Publications
212 results found
Bolaji JA, Bonvini SJ, Wortley MA, et al., 2017, Phthalates trigger respiratory reflexes, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Mohamed NA, Davies RP, Lickiss PD, et al., 2017, Chemical and biological assessment of metal organic frameworks (MOFs) in pulmonary cells and in an acute in vivo model: relevance to pulmonary arterial hypertension therapy, Pulmonary Circulation, Vol: 7, Pages: 1-11, ISSN: 2045-8940
Pulmonary arterial hypertension (PAH) is a progressive and debilitating condition. Despite promoting vasodilation, current drugs have a therapeutic window within which they are limited by systemic side effects. Nanomedicine uses nanoparticles to improve drug delivery and/or reduce side effects. We hypothesize that this approach could be used to deliver PAH drugs avoiding the systemic circulation. Here we report the use of iron metal organic framework (MOF) MIL-89 and PEGylated MIL-89 (MIL-89 PEG) as suitable carriers for PAH drugs. We assessed their effects on viability and inflammatory responses in a wide range of lung cells including endothelial cells grown from blood of donors with/without PAH. Both MOFs conformed to the predicted structures with MIL-89 PEG being more stable at room temperature. At concentrations up to 10 or 30 µg/mL, toxicity was only seen in pulmonary artery smooth muscle cells where both MOFs reduced cell viability and CXCL8 release. In endothelial cells from both control donors and PAH patients, both preparations inhibited the release of CXCL8 and endothelin-1 and in macrophages inhibited inducible nitric oxide synthase activity. Finally, MIL-89 was well-tolerated and accumulated in the rat lungs when given in vivo. Thus, the prototypes MIL-89 and MIL-89 PEG with core capacity suitable to accommodate PAH drugs are relatively non-toxic and may have the added advantage of being anti-inflammatory and reducing the release of endothelin-1. These data are consistent with the idea that these materials may not only be useful as drug carriers in PAH but also offer some therapeutic benefit in their own right.
Smyth E, Solomon A, Birrell MA, et al., 2017, Influence of inflammation and nitric oxide upon platelet aggregation following deposition of diesel exhaust particles in the airways., British Journal of Pharmacology, Vol: 174, Pages: 2130-2139, ISSN: 0007-1188
Background and Purpose: Exposure to nanoparticulate pollution has been implicated in platelet-driven thrombotic events such as myocardial infarction. Inflammation and impairment of NO bioavailability have been proposed as potential causative mechanisms. It is unclear, however, whether airways exposure to combustion-derived nanoparticles such as diesel exhaust particles (DEP) or carbon black (CB) can augment platelet aggregation in vivo and the underlying mechanisms remain undefined. We aimed to investigate the effects of acute lung exposure to DEP and CB on platelet activation and the associated role of inflammation and endothelial-derived NO.Experimental Approach: DEP and CB were intratracheally instilled into wild-type (WT) and eNOS−/− mice and platelet aggregation was assessed in vivo using an established model of radio-labelled platelet thromboembolism. The underlying mechanisms were investigated by measuring inflammatory markers, NO metabolites and light transmission aggregometry.Key Results: Platelet aggregation in vivo was significantly enhanced in WT and eNOS−/− mice following acute airways exposure to DEP but not CB. CB exposure, but not DEP, was associated with significant increases in pulmonary neutrophils and IL-6 levels in the bronchoalveolar lavage fluid and plasma of WT mice. Neither DEP nor CB affected plasma nitrate/nitrite concentration and DEP-induced human platelet aggregation was inhibited by an NO donor.Conclusions and Implications: Pulmonary exposure to DEP and subsequent platelet activation may contribute to the reports of increased cardiovascular risk, associated with exposure to airborne pollution, independent of its effects on inflammation or NO bioavailability.
