: 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. OBJECTIVE: To determine the relationships among lung [18F]FDG uptake, bronchoalveolar lavage (BAL) neutrophil concentrations, and pulmonary function in patients with CF. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Adult↗
PubMed2006

FDG-PET imaging of pulmonary inflammation in healthy volunteers after airway instillation of endotoxin.

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.

Autoradiography↗
PubMed2005

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.

Animals↗
PubMed2005

Physiologic, biochemical, and imaging characterization of acute lung injury in mice.

RATIONALE: Most models of acute lung injury in mice have yet to be fully characterized. OBJECTIVES: To directly compare and contrast endotoxin and oleic acid models of acute lung injury in mice in terms of their physiologic, biochemical, histopathologic, and imaging manifestations. METHODS: Survival studies, lung weights, x-ray computed tomographic scanning, light and electron microscopy, bronchoalveolar lavage, lung uptake of ((18)F)fluorodeoxyglucose, tissue myeloperoxidase, arterial blood gases, mean arterial pressure, and lung tissue prostanoids were measured in separate groups of C57Bl/6 mice (normal animals, endotoxin only [20 microg/g], oleic acid only [0.15 microl/g], or endotoxin + oleic acid). RESULTS: Endotoxin alone caused only mild pulmonary neutrophilic inflammation with little functional or structural damage to the alveolar architecture. In contrast, oleic acid caused severe alveolar damage with the development of alveolar edema of the increased-permeability type with associated abnormalities in gas exchange. When given together, endotoxin and oleic acid acted synergistically to increase pulmonary edema and to worsen gas exchange and hemodynamics, thereby increasing mortality. This synergism was significantly attenuated by the prior administration of the endotoxin antagonist E5564 (eritoran). CONCLUSIONS: Under the conditions of these studies, only mice exposed to oleic acid showed both structural and functional characteristics of acute lung injury. Nevertheless, endotoxin had potent synergistic physiologic effects that increased mortality. Overall, these models, which can be translated to genetically altered mice, are amenable to study with state-of-the-art imaging techniques, and with experimental interventions that can probe the underlying mechanisms of injury.

Animals↗
PubMed2005

Molecular imaging of the lungs.

An emerging suite of new imaging techniques offer the ability to monitor and quantify molecular and cellular processes in the lungs noninvasively. These techniques take advantage of dramatic advances in both imaging technology as well as molecular and cell biology. Molecular imaging is being used with increasing regularity in research protocols, and forms of molecular imaging have found their way into the patient care setting (eg, positron emission tomography imaging in cancer). Such techniques will afford the basic scientist as well as the clinician an unprecedented opportunity for in vivo study of the lung biology that drives normal pulmonary physiology as well as pathophysiology.

Animals↗
PubMed2005

In vivo molecular imaging characterizes pulmonary gene expression during experimental lung transplantation.

Experimental gene therapy is a promising strategy to prevent ischemia-reperfusion (I/R) injury and allograft rejection after lung transplantation, and methods will eventually be needed to characterize pulmonary transgene expression in vivo in humans. Therefore, we studied positron emission tomography (PET) as a means of performing in vivo molecular imaging in rodent models of lung transplantation. Rats were transfected endotracheally with adenovirus encoding a fusion gene of a mutant Herpes simplex virus-1 thymidine kinase and the green fluorescent protein gene (the former serving as an imaging reporter gene). Twenty-four hours after transfection, lungs were transplanted in groups representing normal transplantation, I/R injury and acute allograft rejection. Imaging was obtained either 24 h after transplantation to study reperfusion injury or 4 days after transplantation to study graft rejection. After imaging, lungs were excised and analyzed for thymidine kinase activity. Imaging detected transgene expression in transplanted lungs even in the presence of acute rejection or I/R injury. The PET imaging signal correlated with in vitro lung tissue assays of thymidine kinase activity (r(2) = 0.534). Thus, noninvasive molecular imaging with PET is a feasible, sensitive and quantitative method for characterizing pulmonary transgene expression in experimental lung transplantation.

