indium-oxine and Disease-Models--Animal

The goal of the study was to investigate whether or not gram-negative organisms that secrete antichemotactic factors cause the nonaccumulation pattern of 111In-oxine-labeled white blood cell (111In-WBC) scans.. Staphylococcus aureus (gram-positive) (group 1) was injected into 25 rabbits and Escherichia coli (gram-negative) (group 2) into another 25 to induce infection in the lumbar vertebrae or left thigh bone (femur). Sixteen successfully infected and surviving rabbits from each group were used for imaging and analysis. Of the 16 rabbits, each group included 8 with vertebral infection and 8 with femur infection. For imaging, each rabbit was injected intravenously with 11.1 MBq (300 μCi) 111In-WBC, and images were acquired 24 h later. Microscopic histopathology was performed after decalcification to confirm osteomyelitis.. The 111In-WBC accumulation was observed in 7 (87.5%) of the 8 rabbits infected with S. aureus in the vertebrae and thigh bone. Of the rabbits infected with the gram-negative vertebrae, 1 (12.5%) showed little accumulation of 111In-WBC. Of the 8 rabbits with gram-negative-infected femurs, 1 had high accumulation and another had low accumulation of 111In-WBC, while the rest did not show any uptake. Osteomyelitis was confirmed by histopathology in all the successfully infected rabbits used for imaging.. In the majority of the gram-positive-infected rabbit vertebrae there was high accumulation of 111In-WBC. However, no accumulation of 111In-WBC was observed in most of the vertebrae infected with gram-negative organisms, which release antichemotactic factors that prevent adequate accumulation of WBC at the infected area.

Topics: Animals; Disease Models, Animal; Escherichia coli; Escherichia coli Infections; Femur; Leukocytes; Lumbar Vertebrae; Male; Organometallic Compounds; Osteomyelitis; Oxyquinoline; Rabbits; Radionuclide Imaging; Staphylococcal Infections; Staphylococcus aureus

Treatment options of glioblastoma multiforme are limited due to the blood-brain barrier (BBB). In this study, we investigated the utility of intranasal (IN) delivery as a means of transporting stem cell-based antiglioma therapeutics. We hypothesized that mesenchymal stem cells (MSCs) delivered via nasal application could impart therapeutic efficacy when expressing TNF-related apoptosis-inducing ligand (TRAIL) in a model of human glioma. ¹¹¹In-oxine, histology and magnetic resonance imaging (MRI) were utilized to track MSCs within the brain and associated tumor. We demonstrate that MSCs can penetrate the brain from nasal cavity and infiltrate intracranial glioma xenografts in a mouse model. Furthermore, irradiation of tumor-bearing mice tripled the penetration of (¹¹¹In)-oxine-labeled MSCs in the brain with a fivefold increase in cerebellum. Significant increase in CXCL12 expression was observed in irradiated xenograft tissue, implicating a CXCL12-dependent mechanism of MSCs migration towards irradiated glioma xenografts. Finally, MSCs expressing TRAIL improved the median survival of irradiated mice bearing intracranial U87 glioma xenografts in comparison with nonirradiated and irradiated control mice. Cumulatively, our data suggest that IN delivery of stem cell-based therapeutics is a feasible and highly efficacious treatment modality, allowing for repeated application of modified stem cells to target malignant glioma.

Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Tracking; Chemokine CXCL12; Disease Models, Animal; Gamma Rays; Gene Expression; Glioma; Humans; Magnetic Resonance Imaging; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Organometallic Compounds; Oxyquinoline; TNF-Related Apoptosis-Inducing Ligand; Xenograft Model Antitumor Assays

Identifying and evaluating new therapeutic targets in platelets requires advanced animal models in which platelet responses can be measured directly and in situ. This is important because platelet function is strongly influenced by external factors such as those originating from the vascular endothelium. Our objectives were to record graded, non-lethal thromboembolic platelet responses to platelet agonists in situ in the mouse and to demonstrate an inhibitory effect of aspirin in our model. Radiolabelled platelets were infused into anaesthetized mice and responses to ADP, collagen and thrombin measured as changes in platelet associated counts in miniaturized detection probes placed over the thoracic region. All agonists induced dose-dependent changes in platelet counts due to accumulation of thrombi in the pulmonary vasculature. We confirmed a specific platelet effect by comparing platelet and erythrocyte responses and showing platelet aggregates in the lung vasculature histologically. Simultaneous injection of collagen and adrenaline induced increased and protracted synergistic platelet responses compared with individual injection of these agents and aspirin inhibited collagen-induced responses. We confirmed the clinical relevance of our model by showing that platelet thromboembolism in the mouse, like pulmonary embolism in humans, impaired cardiovascular performance. We present a refined method for measuring platelet agonist dose-responses and thromboembolism in real-time without inducing mortality in the mouse. Our technique will be useful in investigating the molecular determinants of physiological and pathophysiological platelet function in an in-vivo context and will enable investigations of both platelet and non-platelets mediators of thrombus formation.