Robinson RK, Birrell MA, Adcock JJ, et al., 2017, Mechanistic link between diesel exhaust particles and respiratory reflexes, Journal of Allergy and Clinical Immunology, Vol: 141, Pages: 1074-1084.e9, ISSN: 1097-6825
BackgroundDiesel exhaust particles (DEPs) are a major component of particulate matter in Europe's largest cities, and epidemiologic evidence links exposure with respiratory symptoms and asthma exacerbations. Respiratory reflexes are responsible for symptoms and are regulated by vagal afferent nerves, which innervate the airway. It is not known how DEP exposure activates airway afferents to elicit symptoms, such as cough and bronchospasm.ObjectiveWe sought to identify the mechanisms involved in activation of airway sensory afferents by DEPs.MethodsIn this study we use in vitro and in vivo electrophysiologic techniques, including a unique model that assesses depolarization (a marker of sensory nerve activation) of human vagus.ResultsWe demonstrate a direct interaction between DEP and airway C-fiber afferents. In anesthetized guinea pigs intratracheal administration of DEPs activated airway C-fibers. The organic extract (DEP-OE) and not the cleaned particles evoked depolarization of guinea pig and human vagus, and this was inhibited by a transient receptor potential ankyrin-1 antagonist and the antioxidant N-acetyl cysteine. Polycyclic aromatic hydrocarbons, major constituents of DEPs, were implicated in this process through activation of the aryl hydrocarbon receptor and subsequent mitochondrial reactive oxygen species production, which is known to activate transient receptor potential ankyrin-1 on nociceptive C-fibers.ConclusionsThis study provides the first mechanistic insights into how exposure to urban air pollution leads to activation of guinea pig and human sensory nerves, which are responsible for respiratory symptoms. Mechanistic information will enable the development of appropriate therapeutic interventions and mitigation strategies for those susceptible subjects who are most at risk.
Conforti F, Davies ER, Calderwood CJ, et al., 2017, The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis., Oncotarget, Vol: 8, Pages: 48737-48754, ISSN: 1949-2553
Idiopathic pulmonary fibrosis (IPF) is a progressive disease that usually affects elderly people. It has a poor prognosis and there are limited therapies. Since epigenetic alterations are associated with IPF, histone deacetylase (HDAC) inhibitors offer a novel therapeutic strategy to address the unmet medical need. This study investigated the potential of romidepsin, an FDA-approved HDAC inhibitor, as an anti-fibrotic treatment and evaluated biomarkers of target engagement that may have utility in future clinical trials. The anti-fibrotic effects of romidepsin were evaluated both in vitro and in vivo together with any harmful effect on alveolar type II cells (ATII). Bronchoalveolar lavage fluid (BALF) from IPF or control donors was analyzed for the presence of lysyl oxidase (LOX). In parallel with an increase in histone acetylation, romidepsin potently inhibited fibroblast proliferation, myofibroblast differentiation and LOX expression. ATII cell numbers and their lamellar bodies were unaffected. In vivo, romidepsin inhibited bleomycin-induced pulmonary fibrosis in association with suppression of LOX expression. LOX was significantly elevated in BALF of IPF patients compared to controls. These data show the anti-fibrotic effects of romidepsin, supporting its potential use as novel treatment for IPF with LOX as a companion biomarker for evaluation of early on-target effects.
Chung KF, Seiffert J, Chen S, et al., 2017, Inactivation, clearance, and functional effects of lung-instilled short and long silver nanowires in rats, ACS Nano, Vol: 11, Pages: 2652-2664, ISSN: 1936-086X
There is a potential for silver nanowires (AgNWs) to be inhaled, but there is little information on their health effects and their chemical transformation inside the lungs in vivo. We studied the effects of short (S-AgNWs; 1.5 μm) and long (L-AgNWs; 10 μm) nanowires instilled into the lungs of Sprague–Dawley rats. S- and L-AgNWs were phagocytosed and degraded by macrophages; there was no frustrated phagocytosis. Interestingly, both AgNWs were internalized in alveolar epithelial cells, with precipitation of Ag2S on their surface as secondary Ag2S nanoparticles. Quantitative serial block face three-dimensional scanning electron microscopy showed a small, but significant, reduction of NW lengths inside alveolar epithelial cells. AgNWs were also present in the lung subpleural space where L-AgNWs exposure resulted in more Ag+ve macrophages situated within the pleura and subpleural alveoli, compared with the S-AgNWs exposure. For both AgNWs, there was lung inflammation at day 1, disappearing by day 21, but in bronchoalveolar lavage fluid (BALF), L-AgNWs caused a delayed neutrophilic and macrophagic inflammation, while S-AgNWs caused only acute transient neutrophilia. Surfactant protein D (SP-D) levels in BALF increased after S- and L-AgNWs exposure at day 7. L-AgNWs induced MIP-1α and S-AgNWs induced IL-18 at day 1. Large airway bronchial responsiveness to acetylcholine increased following L-AgNWs, but not S-AgNWs, exposure. The attenuated response to AgNW instillation may be due to silver inactivation after precipitation of Ag2S with limited dissolution. Our findings have important consequences for the safety of silver-based technologies to human health.
