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1.  Cytotoxic and proinflammatory effects of PVP-coated silver nanoparticles after intratracheal instillation in rats 
PMCID: PMC3896256  PMID: 24455451
cytotoxicity; inflammation; pulmonary toxicity; silver nanoparticles
2.  Topical Drug Delivery in Chronic Rhinosinusitis Patients before and after Sinus Surgery Using Pulsating Aerosols 
PLoS ONE  2013;8(9):e74991.
PMCID: PMC3770586  PMID: 24040372
3.  Pulmonary surfactant is indispensable in order to simulate the in vivo situation 
The article of Gasser et al. [Part Fibre Toxicol. 24; 9:17, 2012] describes the interaction of carbon nanotubes with cells within a complex cell culture model. Besides various toxicity parameters, the influence of coating with pulmonary surfactant was investigated. Pulmonary surfactant covers the entire alveolar region with the main function of decreasing the surface tension in the alveoli to prevent alveolar collapse. Although each inhaled nanoparticle, reaching the alveoli, will come into contact with pulmonary surfactant which will probably lead to a surfactant coating, pulmonary surfactant components are not commonly integrated in in vitro systems. Gasser and co-workers have shown that this surfactant coating is able to influence the further interaction with cellular systems. Hence, each scientist, working with in vitro systems and nanoparticles, should think of integrating pulmonary surfactant structures in order to harmonize the in vitro systems with the in vivo situation. In the present commentary we discuss the most important points of the manuscript of Gasser et al. and discuss where the usage of pulmonary surfactant can be further optimized.
PMCID: PMC3616821  PMID: 23531298
Nanoparticle; Lung; Pulmonary surfactant; Coating
4.  Particle size-dependent and surface charge-dependent biodistribution of gold nanoparticles after intravenous administration 
We administered 198Au-radio-labelled monodisperse, negatively charged GNP of five different sizes (1.4, 5, 18, 80, 200nm) and 2.8nm GNP with opposite surface charges by intravenous injection into rats. After 24 h the biodistribution of the GNP was quantitatively measured by gamma-spectrometry.
The size and surface charge of GNP strongly determine the biodistribution. Most GNP accumulated in the liver increased from 50% of 1.4nm GNP to > 99% of 200nm GNP. In contrast, there was little size dependent accumulation of 18nm to 200nm GNP in most other organs. However, for GNP between 1.4nm and 5nm the accumulation increased sharply with decreasing size; i.e. a linear increase with the volumetric specific surface area. The differently charged 2.8nm GNP led to significantly different accumulations in several organs.
PMCID: PMC3051057  PMID: 21195759
gold nanoparticles; intravenous injection; female Wystar-Kyoto rat; organ accumulation; in vivo biodistribution; nanoparticle size; nanoparticle surface charge; hepato-biliary clearance; renal clearance
Nanotoxicology  2011;6(1):36-46.
It is of urgent need to identify the exact physico-chemical characteristics which allow maximum uptake and accumulation in secondary target organs of nanoparticulate drug delivery systems after oral ingestion. We administered radiolabelled gold nanoparticles in different sizes (1.4-200 nm) with negative surface charge and 2.8 nm nanoparticles with opposite surface charges by intra-oesophageal instillation into healthy adult female rats. The quantitative amount of the particles in organs, tissues and excrements was measured after 24 h by gamma-spectroscopy. The highest accumulation in secondary organs was mostly found for 1.4 nm particles; the negatively charged particles were accumulated mostly more than positively charged particles. Importantly, 18 nm particles show a higher accumulation in brain and heart compared to other sized particles. No general rule accumulation can be made so far. Therefore, specialized drug delivery systems via the oral route have to be individually designed, depending on the respective target organ.
