duramycin and Disease-Models--Animal

Phosphatidylethanolamine (PE) is one of the most abundant phospholipids in mammalian plasma membranes. In healthy cells, PE resides predominantly in the inner leaflet of the cell membrane. In dead or dying cells on the other hand, PE is externalized to the outer leaflet of the plasma membrane. The exposure of PE on the cell surface has therefore become an attractive target for the molecular imaging of cell death using single-photon emission computed tomography (SPECT) and positron emission tomography (PET). This has motivated the development of PE-specific probes to measure cell death in vitro and non-invasively in vivo. In this review, we highlight the biological roles of PE on cell membranes, and PE exposure as a biomarker of cell death in disease processes, along with the use of PE-binding molecular probes to target PE for the characterization of cell death on a cellular and tissue level. We specifically emphasize the preclinical applications of radiolabeled duramycin for the non-invasive imaging of cell death in animal models of disease and in tumors after therapy. In addition, we discuss the clinical relevance, limitations and future perspectives of this imaging approach of cell death.

Topics: Animals; Apoptosis; Bacteriocins; Biomarkers; Cell Membrane; Disease Models, Animal; Humans; Mice; Molecular Imaging; Neoplasms; Peptides; Phosphatidylethanolamines; Positron-Emission Tomography; Tomography, Emission-Computed, Single-Photon

Topics: Allografts; Animals; Apoptosis; Bacteriocins; Disease Models, Animal; Feasibility Studies; Graft Rejection; Heart Transplantation; Mice, Inbred BALB C; Molecular Imaging; Myocardium; Peptides; Predictive Value of Tests; Radiopharmaceuticals; Single Photon Emission Computed Tomography Computed Tomography; Sodium Pertechnetate Tc 99m

Cancer patients are at high risk of developing deep venous thrombosis (DVT) and venous thromboembolism, a leading cause of mortality in this population. However, it is largely unclear how malignant tumors drive the prothrombotic cascade culminating in DVT.. Here, we addressed the pathophysiology of malignant DVT compared with nonmalignant DVT and focused on the role of tumor microvesicles as potential targets to prevent cancer-associated DVT. We show that microvesicles released by pancreatic adenocarcinoma cells (pancreatic tumor-derived microvesicles [pcMV]) boost thrombus formation in a model of flow restriction of the mouse vena cava. This depends on the synergistic activation of coagulation by pcMV and host tissue factor. Unlike nonmalignant DVT, which is initiated and propagated by innate immune cells, thrombosis triggered by pcMV was largely independent of myeloid leukocytes or platelets. Instead, we identified externalization of the phospholipid phosphatidylethanolamine as a major mechanism controlling the prothrombotic activity of pcMV. Disrupting phosphatidylethanolamine-dependent activation of factor X suppressed pcMV-induced DVT without causing changes in hemostasis.. Together, we show here that the pathophysiology of pcMV-associated experimental DVT differs markedly from innate immune cell-promoted nonmalignant DVT and is therefore amenable to distinct antithrombotic strategies. Targeting phosphatidylethanolamine on tumor microvesicles could be a new strategy for prevention of cancer-associated DVT without causing bleeding complications.

Topics: Adenocarcinoma; Animals; Bacteriocins; Blood Coagulation; Cell Line, Tumor; Cell-Derived Microparticles; Disease Models, Animal; Drug Design; Factor Xa; Fibrinolytic Agents; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Targeted Therapy; Pancreatic Neoplasms; Peptides; Phosphatidylethanolamines; Signal Transduction; Thromboplastin; Vena Cava, Inferior; Venous Thrombosis

Noninvasive radionuclide imaging has the potential to identify and assess mechanisms involved in particular stages of lung injury that occur with acute respiratory distress syndrome, for example. Lung uptake of (99m)Tc-hexamethylpropyleneamine oxime (HMPAO) is reported to be partially dependent on the redox status of the lung tissue whereas (99m)Tc-duramycin, a new marker of cell injury, senses cell death via apoptosis or necrosis. Thus, we investigated changes in lung uptake of these agents in rats exposed to hyperoxia for prolonged periods, a common model of acute lung injury.. Male Sprague-Dawley rats were preexposed to either normoxia (21% O(2)) or hyperoxia (85% O(2)) for up to 21 d. For imaging, the rats were anesthetized and injected intravenously with either (99m)Tc-HMPAO or (99m)Tc-duramycin (both 37-74 MBq), and planar images were acquired using a high-sensitivity modular γ-camera. Subsequently, (99m)Tc-macroagreggated albumin (37 MBq, diameter 10-40 μm) was injected intravenously, imaged, and used to define a lung region of interest. The lung-to-background ratio was used as a measure of lung uptake.. Hyperoxia exposure resulted in a 74% increase in (99m)Tc-HMPAO lung uptake, which peaked at 7 d and persisted for the 21 d of exposure. (99m)Tc-duramycin lung uptake was also maximal at 7 d of exposure but decreased to near control levels by 21 d. The sustained elevation of (99m)Tc-HMPAO uptake suggests ongoing changes in lung redox status whereas cell death appears to have subsided by 21 d.. These results suggest the potential use of (99m)Tc-HMPAO and (99m)Tc-duramycin as redox and cell-death imaging biomarkers, respectively, for the in vivo identification and assessment of different stages of lung injury.

Topics: Animals; Bacteriocins; Biological Transport; Chronic Disease; Disease Models, Animal; Hyperoxia; Lung; Male; Oxidative Stress; Peptides; Radionuclide Imaging; Rats; Rats, Sprague-Dawley; Technetium Tc 99m Exametazime