Calderon L, Han TT, McGilvery CM, et al., 2017, Release of airborne particles and Ag and Zn compounds from nanotechnology-enabled consumer sprays: Implications for inhalation exposure, ATMOSPHERIC ENVIRONMENT, Vol: 155, Pages: 85-96, ISSN: 1352-2310
The increasing prevalence and use of nanotechnology-enabled consumer products have increased potential consumer exposures to nanoparticles; however, there is still a lack of data characterizing such consumer exposure. The research reported here investigated near-field airborne exposures due to the use of 13 silver (Ag)-based and 5 zinc (Zn)-based consumer sprays. The products were sprayed into a specially designed glove box, and all products were applied with equal spraying duration and frequency. Size distribution and concentration of the released particles were assessed using a Scanning Mobility Particle Sizer and an Aerodynamic Particle Sizer. Inductively coupled plasma mass spectrometry (ICP-MS) was used to investigate the presence of metals in all investigated products. Spray liquids and airborne particles from select products were examined using transmission electron microscopy (TEM) and Energy Dispersive X-ray Spectroscopy (EDS). We found that all sprays produced airborne particles ranging in size from nano-sized particles (<100 nm) to coarse particles (>2.5 μm); however, there was a substantial variation in the released particle concentration depending on a product. The total aerosol mass concentration was dominated by the presence of coarse particles, and it ranged from ∼30 μg/m3 to ∼30,000 μg/m3. The TEM verified the presence of nanoparticles and their agglomerates in liquid and airborne states. The products were found to contain not only Ag and Zn compounds - as advertised on the product labeling - but also a variety of other metals including lithium, strontium, barium, lead, manganese and others. The results presented here can be used as input to model population exposures as well as form a basis for human health effects studies due to the use nanotechnology-enabled products.
Thorley A, Ogger P, Legorburo-Schofield M, et al., 2017, Nintedanib Effectively Inhibits Carbon Nanotube-Induced Fibrotic Responses In Human Alveolar Epithelial Cells, Fibroblasts And Pulmonary Microvascular Endothelial Cells, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Sweeney S, Hu S, Ruenraroengsak P, et al., 2016, Carboxylation of multiwalled carbon nanotubes reduces their toxicity in primary human alveolar macrophages, Environmental Science: Nano, Vol: 3, Pages: 1340-1350, ISSN: 2051-8153
Surface functionalisation of multiwalled carbon nanotubes (MWCNT) is commonly used to facilitate their various and diverse applications. Inhaled nanomaterials, such as MWCNTs, have a high deposition rate in the alveolar units of the deep lung, where alveolar macrophages (AM) provide the front line of cellular immune defence by removing foreign matter (microbes, particles etc.). The toxicity of MWCNTs (with or without functionalisation) towards primary human AMs is not known. We investigated the physicochemical characteristics and toxicity of two MWCNT materials: acid purified ‘Purified-MWCNT’ and concentrated acid functionalised ‘COOH-MWCNT’. We hypothesised that the bioreactivity with primary human AM would differ between the materials. Full characterisation of the MWCNTs revealed that –COOH functionalisation yielded shorter MWCNTs, accompanied by a greater occurrence of framework defects, in comparison to Purified-MWCNT. In agreement with our hypothesis that the bioreactivity would differ, Purified-MWCNT were significantly more toxic as measured by reduced cell viability and increased inflammatory mediator release. For example, IL-1β and IL-8 release by AMs significantly increased 3.5- and 2.4-fold, respectively (P < 0.05), 24 hours after treatment with Purified-MWCNT. In contrast, IL-1β and IL-8 release by AMs did not significantly change 24 hours after treatment with COOH-MWCNT. We determined that the mechanism of this toxicity is likely due to activation of the inflammasome, as lipopolysaccharide priming of primary human AMs was necessary to see the inflammatory response and this was accompanied by lysosomal disruption and increased generation of reactive oxygen species. This study contributes further to our understanding of the effects of MWCNTs and surface modification on highly relevant human lung AMs; the findings have important implications for the manufacture, application and use of MWCNTs. In particular, this is
Zhang JJ, Lee KB, He L, et al., 2016, Effects of a nanoceria fuel additive on the physicochemical properties of diesel exhaust particles., Environmental Science: Processes & Impacts, Vol: 18, Pages: 1333-1342, ISSN: 2050-7887