PMCID: PMC3267526  PMID: 21309618
Gold NP; gavage; absorption; gastro-intestinal tract; in vivo biodistribution
PMCID: PMC2956709  PMID: 20920269
7.  Deposition and biokinetics of inhaled nanoparticles 
PMCID: PMC2826283  PMID: 20205860
Ambient particulate matter (PM)-associated metals have been shown to play an important role in cardiopulmonary health outcomes. To study the modulation of PM-induced inflammation by leached off metals, we investigated intracellular solubility of radio-labeled iron oxide (59Fe2O3) particles of 0.5 and 1.5 μm geometric mean diameter. Fe2O3 particles were examined for the induction of the release of interleukin 6 (IL-6) as pro-inflammatory and prostaglandin E2 (PGE2) as anti-inflammatory markers in cultured alveolar macrophages (AM) from Wistar Kyoto (WKY) rats. In addition, we exposed male WKY rats to monodispersed Fe2O3 particles by intratracheal instillation (1.3 or 4.0 mg/kg body weight) to examine in vivo inflammation.
Particles of both sizes are insoluble extracellularly in the media but moderately soluble in AM with an intracellular dissolution rate of 0.0037 ± 0.0014 d-1 for 0.5 μm and 0.0016 ± 0.0012 d-1 for 1.5 μm 59Fe2O3 particles. AM exposed in vitro to 1.5 μm particles (10 μg/mL) for 24 h increased IL-6 release (1.8-fold; p < 0.05) and also PGE2 synthesis (1.9-fold; p < 0.01). By contrast, 0.5 μm particles did not enhance IL-6 release but strongly increased PGE2 synthesis (2.5-fold, p < 0.005). Inhibition of PGE2 synthesis by indomethacin caused a pro-inflammatory phenotype as noted by increased IL-6 release from AM exposed to 0.5 μm particles (up to 3-fold; p < 0.005). In the rat lungs, 1.5 but not 0.5 μm particles (4.0 mg/kg) induced neutrophil influx and increased vascular permeability.
Fe2O3 particle-induced neutrophilic inflammatory response in vivo and pro-inflammatory cytokine release in vitro might be modulated by intracellular soluble iron via PGE2 synthesis. The suppressive effect of intracellular released soluble iron on particle-induced inflammation has implications on how ambient PM-associated but soluble metals influence pulmonary toxicity of ambient PM.
PMCID: PMC2806337  PMID: 20028532
9.  Source apportionment of ambient fine particle size distribution using positive matrix factorization in Erfurt, Germany 
The Science of the total environment  2008;398(1-3):133-144.
Particle size distribution data collected between September 1997 and August 2001 in Erfurt, Germany were used to investigate the sources of ambient particulate matter by positive matrix factorization (PMF). A total of 29,313 hourly averaged particle size distribution measurements covering the size range of 0.01 to 3.0 μm were included in the analysis. The particle number concentrations (cm−3) for the 9 channels in the ultrafine range, and mass concentrations (ng m−3) for the 41 size bins in the accumulation mode and particle up to 3 μm in aerodynamic diameter were used in the PMF. The analysis was performed separately for each season. Additional analyses were performed including calculations of the correlations of factor contributions with gaseous pollutants (O3, NO, NO2, CO and SO2) and particle composition data (sulfate, organic carbon and elemental carbon), estimating the contributions of each factor to the total number and mass concentration, identifying the directional locations of the sources using the conditional probability function, and examining the diurnal patterns of factor scores. These results were used to assist in the interpretation of the factors. Five factors representing particles from airborne soil, ultrafine particles from local traffic, secondary aerosols from local fuel combustion, particles from remote traffic sources, and secondary aerosols from multiple sources were identified in all seasons.
PMCID: PMC2586140  PMID: 18433834
10.  Efficient Elimination of Inhaled Nanoparticles from the Alveolar Region: Evidence for Interstitial Uptake and Subsequent Reentrainment onto Airways Epithelium 
Environmental Health Perspectives  2007;115(5):728-733.
There is ongoing discussion that inhaled nanoparticles (NPs, < 100 nm) may translocate from epithelial deposition sites of the lungs to systemic circulation.
Objectives and Methods
We studied the disappearance of NPs from the epithelium by sequential lung retention and clearance and bronchoalveolar lavage (BAL) measurements in healthy adult Wistar Kyoto (WKY) rats at various times over 6 months after administration of a single 60- to 100-min intratracheal inhalation of iridium-192 (192Ir)–radiolabeled NPs. A complete 192Ir balance of all organs, tissues, excretion, remaining carcass, and BAL was performed at each time point.