Topics: Adenosine Diphosphate; Anesthesia; Animals; Aspirin; Blood Platelets; Collagen; Disease Models, Animal; Dose-Response Relationship, Drug; Erythrocytes; Hemodynamics; Indium Radioisotopes; Injections, Intravenous; Male; Mice; Mice, Inbred BALB C; Organometallic Compounds; Oxyquinoline; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Platelet Transfusion; Pulmonary Embolism; Reproducibility of Results; Thrombin; Thromboembolism; Time Factors

Cell-based therapy by transplantation of progenitor cells has emerged as a promising development for organ repair, but non-invasive imaging approaches are required to monitor the fate of transplanted cells. Radioactive labelling with (111)In-oxine has been used in preclinical trials. This study aimed to validate (111)In-oxine labelling and subsequent in vivo and ex vivo detection of haematopoietic progenitor cells.. Murine haematopoietic progenitor cells (10(6), FDCPmix) were labelled with 0.1 MBq (low dose) or 1.0 MBq (high dose) (111)In-oxine and compared with unlabelled controls. Cellular retention of (111)In, viability and proliferation were determined up to 48 h after labelling. Labelled cells were injected into the cavity of the left or right cardiac ventricle in mice. Scintigraphic images were acquired 24 h later. Organ samples were harvested to determine the tissue-specific activity.. Labelling efficiency was 75 +/- 14%. Cellular retention of incorporated (111)In after 48 h was 18 +/- 4%. Percentage viability after 48 h was 90 +/- 1% (control), 58 +/- 7% (low dose) and 48 +/- 8% (high dose) (p<0.0001). Numbers of viable cells after 48 h (normalised to 0 h) were 249 +/- 51% (control), 42 +/- 8% (low dose) and 32 +/- 5% (high dose) (p<0.0001). Cells accumulated in the spleen (86.6 +/- 27.0% ID/g), bone marrow (59.1 +/- 16.1% ID/g) and liver (30.3 +/- 9.5% ID/g) after left ventricular injection, whereas most of the cells were detected in the lungs (42.4 +/- 21.8% ID/g) after right ventricular injection.. Radiolabelling of haematopoietic progenitor cells with (111)In-oxine is feasible, with high labelling efficiency but restricted stability. The integrity of labelled cells is significantly affected, with substantially reduced viability and proliferation and limited migration after systemic transfusion.

Topics: Animals; Cell Proliferation; Cell Survival; Disease Models, Animal; Female; Heart Ventricles; Hematopoietic Stem Cells; Indium Radioisotopes; Lung; Mice; Mice, Inbred C57BL; Organometallic Compounds; Oxyquinoline; Radionuclide Imaging; Radiopharmaceuticals; Time Factors

To determine the feasibility of in vivo localization and quantification of indium 111 (111In)-oxine-labeled bone marrow (BM) with high-resolution whole-body helical single photon emission computed tomography (SPECT) in an established murine model of atherosclerosis and vascular repair.. The institutional animal care and use committee approved this study. BM from young B6 Rosa 26 Lac Z+/+ mice was radiolabeled with 111In-oxine. On days 1, 4, and 7 after administration of radiolabeled cells, five C57/BL6 apolipoprotein E-deficient mice and five wild-type (WT) control mice were imaged with whole-body high-resolution helical SPECT. Quantification with SPECT was compared with ex vivo analysis by means of gamma counting. Autoradiography and beta-galactosidase staining were used to verify donor cell biodistribution. Linear regression was used to assess the correlation between continuous variables. Two-tailed Student t test was used to compare values between groups, and paired two-tailed t test was used to assess changes within subjects at different time points.. SPECT image contrast was high, with clear visualization of BM, liver, and spleen 7 days after administration of radiolabeled cells. SPECT revealed that 42% and 58% more activity was localized to the aorta and BM (P<.05 for both), respectively, in apolipoprotein E-deficient mice versus WT mice. Furthermore, 28% and 27% less activity was localized to the liver and spleen (P<.05 for both), respectively, in apolipoprotein E-deficient mice versus WT mice. SPECT and organ gamma counts showed good quantitative correlation (r=0.9). beta-Galactosidase staining and microautoradiography of recipient aortas showed donor cell localization to the intima of visible atherosclerotic plaque but not to unaffected regions of the vessel wall.. High-resolution in vivo helical pinhole SPECT can be used to monitor and quantify early biodistribution of 111In-oxine-labeled BM in a murine model of progenitor cell therapy for atherosclerosis.