Nanoceria (i.e., CeO2 nanoparticles) fuel additives have been used in Europe and elsewhere to improve fuel efficiency. Previously we have shown that the use of a commercial fuel additive Envirox™ in a diesel-powered electricity generator reduced emissions of diesel exhaust particle (DEP) mass and other pollutants. However, such additives are currently not permitted for use in on-road vehicles in North America, largely due to limited data on the potential health impact. In this study, we characterized a variety of physicochemical properties of DEPs emitted from the same engine. Our methods include novel techniques such as Raman spectrometry for analyzing particle surface structure and an assay for DEP oxidative potential. Results show that with increasing Envirox™ concentrations in the fuel (0×, 0.1×, 1×, and 10× of manufacturer recommended 0.5 mL Envirox™ per liter fuel), DEP sizes decreased from 194.6 ± 20.1 to 116.3 ± 14.8 nm; the zeta potential changed from -28.4 mV to -22.65 mV; DEP carbon content decreased from 91.8% to 79.4%; cerium and nitrogen contents increased from 0.3% to 6.5% and 0.2% to 0.6%, respectively; the ratio of organic carbon (OC) to elemental carbon (EC) increased from 22.9% to 38.7%; and the ratio of the disordered carbon structure to the ordered carbon structure (graphitized carbon) in DEPs decreased. Compared to DEPs emitted from 0×, 0.1×, and 1× fuels, DEPs from the 10× fuel had a lower oxidative potential likely due to the increased ceria content because pure ceria nanoparticles exhibited the lowest oxidative potential compared to all the DEPs. Since the physicochemical parameters tested here are among the determinants of particle toxicity, our findings imply that adding ceria nanoparticles into diesel may alter the toxicity of DEPs. The findings from the present study, hence, can help future studies that will examine the impact of nanoceria additives on DEP to
Serrano-Mollar A, Gay-Jordi G, Guillamat-Prats R, et al., 2016, Safety and Tolerability of Alveolar Type II Cell Transplantation in Idiopathic Pulmonary Fibrosis., Chest, Vol: 150, Pages: 533-543, ISSN: 0012-3692
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited response to currently available therapies. Alveolar type II (ATII) cells act as progenitor cells in the adult lung, contributing to alveolar repair during pulmonary injury. However, in IPF, ATII cells die and are replaced by fibroblasts and myofibroblasts. In previous preclinical studies, we demonstrated that ATII-cell intratracheal transplantation was able to reduce pulmonary fibrosis. The main objective of this study was to investigate the safety and tolerability of ATII-cell intratracheal transplantation in patients with IPF. METHODS: We enrolled 16 patients with moderate and progressive IPF who underwent ATII-cell intratracheal transplantation through fiberoptic bronchoscopy. We evaluated the safety and tolerability of ATII-cell transplantation by assessing the emergent adverse side effects that appeared within 12 months. Moreover, pulmonary function, respiratory symptoms, and disease extent during 12 months of follow-up were evaluated. RESULTS: No significant adverse events were associated with the ATII-cell intratracheal transplantation. After 12 months of follow-up, there was no deterioration in pulmonary function, respiratory symptoms, or disease extent. CONCLUSIONS: Our results support the hypothesis that ATII-cell intratracheal transplantation is safe and well tolerated in patients with IPF. This study opens the door to designing a clinical trial to elucidate the potential beneficial effects of ATII-cell therapy in IPF.
Theodorou IG, Ruenraroengsak P, Gow A, et al., 2016, Effect of pulmonary surfactant on the dissolution, stability and uptake of zinc oxide nanowires by human respiratory epithelial cells., Nanotoxicology, Vol: 10, Pages: 1351-1362, ISSN: 1743-5404
Inhaled nanoparticles (NPs) have high-deposition rates in the alveolar region of the lung but the effects of pulmonary surfactant (PS) on nanoparticle bioreactivity are unclear. Here, the impact of PS on the stability and dissolution of ZnO nanowires (ZnONWs) was investigated, and linked with their bioreactivity in vitro with human alveolar epithelial type 1-like cells (TT1). Pre-incubation of ZnONWs with Curosurf® (a natural porcine PS) decreased their dissolution at acidic pH, through the formation of a phospholipid corona. Confocal live cell microscopy confirmed that Curosurf® lowered intracellular dissolution, thus delaying the onset of cell death compared to bare ZnONWs. Despite reducing dissolution, Curosurf® significantly increased the uptake of ZnONWs within TT1 cells, ultimately increasing their toxicity after 24 h. Although serum improved ZnONW dispersion in suspension similar to Curosurf®, it had no effect on ZnONW internalization and toxicity, indicating a unique role of PS in promoting particle uptake. In the absence of PS, ZnONW length had no effect on dissolution kinetics or degree of cellular toxicity, indicating a less important role of length in determining ZnONW bioreactivity. This work provides unique findings on the effects of PS on the stability and toxicity of ZnONWs, which could be important in the study of pulmonary toxicity and epithelial-endothelial translocation of nanoparticles in general.
