Kupffer cells are central in the removal of nanoparticles from the organism

<p>Abstract</p> <p>Background</p> <p>The study aims at revealing the fate of nanoparticles administered intravenously and intraperitoneally to adult female mice, some of which were pregnant. Gold nanoparticles were chosen as a model because these particles have been found to be chemically inert and at the same time are easily traced by autometallography (AMG) at both ultrastructural and light microscopic levels.</p> <p>Results</p> <p>Gold nanoparticles were injected intravenously (IV) or intraperitoneally (IP) and traced after 1, 4 or 24 hours. For IV injections 2 and 40 nm particles were used; for IP injections 40 nm particles only. The injected nanoparticles were found in macrophages only, and at moderate exposure primarily in the Kupffer cells in the liver. IV injections resulted in a rapid accumulation/clustering of nanoparticles in these liver macrophages, while the uptake in spleen macrophages was moderate. IP injections were followed by a delayed uptake in the liver and included a moderate uptake in macrophages located in mesenteric lymph nodes, spleen and small intestine. Ultrastructurally, the AMG silver enhanced nanocrystals were found in lysosome-like organelles of the Kupffer cells and other macrophages wherever located.</p> <p>Accumulations of gold nanoparticles were not found in any other organs analysed, i.e. kidneys, brain, lungs, adrenals, ovaries, placenta, and fetal liver, and the control animals were all void of AMG staining.</p> <p>Conclusion</p> <p>Our results suggest that: (1) inert gold nanoparticles do not penetrate cell membranes by non-endocytotic mechanisms, but are rather taken up by endocytosis; (2) gold nanoparticles, independent of size, are taken up primarily by Kupffer cells in the liver and secondarily by macrophages in other places; (3) gold nanoparticles do not seem to penetrate the placenta barrier; (4) the blood-brain barrier seems to protect the central nervous system from gold nanoparticles; (5) 2 nanometer gold particles seem to be removed not only by endocytosis by macrophages, and we hypothesize that part of these tiny nanoparticles are released into the urine as a result of simple filtration in the renal glomeruli.</p

Chemical Blocking of Zinc Ions in CNS Increases Neuronal Damage Following Traumatic Brain Injury (TBI) in Mice

Traumatic brain injury (TBI) is one of the leading causes of disability and death among young people. Although much is already known about secondary brain damage the full range of brain tissue responses to TBI remains to be elucidated. A population of neurons located in cerebral areas associated with higher cognitive functions harbours a vesicular zinc pool co-localized with glutamate. This zinc enriched pool of synaptic vesicles has been hypothesized to take part in the injurious signalling cascade that follows pathological conditions such as seizures, ischemia and traumatic brain injury. Pathological release of excess zinc ions from pre-synaptic vesicles has been suggested to mediate cell damage/death to postsynaptic neurons.In order to substantiate the influence of vesicular zinc ions on TBI, we designed a study in which damage and zinc movements were analysed in several different ways. Twenty-four hours after TBI ZnT3-KO mice (mice without vesicular zinc) were compared to littermate Wild Type (WT) mice (mice with vesicular zinc) with regard to histopathology. Furthermore, in order to evaluate a possible neuro-protective dimension of chemical blocking of vesicular zinc, we treated lesioned mice with either DEDTC or selenite. Our study revealed that chemical blocking of vesicular zinc ions, either by chelation with DEDTC or accumulation in zinc-selenium nanocrystals, worsened the effects on the aftermath of TBI in the WT mice by increasing the number of necrotic and apoptotic cells within the first 24 hours after TBI, when compared to those of chemically untreated WT mice.ZnT3-KO mice revealed more damage after TBI compared to WT controls. Following treatment with DEDTC or selenium an increase in the number of both dead and apoptotic cells were seen in the controls within the first 24 hours after TBI while the degree of damage in the ZnT3-KO mice remained largely unchanged. Further analyses revealed that the damage development in the two mouse strains was almost identical after either zinc chelation or zinc complexion therapy

Biodistribution of gold nanoparticles in mouse lung following intratracheal instillation