Animals↗
PubMed2005

Molecular imaging of pulmonary gene expression with positron emission tomography.

Gene expression imaging is one form of molecular imaging used to visualize, characterize, and quantify, spatially and temporally, normal as well as pathologic processes at cellular and subcellular levels within intact living organisms. Most studies to date have employed positron emission tomography as the imaging platform to detect, monitor, and quantify gene expression in the lungs. These studies have shown that imaging can be used to determine the onset and duration of transgene expression, the effectiveness of different gene delivery systems, and the linearity of vector dose-response relationships. This rapidly developing field can be expected to provide useful new tools with which to study gene expression in transgenic animals and in humans during gene therapy.

Animals↗
PubMed2004

Respiratory viral infections are a distinct risk for bronchiolitis obliterans syndrome and death.

Bronchiolitis obliterans syndrome (BOS) is the major obstacle to long-term survival after lung transplantation, in part because its pathogenesis is poorly understood and treatment options are limited. To identify unique risk factors for BOS and death, we performed a retrospective cohort study on 259 consecutive adult lung transplant recipients over a 5-year period. The demographic and clinical characteristics of this population were analyzed for an association between BOS or death and potential risk factors, including community-acquired respiratory viral (CARV) infections, acute rejection, and cytomegalovirus pneumonitis. Respiratory syncytial virus, parainfluenza, influenza, and adenovirus accounted for 21 CARV infections. Univariate and multivariate time-dependent Cox regression analyses demonstrated that this CARV group was more likely to develop BOS, death, and death from BOS. Furthermore, these trends were more pronounced in patients with evidence of lower respiratory tract-CARV (lower-CARV) infections. Notably, the CARV and lower-CARV infections were risk factors for BOS, death, and death from BOS distinct from the risk attributable to acute rejection. Identification of CARV and lower-CARV infections as BOS and mortality risk factors has important clinical implications and may provide insight into disease pathogenesis and accelerate the development of novel treatment strategies to modify post-CARV BOS.

Bronchiolitis Obliterans↗
PubMed2004

Molecular imaging for pediatric lung diseases.

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.

Diagnostic Imaging↗
PubMed2004

Rapid and reproducible radiosynthesis of [18F] FHBG.

9-(4-[18F] Fluoro-3-hydroxymethylbutyl) guanine ([18F] FHBG), an imaging agent for gene therapy using PET, was prepared in a one-pot, two-step synthesis. Microwave (MW) mediated nucleophilic fluorination of N2, monomethoxytrityl-9-[4-(tosyl)-3-monomethoxytrityl-methylbutyl] guanine using no-carrier-added [18F] fluoride, followed by deprotection with hydrochloric acid and HPLC purification, gave [18F] FHBG. The radiochemical yield (decay corrected) was 12+/-5% (n = 35), the synthesis time was 55-60 min, and the radiochemical purity was >99%. The compound was used for lung imaging and was injected into Sprague-Dawley rats previously infected with the herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene. MicroPET imaging showed accumulation confined to the lungs.

Animals↗
PubMed2004

Molecular imaging of host-pathogen interactions in intact small animals.

Characterization and non-invasive measurement of host-pathogen interactions in living cells, animal models and humans at the cellular and molecular levels is now possible using remote imaging detectors. Positron emission tomography scanners, highly sensitive cooled charge-coupled device cameras for bioluminescence and fluorescence imaging as well as high-magnetic-field magnetic resonance imaging scanners can be used to study such diverse processes as pathogen tropism, pathogen life cycle, signal transduction, host response, cell trafficking and gene transfer. In many cases, images from more than one modality can be fused, allowing structure-function and multifunction relationships to be studied on a tissue-restricted or regional basis. These new instruments, when used in conjunction with targeted contrast agents, reporter substrates and radiopharmaceuticals, enable "molecular imaging" with enormous potential for elucidating host-pathogen interactions in intact animal models.

Animals↗