Seiffert J, Buckley A, Leo B, et al., 2016, Pulmonary effects of inhalation of spark-generated silver nanoparticles in Brown-Norway and Sprague-Dawley rats, Respiratory Research, Vol: 17, ISSN: 1465-993X
BackgroundThe increasing use of silver nanoparticles (AgNPs) in consumer products is concerning. Weexamined the potential toxic effects when inhaled in Brown-Norway (BN) rats with a preinflammatorystate compared to Sprague-Dawley (SD) rats.MethodsWe determined the effect of AgNPs generated from a spark generator (mass concentration:600-800 µg/mm3; mean diameter: 13-16 nm; total lung doses: 8 [Low] and 26-28 [High] µg)inhaled by the nasal route in both rat strains. Rats were sacrificed at day 1 and day 7 afterexposure and measurement of lung function.ResultsIn both strains, there was an increase in neutrophils in bronchoalveolar lavage (BAL) fluid at24 hours at the high dose, with concomitant eosinophilia in BN rats. While BAL inflammatorycells were mostly normalised by Day 7, lung inflammation scores remained increasedalthough not the tissue eosinophil scores. Total protein levels were elevated at both lungdoses in both strains. There was an increase in BAL IL-1β, KC, IL-17, CCL2 and CCL3 levels inboth strains at Day 1, mostly at high dose. Phospholipid levels were increased at the highdose in SD rats at Day 1 and 7, while in BN rats, this was only seen at Day 1; surfactantprotein D levels decreased at day 7 at the high dose in SD rats, but was increased at Day 1 atthe low dose in BN rats. There was a transient increase in central airway resistance and intissue elastance in BN rats at Day 1 but not in SD rats. Positive silver-staining was seenparticularly in lung tissue macrophages in a dose and time-dependent response in bothstrains, maximal by day 7. Lung silver levels were relatively higher in BN rat and present atday 7 in both strains.ConclusionsPresence of cellular inflammation and increasing silver-positive macrophages in lungs at day7, associated with significant levels of lung silver indicate that lung toxicity is persistent evenwith the absence of airway luminal inflammation at that time-point. The higher levels andpersistence of lung silve
Ruenraromgsak P, Chen S, Hu S, et al., 2016, Translocation of functionalized multi-walled carbon nanotubes across human pulmonary alveolar epithelium: dominant role of epithelial type 1 cells, ACS Nano, Vol: 10, Pages: 5070-5085, ISSN: 1936-0851
Uptake and translocation of short functionalized multi-walled carbon nanotubes (short-fMWCNTs) through the pulmonary respiratory epithelial barrier depend on physicochemical property and cell type. Two monoculture models, immortalized human alveolar epithelial type 1 (TT1) cells and primary human alveolar epithelial type 2 cells (AT2), which constitute the alveolar epithelial barrier, were employed to investigate the uptake and transport of 300 and 700 nm in length, poly(4-vinylpyridine)-functionalized, multi-walled carbon nanotubes (p(4VP)-MWCNTs) using quantitative imaging and spectroscopy techniques. The p(4VP)-MWCNT exhibited no toxicity on TT1 and AT2 cells, but significantly decreased barrier integrity (*p < 0.01). Uptake of p(4VP)-MWCNTs was observed in 70% of TT1 cells, correlating with compromised barrier integrity and basolateral p(4VP)-MWCNT translocation. There was a small but significantly greater uptake of 300 nm p(4VP)-MWCNTs than 700 nm p(4VP)-MWCNTs by TT1 cells. Up to 3% of both the 300 and 700 nm p(4VP)-MWCNTs reach the basal chamber; this relatively low amount arose because the supporting transwell membrane minimized the amount of p(4VP)-MWCNT translocating to the basal chamber, seen trapped between the basolateral cell membrane and the membrane. Only 8% of AT2 cells internalized p(4VP)-MWCNT, accounting for 17% of applied p(4VP)-MWCNT), with transient effects on barrier function, which initially fell then returned to normal; there was no MWCNT basolateral translocation. The transport rate was MWCNT length modulated. The comparatively lower p(4VP)-MWCNT uptake by AT2 cells is proposed to reflect a primary barrier effect of type 2 cell secretions and the functional differences between the type 1 and type 2 alveolar epithelial cells.