Directly after inhalation we found free NPs in the BAL; later, NPs were predominantly associated with alveolar macropages (AMs). After 3 weeks, lavageable NP fractions decreased to 0.06 of the actual NP lung burden. This is in stark contrast to the AM-associated fraction of micron-sized particles reported in the literature. These particles remained constant at about 0.8 throughout a 6-month period. Three weeks after inhalation, 80% of the retained Ir NPs was translocated into epithelium and interstitium.
There is a strong size-selective difference in particle immobilization. Furthermore, AM-mediated NP transport to the larynx originates not only from the NP fraction retained on the epithelium but also from NPs being reentrained from the interstitium to the luminal side of epithelium. We conclude that NPs are much less phagocytized by AMs than large particles but are effectively removed from the lung surface into the interstitium. Even from these interstitial sites, they undergo AM-mediated long-term NP clearance to the larynx.
PMCID: PMC1867986  PMID: 17520060
alveolar macrophages; bronchoalveolar lavage; clearance; inhalation; nanoparticles; reentrainment; relocation; retention; translocation
11.  Motion and twisting of magnetic particles ingested by alveolar macrophages in the human lung: effect of smoking and disease 
Spherical 1.3 μm diameter ferrimagnetic iron oxide particles were inhaled by 17 healthy volunteers (40 – 65 years), 15 patients with sarcoidosis (SAR), 12 patients with idiopathic pulmonary fibrosis (IPF), and 18 patients with chronic obstructive bronchitis (COB). The retained particles were magnetized and aligned in an external 100 mT magnetic field. All magnetized particles induce a weak magnetic field of the lung, which was detected by a sensitive SQUID (superconducting quantum interference device) sensor. Cytoskeletal reorganizations within macrophages and intracellular transport cause stochastic magnetic dipole rotations, which are reflected in a decay of the magnetic lung field, called relaxation. Directed phagosome motion was induced in a weak magnetic twisting field. The resistance of the cytoplasm to particle twisting was characterized by the viscosity and the stiffness (ratio between stress to strain) of the cytoskeleton.
One week after particle inhalation and later macrophage motility (relaxation) and cytoskeletal stiffness was not influenced by cigarette smoking, neither in healthy subjects, nor in the patients. Patients with IPF showed in tendency a faster relaxation (p = 0.06). Particle twisting revealed a non-Newtonian viscosity with a pure viscous and a viscoelastic compartment. The viscous shear was dominant, and only 27% of the shear recoiled and reflected viscoelastic properties. In patients with IPF, the stiffness was reduced by 60% (p < 0.02). An analysis of the shear rate and stress dependence of particle twisting allows correlating the rheological compartments to cytoskeletal subunits, in which microtubules mediate the pure viscous (non-recoverable) shear and microfilaments mediate the viscoelastic (recoverable) behavior. The missing correlation between relaxation and particle twisting shows that both stochastic and directed phagosome motion reflect different cytoskeletal mechanisms.
Faster relaxation and a soft cytoskeleton in patients with IPF indicate alterations in cytoskeleton dependent functions of alveolar macrophages, which may cause dysfunction's in the alveolar defense, like a slower migration, a retarded phagocytosis, a disturbed phagosome lysosome fusion and an impaired clearance.
PMCID: PMC1524958  PMID: 16700919
12.  Ultrafine particles cause cytoskeletal dysfunctions in macrophages: role of intracellular calcium 
Particulate air pollution is reported to cause adverse health effects in susceptible individuals. Since most of these particles are derived form combustion processes, the primary composition product is carbon with a very small diameter (ultrafine, less than 100 nm in diameter). Besides the induction of reactive oxygen species and inflammation, ultrafine particles (UFP) can cause intracellular calcium transients and suppression of defense mechanisms of alveolar macrophages, such as impaired migration or phagocytosis.