Topics: Animals; Atherosclerosis; Bone Marrow Cells; Bone Marrow Transplantation; Disease Models, Animal; Feasibility Studies; Image Enhancement; Mice; Mice, Inbred C57BL; Mice, Knockout; Organometallic Compounds; Oxyquinoline; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon

The increasing knowledge of the molecular basis of leukocyte trafficking results in the development of novel anti-inflammatory strategies for inflammatory bowel disease (IBD). For optimal evaluation of therapy efficacy, information about inflammatory activity in bowel segments or lymphocyte recirculation and kinetics in the follow-up of experimental treatment for IBD is needed. The aim of this study was to evaluate a non-invasive scintigraphic technique, able to assess lymphocyte trafficking in a trinitrobenzene sulfonic acid (TNBS) induced mouse colitis model of IBD.. TNBS sensitized and non-sensitized murine total splenocytes were labeled in vitro with 111In-oxine and injected into either control or TNBS colitis BALB/c mice. Biodistribution and specific radioactive uptake, representing transferred cells, were determined by serial dedicated animal planar scintigraphy and pinhole SPECT of the abdomen 4, 24 and 48h post injection of labeled cells. In addition, the severity of inflammation was determined by histological scoring.. Migration of 111In labeled splenocytes to the colon increased in time and was maximal at 48h after administration. The highest specific radioactive uptake ratio in the colon after 48h was observed in mice with TNBS colitis that received TNBS sensitized lymphocytes. Histological scoring confirmed the presence of colitis in the TNBS treated groups.. Homing of TNBS-sensitized lymphocytes can be assessed in vivo by means of dedicated animal pinhole SPECT. Generally, this technique enables serial measurement of specific cell trafficking with potential of in vivo evaluation of novel anti-inflammatory strategies in inflammatory bowel disease.

Topics: Animals; Cell Movement; Colitis; Colon; Disease Models, Animal; Female; Inflammatory Bowel Diseases; Lymphocytes; Mice; Mice, Inbred BALB C; Organometallic Compounds; Oxyquinoline; Radiopharmaceuticals; Receptors, Lymphocyte Homing; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; Trinitrobenzenesulfonic Acid

Transplantation of progenitor cells (PCs) has been shown to improve neovascularization and left ventricular function after myocardial ischemia. The fate of transplanted PCs has been monitored by fluorescence labeling or by genetic modifications introducing reporter genes. However, these techniques are limited by the need to kill the experimental animal. The aim of this study was to radiolabel CD34(+) hematopoietic PCs (HPCs) with (111)In-oxine and to evaluate the feasibility of this in vivo method for monitoring myocardial homing of transplanted cells in a rat myocardial infarction model.. Human HPCs were isolated from mobilized peripheral blood and labeled with (111)In-oxine. Labeled HPCs were injected into the cavity of the left ventricle in nude rats 24 h after induction of myocardial infarction (n = 4) or sham operation (n = 4). Scintigraphic images were acquired up to 96 h after HPC injection. After animals were killed, tissue samples of various organs were harvested to calculate tissue-specific activity and for immunostaining.. Labeling efficiency of HPCs was 32% +/- 11%. According to trypan-blue staining, viability of radiolabeled HPCs was impaired by 30% after 48 and 96 h in comparison with unlabeled cells, whereas proliferation and differentiation of HPCs was nullified after 7 d, as assessed by colony-forming assays. After injection of HPCs, the specific activity ratio of heart to peripheral muscle tissue increased from 1.10 +/- 0.32 in sham-operated rats to 2.47 +/- 0.92 (P = 0.020) in infarcted rats. However, the overall radioactivity detected in the heart was only about 1%. A transient high lung uptake of 17% +/- 6% was observed within the first hour after infusion of HPCs. At 24 h after injection, the initial lung activity had shifted toward liver, kidneys, and spleen, resulting in an increase of radioactivity in these organs from 37% +/- 6% to 57% +/- 5%.. Radiolabeling with (111)In-oxine is a feasible in vivo method for monitoring transplanted HPCs in a rat myocardial infarction model. The potential to detect differences in myocardial homing between infarcted and normal hearts suggests that this method may provide a noninvasive imaging approach for clinical trials using transplanted HPCs in patients. Our findings, however, also demonstrated a negative effect of (111)In-oxine on cellular function, which resulted in complete impairment of HPC proliferation and differentiation. For future trials in stem cell imaging with (111)In-oxine, therefore, it will be mandatory to carefully check for radiation-induced cell damage.