Sarkar S, Carranza C, Theodorou I, et al., 2016, Impact of Silver and Carbon Nanoparticle Exposures on Macrophage Responses to Mycobacterium tuberculosis (M.tb), Annual Meeting of the American-Association-of-Immunologists (AAI), Publisher: AMER ASSOC IMMUNOLOGISTS, ISSN: 0022-1767
Sweeney S, Leo BF, Chen S, et al., 2016, Pulmonary surfactant mitigates silver nanoparticle toxicity in human alveolar type-I-like epithelial cells., Colloids and Surfaces B - Biointerfaces, Vol: 145, Pages: 167-175, ISSN: 1873-4367
Accompanying increased commercial applications and production of silver nanomaterials is an increased probability of human exposure, with inhalation a key route. Nanomaterials that deposit in the pulmonary alveolar region following inhalation will interact firstly with pulmonary surfactant before they interact with the alveolar epithelium. It is therefore critical to understand the effects of human pulmonary surfactant when evaluating the inhalation toxicity of silver nanoparticles. In this study, we evaluated the toxicity of AgNPs on human alveolar type-I-like epithelial (TT1) cells in the absence and presence of Curosurf(®) (a natural pulmonary surfactant substitute), hypothesising that the pulmonary surfactant would act to modify toxicity. We demonstrated that 20nm citrate-capped AgNPs induce toxicity in human alveolar type I-like epithelial cells and, in agreement with our hypothesis, that pulmonary surfactant acts to mitigate this toxicity, possibly through reducing AgNP dissolution into cytotoxic Ag(+) ions. For example, IL-6 and IL-8 release by TT1 cells significantly increased 10.7- and 35-fold, respectively (P<0.01), 24h after treatment with 25μg/ml AgNPs. In contrast, following pre-incubation of AgNPs with Curosurf(®), this effect was almost completely abolished. We further determined that the mechanism of this toxicity is likely associated with Ag(+) ion release and lysosomal disruption, but not with increased reactive oxygen species generation. This study provides a critical understanding of the toxicity of AgNPs in target human alveolar type-I-like epithelial cells and the role of pulmonary surfactant in mitigating this toxicity. The observations reported have important implications for the manufacture and application of AgNPs, in particular for applications involving use of aerosolised AgNPs.
Botelho DJ, Leo BF, Massa CB, et al., 2016, Low-dose AgNPs reduce lung mechanical function and innate immune defense in the absence of cellular toxicity, NANOTOXICOLOGY, Vol: 10, Pages: 118-127, ISSN: 1743-5390
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Robinson RK, Birrell MA, Wortley MA, et al., 2016, Diesel Activates Airway Sensory Nerves To Initiate Respiratory Symptoms, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Cryer AM, Ruenraroengsak P, Tetley TD, et al., 2015, SYNTHESIS OF GOLD-BASED NANOMEDICINES TO TREAT NON-SMALL CELL LUNG CANCER, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A58-A59, ISSN: 0040-6376
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Sarkar S, Leo BF, Carranza C, et al., 2015, Modulation of human macrophage responses to mycobacterium tuberculosis by silver nanoparticles of different size and surface modification, PLOS One, Vol: 10, ISSN: 1932-6203
Exposure to silver nanoparticles (AgNP) used in consumer products carries potential health risks including increased susceptibility to infectious pathogens. Systematic assessments of antimicrobial macrophage immune responses in the context of AgNP exposure are important because uptake of AgNP by macrophages may lead to alterations of innate immune cell functions. In this study we examined the effects of exposure to AgNP with different particle sizes (20 and 110 nm diameters) and surface chemistry (citrate or polyvinlypyrrolidone capping) on cellular toxicity and innate immune responses against Mycobacterium tuberculosis (M.tb) by human monocyte-derived macrophages (MDM). Exposures of MDM to AgNP significantly reduced cellular viability, increased IL8 and decreased IL10 mRNA expression. Exposure of M.tb-infected MDM to AgNP suppressed M.tb-induced expression of IL1B, IL10, and TNFA mRNA. Furthermore, M.tb-induced IL-1β, a cytokine critical for host resistance to M.tb, was inhibited by AgNP but not by carbon black particles indicating that the observed immunosuppressive effects of AgNP are particle specific. Suppressive effects of AgNP on the M.tb-induced host immune responses were in part due to AgNP-mediated interferences with the TLR signaling pathways that culminate in the activation of the transcription factor NF-κB. AgNP exposure suppressed M.tb-induced expression of a subset of NF-κB mediated genes (CSF2, CSF3, IFNG, IL1A, IL1B, IL6, IL10, TNFA, NFKB1A). In addition, AgNP exposure increased the expression of HSPA1A mRNA and the corresponding stress-induced Hsp72 protein. Up-regulation of Hsp72 by AgNP can suppress M.tb-induced NF-κB activation and host immune responses. The observed ability of AgNP to modulate infectious pathogen-induced immune responses has important public health implications.