In this study the role of intracellular calcium transients caused by UFP was studied on cytoskeleton related functions in J774A.1 macrophages. Different types of fine and ultrafine carbon black particles (CB and ufCB, respectively), such as elemental carbon (EC90), commercial carbon (Printex 90), diesel particulate matter (DEP) and urban dust (UD), were investigated. Phagosome transport mechanisms and mechanical cytoskeletal integrity were studied by cytomagnetometry and cell viability was studied by fluorescence microscopy. Macrophages were exposed in vitro with 100 and 320 μg UFP/ml/million cells for 4 hours in serum free medium. Calcium antagonists Verapamil, BAPTA-AM and W-7 were used to block calcium channels in the membrane, to chelate intracellular calcium or to inhibit the calmodulin signaling pathways, respectively.
Impaired phagosome transport and increased cytoskeletal stiffness occurred at EC90 and P90 concentrations of 100 μg/ml/million cells and above, but not with DEP or UD. Verapamil and W-7, but not BAPTA-AM inhibited the cytoskeletal dysfunctions caused by EC90 or P90. Additionally the presence of 5% serum or 1% bovine serum albumin (BSA) suppressed the cytoskeletal dysfunctions. Cell viability showed similar results, where co-culture of ufCB together with Verapamil, W-7, FCS or BSA produced less cell dead compared to the particles only.
PMCID: PMC1262770  PMID: 16202162
Ultrafine particles; cytoskeleton; stiffness; viscoelasticity; phagosome transport; relaxation; intracellular calcium
Translocation of ultrafine particles (UFP) into the blood that returns from the lungs to the heart has been forwarded as a mechanism for particle-induced cardiovascular effects. The objective of this study was to evaluate the role of the endothelial barrier in the translocation of inhaled UFP from the lung into circulation.
The isolated perfused rat lung (IPRL) was used under negative pressure ventilation, and radioactive iridium particles (18 nm, CMD, 192Ir-UFP) were inhaled during 60 minutes to achieve a lung burden of 100 – 200 μg. Particle inhalation was done under following treatments: i) control perfusion, ii) histamine (1 μM in perfusate, iii) luminal histamine instillation (1 mM), and iv) luminal instillation of H2O2. Particle translocation to the perfusate was assessed by the radioactivity of 192Ir isotope. Lung permeability by the use of Tc99m-labeled diethylene triamine pentaacetic acid (DTPA). In addition to light microscopic morphological evaluation of fixed lungs, alkaline phosphatase (AKP) and angiotensin converting enzyme (ACE) in perfusate were measured to assess epithelial and endothelial integrity.
Particle distribution in the lung was homogenous and similar to in vivo conditions. No translocation of Ir particles at negative pressure inhalation was detected in control IPL, but lungs pretreated with histamine (1 μM) in the perfusate or with luminal H2O2 (0.5 mM) showed small amounts of radioactivity (2–3 % dose) in the single pass perfusate starting at 60 min of perfusion. Although the kinetics of particle translocation were different from permeability for 99mTc-DTPA, the pretreatments (H2O2, vascular histamine) caused similar changes in the translocation of particles and soluble mediator. Increased translocation through epithelium and endothelium with a lag time of one hour occurred in the absence of epithelial and endothelial damage.
Permeability of the lung barrier to UFP or nanoparticles is controlled both at the epithelial and endothelial level. Conditions that affect this barrier function such as inflammation may affect translocation of NP.
PMCID: PMC1180470  PMID: 15982423
endothelium; translocation; ultrafine particles; isolated perfused lung; permeability.
Environmental Health Perspectives  2004;112(3):369-377.
PMCID: PMC1241869  PMID: 14998755
Diseased lungs are of specific interest, since these are the main recipients of inhalation therapy. We, therefore, used Scnn1b-transgenic (Tg) mice as a model of chronic obstructive pulmonary disease (COPD) and compared uptake and localization of inhaled AuNP in surface macrophages and lung tissue to wild-type (Wt) mice.
Scnn1b-Tg and Wt mice inhaled a 21-nm AuNP aerosol for 2 h. Immediately (0 h) or 24 h thereafter, bronchoalveolar lavage (BAL) macrophages and whole lungs were prepared for stereological analysis of AuNP by electron microscopy.