<p>Abstract</p> <p>Background</p> <p>The fate of gold nanoparticles, 2, 40 and 100 nm, administered intratracheally to adult female mice was examined. The nanoparticles were traced by autometallography (AMG) at both ultrastructural and light microscopic levels. Also, the gold content was quantified by inductively coupled plasma mass spectrometry (ICP-MS) and neutron activation analysis (NAA). The liver is the major site of deposition of circulating gold nanoparticles. Therefore the degree of translocation was determined by the hepatic deposition of gold. Mice were instilled with 5 intratracheal doses of gold nanoparticles distributed over a period of 3 weeks and were killed 24 h after the last dose. One group of mice were given a single intratracheal dose and were killed after 1 h.</p> <p>Results</p> <p>The instilled nanoparticles were found in lung macrophages already 1 h after a single instillation. In mice instilled treated repeatedly during 3 weeks, the load was substantial. Ultrastructurally, AMG silver enhanced gold nanoparticles were found in lysosome-/endosome-like organelles of the macrophages and analysis with AMG, ICP-MS and NAA of the liver revealed an almost total lack of translocation of nanoparticles. In mice given repeated instillations of 2 nm gold nanoparticles, 1.4‰ (by ICP-MS) to 1.9‰ (by NAA) of the instilled gold was detected in the liver. With the 40 nm gold, no gold was detected in the liver (detection level 2 ng, 0.1‰) except for one mouse in which 3‰ of the instilled gold was found in the liver. No gold was detected in any liver of mice instilled with 100 nm gold (detection level 2 ng, 0.1‰) except in a single animal with 0.39‰ of the dose in the liver.</p> <p>Conclusion</p> <p>We found that that: (1) inert gold nanoparticles, administered intratracheally are phagocytosed by lung macrophages; (2) only a tiny fraction of the gold particles is translocated into systemic circulation. (3) The translocation rate was greatest with the 2 nm gold particles.</p

Zinc Overload Enhances APP Cleavage and Aβ Deposition in the Alzheimer Mouse Brain

BACKGROUND: Abnormal zinc homeostasis is involved in β-amyloid (Aβ) plaque formation and, therefore, the zinc load is a contributing factor in Alzheimer's disease (AD). However, the involvement of zinc in amyloid precursor protein (APP) processing and Aβ deposition has not been well established in AD animal models in vivo. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, APP and presenilin 1 (PS1) double transgenic mice were treated with a high dose of zinc (20 mg/ml ZnSO4 in drinking water). This zinc treatment increased APP expression, enhanced amyloidogenic APP cleavage and Aβ deposition, and impaired spatial learning and memory in the transgenic mice. We further examined the effects of zinc overload on APP processing in SHSY-5Y cells overexpressing human APPsw. The zinc enhancement of APP expression and cleavage was further confirmed in vitro. CONCLUSIONS/SIGNIFICANCE: The present data indicate that excess zinc exposure could be a risk factor for AD pathological processes, and alteration of zinc homeostasis is a potential strategy for the prevention and treatment of AD

Zinc-Enriched Endocrine Cells in the Rat Pituitary. A Combined Autometallographic and Immunohistochemical Study.

Zinc ions have been demonstrated in the anterior pituitary of rat by autometallography (AMG) which involves in vivo exposure to sodium selenite leading to creation of zinc selenide crystal lattices that are later silver enhanced by AMG in the sections. In this study, autometallography is combined with immunohistochemistry in order to present the coexistence of zinc ions and hormones in endocrine cells of the rat pituitary. The results showed that the majority of zinc-enriched (ZEN) cells are somatotrophs. All the somatotrophs observed were loaded with AMG grains. Zinc ions were also found to be present in gonadotrophs, corticotrophs and thyrotrophs. A low density of AMG silver grains was found in about 60% of gonadotrophs, 8% of corticotrophs and less than 10% of thyrotrophs. Lactotrophs did not appear to contain zinc ions. The present observations may provide a clue to the physiological function of zinc ions in the rat pituitary.link_to_subscribed_fulltex

Cultured macrophages cause dissolucytosis of metallic silver

The present study proves that cultured macrophages can liberate silver ions from metallic silver surfaces by a process called dissolucytosis. Macrophages (J774) were grown on a silver plate for different periods of time and after fixation in glutaraldehyde, they were subjected to autometallograhy in order to amplify possible cellular silver-sulphur nanocrystals. Light and electron microscopic analysis of the cells revealed that silver ions released from the plate had been taken up by the macrophages and accumulated in lysosome- like structures. We found that the liberation of silver ions takes place extracellularly and is caused by chemical activity in a dissolution membrane, most likely secreted and organized by the macrophages. The liberation and the subsequent uptake of silver ions in the macrophages is a relatively fast process and the resulting silver-sulphur nanocrystals can be observed in macrophages that have been in contact with metallic silver for only a few minutes. Our findings indicate that the speed of dissolucytosis is highly influenced by the chemical nature of the object exposed to the dissolucytotic process which is likely to occur whenever macrophages encounter a non-phagocytosable foreign object