Robinson R, Wortley M, Dubuis E, et al., 2015, Organic components of diesel exhaust particles (DEP) activate airway sensory nerves via transient receptor potential ankrin-1 (TRPA1) ion channels, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Mukherjee D, Porter A, Ryan M, et al., 2015, Modeling in vivo interactions of engineered nanoparticles in the pulmonary alveolar lining fluid, Nanomaterials, Vol: 5, Pages: 1223-1249, ISSN: 2079-4991
Increasing use of engineered nanomaterials (ENMs) in consumer products may result in widespread human inhalation exposures. Due to their high surface area per unit mass, inhaled ENMs interact with multiple components of the pulmonary system, and these interactions affect their ultimate fate in the body. Modeling of ENM transport and clearance in vivo has traditionally treated tissues as well-mixed compartments, without consideration of nanoscale interaction and transformation mechanisms. ENM agglomeration, dissolution and transport, along with adsorption of biomolecules, such as surfactant lipids and proteins, cause irreversible changes to ENM morphology and surface properties. The model presented in this article quantifies ENM transformation and transport in the alveolar air to liquid interface and estimates eventual alveolar cell dosimetry. This formulation brings together established concepts from colloidal and surface science, physics, and biochemistry to provide a stochastic framework capable of capturing essential in vivo processes in the pulmonary alveolar lining layer. The model has been implemented for in vitro solutions with parameters estimated from relevant published in vitro measurements and has been extended here to in vivo systems simulating human inhalation exposures. Applications are presented for four different ENMs, and relevant kinetic rates are estimated, demonstrating an approach for improving human in vivo pulmonary dosimetry.
Theodorou IG, Botelho D, Schwander S, et al., 2015, Static and Dynamic Microscopy of the Chemical Stability and Aggregation State of Silver Nanowires in Components of <i>Murine</i> Pulmonary Surfactant, ENVIRONMENTAL SCIENCE & TECHNOLOGY, Vol: 49, Pages: 8048-8056, ISSN: 0013-936X
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Tetley TD, Ruenraroengsak P, 2015, Differential bioreactivity of neutral, cationic and anionic polystyrene nanoparticles with cells from the human alveolar compartment: robust response of alveolar type 1 epithelial cells, Particle and Fibre Toxicology, Vol: 12, ISSN: 1743-8977
BackgroundEngineered nanoparticles (NP) are being developed for inhaled drug delivery. This route is non-invasive and the major target; alveolar epithelium provides a large surface area for drug administration and absorption, without first pass metabolism. Understanding the interaction between NPs and target cells is crucial for safe and effective NP-based drug delivery. We explored the differential effect of neutral, cationic and anionic polystyrene latex NPs on the target cells of the human alveolus, using primary human alveolar macrophages (MAC) and primary human alveolar type 2 (AT2) epithelial cells and a unique human alveolar epithelial type I-like cell (TT1). We hypothesized that the bioreactivity of the NPs would relate to their surface chemistry, charge and size as well as the functional role of their interacting cells in vivo.MethodsAmine- (ANP) and carboxyl- surface modified (CNP) and unmodified (UNP) polystyrene NPs, 50 and 100 nm in diameter, were studied. Cells were exposed to 1–100 μg/ml (1.25-125 μg/cm 2 ; 0 μg/ml control) NP for 4 and 24 h at 37 °C with or without the antioxidant, N-acetyl cysteine (NAC). Cells were assessed for cell viability, reactive oxygen species (ROS), oxidised glutathione (GSSG/GSH ratio), mitochondrial integrity, cell morphology and particle uptake (using electron microscopy and laser scanning confocal microscopy).ResultsANP-induced cell death occurred in all cell types, inducing increased oxidative stress, mitochondrial disruption and release of cytochrome C, indicating apoptotic cell death. UNP and CNP exhibited little cytotoxicity or mitochondrial damage, although they induced ROS in AT2 and MACs. Addition of NAC reduced epithelial cell ROS, but not MAC ROS, for up to 4 h. TT1 and MAC cells internalised all NP formats, whereas only a small fraction of AT2 cells internalized ANP (not UNP or CNP). TT1 cells were the most resistant to the effects of UNP and CNP.ConclusionANP induced marked oxidative damage