AuNP were mainly found as singlets or small agglomerates of ≤ 100 nm diameter, at the epithelial surface and within lung-surface structures. Macrophages contained also large AuNP agglomerates (> 100 nm). At 0 h after aerosol inhalation, 69.2±4.9% AuNP were luminal, i.e. attached to the epithelial surface and 24.0±5.9% in macrophages in Scnn1b-Tg mice. In Wt mice, 35.3±32.2% AuNP were on the epithelium and 58.3±41.4% in macrophages. The percentage of luminal AuNP decreased from 0 h to 24 h in both groups. At 24 h, 15.5±4.8% AuNP were luminal, 21.4±14.2% within epithelial cells and 63.0±18.9% in macrophages in Scnn1b-Tg mice. In Wt mice, 9.5±5.0% AuNP were luminal, 2.2±1.6% within epithelial cells and 82.8±0.2% in macrophages. BAL-macrophage analysis revealed enhanced AuNP uptake in Wt animals at 0 h and in Scnn1b-Tg mice at 24 h, confirming less efficient macrophage uptake and delayed clearance of AuNP in Scnn1b-Tg mice.
Inhaled AuNP rapidly bound to the alveolar epithelium in both Wt and Scnn1b-Tg mice. Scnn1b-Tg mice showed less efficient AuNP uptake by surface macrophages and concomitant higher particle internalization by alveolar type I epithelial cells compared to Wt mice. This likely promotes AuNP depth translocation in Scnn1b-Tg mice, including enhanced epithelial targeting. These results suggest AuNP nanocarrier delivery as successful strategy for therapeutic targeting of alveolar epithelial cells and macrophages in COPD.
PMCID: PMC3660288  PMID: 23680060
Aerosol; COPD; Electron microscopy; Gold nanoparticles; Inhalation; Lungs; Macrophages; Stereology
16.  The procoagulant effects of fine particulate matter in vivo 
PMCID: PMC3068090  PMID: 21406084
17.  Expert elicitation on ultrafine particles: likelihood of health effects and causal pathways 
Exposure to fine ambient particulate matter (PM) has consistently been associated with increased morbidity and mortality. The relationship between exposure to ultrafine particles (UFP) and health effects is less firmly established. If UFP cause health effects independently from coarser fractions, this could affect health impact assessment of air pollution, which would possibly lead to alternative policy options to be considered to reduce the disease burden of PM. Therefore, we organized an expert elicitation workshop to assess the evidence for a causal relationship between exposure to UFP and health endpoints.
An expert elicitation on the health effects of ambient ultrafine particle exposure was carried out, focusing on: 1) the likelihood of causal relationships with key health endpoints, and 2) the likelihood of potential causal pathways for cardiac events. Based on a systematic peer-nomination procedure, fourteen European experts (epidemiologists, toxicologists and clinicians) were selected, of whom twelve attended. They were provided with a briefing book containing key literature. After a group discussion, individual expert judgments in the form of ratings of the likelihood of causal relationships and pathways were obtained using a confidence scheme adapted from the one used by the Intergovernmental Panel on Climate Change.
The likelihood of an independent causal relationship between increased short-term UFP exposure and increased all-cause mortality, hospital admissions for cardiovascular and respiratory diseases, aggravation of asthma symptoms and lung function decrements was rated medium to high by most experts. The likelihood for long-term UFP exposure to be causally related to all cause mortality, cardiovascular and respiratory morbidity and lung cancer was rated slightly lower, mostly medium. The experts rated the likelihood of each of the six identified possible causal pathways separately. Out of these six, the highest likelihood was rated for the pathway involving respiratory inflammation and subsequent thrombotic effects.
The overall medium to high likelihood rating of causality of health effects of UFP exposure and the high likelihood rating of at least one of the proposed causal mechanisms explaining associations between UFP and cardiac events, stresses the importance of considering UFP in future health impact assessments of (transport-related) air pollution, and the need for further research on UFP exposure and health effects.
PMCID: PMC2731037  PMID: 19630955

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