Topics: Animals; Antigens, CD34; Disease Models, Animal; Feasibility Studies; Female; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Isotope Labeling; Myocardial Infarction; Organometallic Compounds; Oxyquinoline; Radionuclide Imaging; Radiopharmaceuticals; Rats; Rats, Nude; Treatment Outcome

Loss of gut barrier function after burn injury can be important in the pathogenesis of systemic infections and organ dysfunction. The purpose of this study was to determine how rapidly impairment of gut barrier function occurs after burn injury and how long it persists. BALB/c mice were gavaged with 10(10) (111)In-oxine-labeled Escherichia coli 3 h before inflicting a 20% total body surface area burn. They were then killed at 5, 15, 30, 60, 120, or 240 min post-burn. Additional mice were given a 20% or 30% burn injury and were randomized into eight groups, which were killed at either 4 h or 1, 2, 4, 7, 14, or 21 days post-burn. Each mouse was gavaged with 10(10) (111)In-oxine-labeled E. coli 4 h before sacrifice to determine the magnitude of translocation. Gut barrier function was impaired as early as 5 min post-burn and was maximal by 4 h. Rapid improvement was observed by 24 h, followed by slow improvement, but with persistent abnormality through 21 days post-burn. Killing of translocated bacteria was impaired at 4 h and day 7 post-burn, according to the percentage of viable E. coli that remained alive in the tissues. The magnitude of gut dysfunction following burn injury is temporally related.

Topics: Animals; Bacterial Translocation; Burns; Disease Models, Animal; Escherichia coli; Female; Intestines; Liver; Lymph Nodes; Mice; Mice, Inbred BALB C; Organometallic Compounds; Oxyquinoline; Spleen

The inhibiting effect of nitric oxide on the aggregation and adhesion of neutrophils and platelets has been well documented in vitro. In vivo evidence, however, is more scant. In this study, we studied the effects of inhaled nitric oxide on pulmonary cellular sequestration in our sham hemodialysis model. Accumulation of neutrophils and platelets in the lungs has been shown to be an early event in this model.. Prospective, randomized, controlled study.. Animal laboratory at a university medical center.. Twenty-six anesthetized, mechanically ventilated pigs.. 111Indium-oxine was used to selectively label neutrophils or platelets and the activity over the lungs was followed dynamically with a gamma camera. Sham hemodialysis, using a cuprophan hollow-fiber dialyzer, was instituted via catheters in the femoral vessels. The animals were divided into two main groups: a) the nitric oxide recipient group (n = 12, with platelets labeled in seven animals and neutrophils labeled in five animals); and b) the control group (n = 14, with platelets labeled in seven animals and neutrophils labeled in seven animals). The animals in the former group were given 50 parts per million of nitric oxide in the inspiratory gas from the beginning of dialysis and for 30 mins onward.. Inhalation of nitric oxide attenuated the increase in activity over the lungs in both the neutrophil and platelet groups during sham hemodialysis. In addition, an inhibiting effect on the increase in pulmonary pressure was noted.. Apart from the effects of nitric oxide on central hemodynamics in this model, the scintigraphic findings indicate an in vivo effect of nitric oxide on the accumulation of platelets and neutrophils in the lungs, probably due to inhibition of the adhesion and/or aggregation of these cells.

Topics: Adhesiveness; Administration, Inhalation; Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Indium Radioisotopes; Neutrophils; Nitric Oxide; Organometallic Compounds; Oxyquinoline; Platelet Adhesiveness; Platelet Aggregation; Platelet Aggregation Inhibitors; Random Allocation; Renal Dialysis; Swine; Time Factors

Intestinal wall necrosis without perforation was produced in six dogs. Another group of three dogs served as a control. The histologic findings, the degree of ischemia and scintigraphic images obtained after the infusions of autologous white blood cells labelled with indium-111 oxine were correlated. Positive scans were obtained in all the dogs with proven intestinal ischemia. Negative scans appeared in the dogs without ischemic insult and a false-positive scan were observed in a control dog with diarrhea.

Topics: Animals; Disease Models, Animal; Dogs; Ileum; Indium Radioisotopes; Ischemia; Leukocyte Transfusion; Leukocytes; Necrosis; Organometallic Compounds; Oxyquinoline; Radionuclide Imaging; Time Factors

The impaired deformability and heterogeneity of erythrocytes in sickle cell disease endows them with abnormal microvascular flow dynamics. In the sickle cell exchange-transfused rat model, sickle cells exhibit lower volumetric flux and shear rates compared to normal (HbAA) or autologous rat cells. A subpopulation of dense sickle cells and irreversibly sickled cells show a propensity to induce occlusion at precapillary arterioles, residing at such sites for several seconds and causing local rheological disequilibrium. Radionuclide studies with indium-111 demonstrate preferential uptake of labeled HbSS cells in pulmonary microcirculation. These data are relevant to the factors that are involved in the initiation and propagatin of vaso-occlusion resulting in derangement of homeostasis in certain microvascular beds and perhaps painful crisis and selective organ injury.

Topics: Anemia, Sickle Cell; Animals; Blood Flow Velocity; Disease Models, Animal; Erythrocytes; Indium Radioisotopes; Infarction; Male; Mesentery; Microcirculation; Organometallic Compounds; Oxyquinoline; Radionuclide Imaging; Rats; Rats, Inbred Strains