Sweeney S, Theodorou IG, Zambianchi M, et al., 2015, Silver nanowire interactions with primary human alveolar type-II epithelial cell secretions: contrasting bioreactivity with human alveolar type-I and type-II epithelial cells., Nanoscale, Vol: 7, Pages: 10398-10409, ISSN: 2040-3372
Inhaled nanoparticles have a high deposition rate in the alveolar units of the deep lung. The alveolar epithelium is composed of type-I and type-II epithelial cells (ATI and ATII respectively) and is bathed in pulmonary surfactant. The effect of native human ATII cell secretions on nanoparticle toxicity is not known. We investigated the cellular uptake and toxicity of silver nanowires (AgNWs; 70 nm diameter, 1.5 μm length) with human ATI-like cells (TT1), in the absence or presence of Curosurf® (a natural porcine pulmonary surfactant with a low amount of protein) or harvested primary human ATII cell secretions (HAS; containing both the complete lipid as well as the full protein complement of human pulmonary surfactant i.e. SP-A, SP-B, SP-C and SP-D). We hypothesised that Curosurf® or HAS would confer improved protection for TT1 cells, limiting the toxicity of AgNWs. In agreement with our hypothesis, HAS reduced the inflammatory and reactive oxygen species (ROS)-generating potential of AgNWs with exposed TT1 cells. For example, IL-8 release and ROS generation was reduced by 38% and 29%, respectively, resulting in similar levels to that of the non-treated controls. However in contrast to our hypothesis, Curosurf® had no effect. We found a significant reduction in AgNW uptake by TT1 cells in the presence of HAS but not Curosurf. Furthermore, we show that the SP-A and SP-D are likely to be involved in this process as they were found to be specifically bound to the AgNWs. While ATI cells appear to be protected by HAS, evidence suggested that ATII cells, despite no uptake, were vulnerable to AgNW exposure (indicated by increased IL-8 release and ROS generation and decreased intracellular SP-A levels one day post-exposure). This study provides unique findings that may be important for the study of lung epithelial-endothelial translocation of nanoparticles in general and associated toxicity within the alveolar unit.
Sweeney S, Grandolfo D, Ruenraroengsak P, et al., 2015, Functional consequences for primary human alveolar macrophages following treatment with long, but not short, multiwalled carbon nanotubes, International Journal of Nanomedicine, Vol: 10, Pages: 3115-3129, ISSN: 1178-2013
Melbourne J, Clancy A, Seiffert J, et al., 2015, An investigation of the carbon nanotube - Lipid interface and its impact upon pulmonary surfactant lipid function., Biomaterials, Vol: 55, Pages: 24-32, ISSN: 1878-5905
Multiwalled carbon nanotubes (MWCNTs) are now synthesized on a large scale, increasing the risk of occupational inhalation. However, little is known of the MWCNT-pulmonary surfactant (PS) interface and its effect on PS functionality. The Langmuir-Blodgett trough was used to evaluate the impact of MWCNTs on fundamental properties of PS lipids which influence PS function, i.e. compression resistance and maximum obtainable pressure. Changes were found to be MWCNT length-dependent. 'Short' MWCNTs (1.1 μm, SD = 0.61) penetrated the lipid film, reducing the maximum interfacial film pressure by 10 mN/m (14%) in dipalmitoylphosphatidylcholine (DPPC) and PS, at an interfacial MWCNT-PS lipid mass ratio range of 50:1 to 1:1. 'Long' commercial MWCNTs (2.1 μm, SD = 1.2) caused compression resistance at the same mass loadings. 'Very long' MWCNTs (35 μm, SD = 19) sequestered DPPC and were squeezed out of the DPPC film. High resolution transmission electron microscopy revealed that all MWCNT morphologies formed DPPC coronas with ordered arrangements. These results provide insight into how nanoparticle aspect ratio affects the interaction mechanisms with PS, in its near-native state at the air-water interface.
Botelho D, Shaffer M, Porter A, et al., 2015, Lung Lining Interaction Determines the Fate of Multi-Walled Carbon Nanotubes (MWCNTs) <i>in vivo</i>, Experimental Biology Meeting, Publisher: FEDERATION AMER SOC EXP BIOL, ISSN: 0892-6638
Seiffert J, Hussain F, Wiegman C, et al., 2015, Pulmonary Toxicity of Instilled Silver Nanoparticles: Influence of Size, Coating and Rat Strain, PLOS ONE, Vol: 10, ISSN: 1932-6203
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Marchetti M, Shaffer MSP, Zambianchi M, et al., 2015, Adsorption of surfactant protein D from human respiratory secretions by carbon nanotubes and polystyrene nanoparticles depends on nanomaterial surface modification and size, PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 370, ISSN: 0962-8436
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