Imperial College London

Professor Terry Tetley

Faculty of MedicineNational Heart & Lung Institute

Consul (Non-Clinical) for the Faculty of Medicine
 
 
 
//

Contact

 

+44 (0)20 7594 2984t.tetley Website

 
 
//

Location

 

Cale StreetRoyal Brompton Campus

//

Summary

 

Publications

Publication Type
Year
to

168 results found

Calderon L, Han TT, McGilvery CM, Yang L, Subramaniam P, Lee K-B, Schwander S, Tetley TD, Georgopoulos PG, Ryan M, Porter AE, Smith R, Chung KF, Lioy PJ, Zhang J, Mainelis G, Calderón L, Han TT, McGilvery CM, Yang L, Subramaniam P, Lee KB, Schwander S, Tetley TD, Georgopoulos PG, Ryan M, Porter AE, Smith R, Chung KF, Lioy PJ, Zhang J, Mainelis G, Calderón L, Han TT, McGilvery CM, Yang L, Subramaniam P, Lee K-B, Schwander S, Tetley TD, Georgopoulos PG, Ryan M, Porter AE, Smith R, Chung KF, Lioy PJ, Zhang J, Mainelis G, Calderon L, Han TT, McGilvery CM, Yang L, Subramaniam P, Lee K-B, Schwander S, Tetley TD, Georgopoulos PG, Ryan M, Porter AE, Smith R, Chung KF, Lioy PJ, Zhang J, Mainelis Get 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

© 2017 Elsevier Ltd 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/m 3 to ∼30,000 μg/m 3 . 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.

JOURNAL ARTICLE

Chung KF, Seiffert J, Chen S, Theodorou IG, Goode AE, Leo BF, McGilvery CM, Hussain F, Wiegman C, Rossios C, Zhu J, Gong J, Tariq F, Yufit V, Monteith AJ, Hashimoto T, Skepper JN, Ryan MP, Zhang J, Tetley TD, Porter AE, Chung KF, Seiffert J, Chen S, Theodorou IG, Goode AE, Leo BF, McGilvery CM, Hussain F, Wiegman C, Rossios C, Zhu J, Gong J, Tariq F, Yufit V, Monteith AJ, Hashimoto T, Skepper JN, Ryan MP, Zhang J, Tetley TD, Porter AE, Chung KF, Seiffert J, Chen S, Theodorou IG, Goode AE, Leo BF, McGilvery CM, Hussain F, Wiegman C, Rossios C, Zhu J, Gong J, Tariq F, Yufit V, Monteith AJ, Hashimoto T, Skepper JN, Ryan MP, Zhang J, Tetley TD, Porter AE, Chung KF, Seiffert J, Chen S, Theodorou IG, Goode AE, Leo BF, McGilvery CM, Hussain F, Wiegman C, Rossios C, Zhu J, Gong J, Tariq F, Yufit V, Monteith AJ, Hashimoto T, Skepper JN, Ryan MP, Zhang J, Tetley TD, Porter AE, Chung KF, Seiffert J, Chen S, Theodorou IG, Goode AE, Leo BF, McGilvery CM, Hussain F, Wiegman C, Rossios C, Zhu J, Gong J, Tariq F, Yufit V, Monteith AJ, Hashimoto T, Skepper JN, Ryan MP, Zhang J, Tetley TD, Porter AE, Chung KF, Seiffert J, Chen S, Theodorou IG, Goode AE, Leo BF, McGilvery CM, Hussain F, Wiegman C, Rossios C, Zhu J, Gong J, Tariq F, Yufit V, Monteith AJ, Hashimoto T, Skepper JN, Ryan MP, Zhang J, Tetley TD, Porter AEet 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: 1936-0851

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.

JOURNAL ARTICLE

Conforti F, Davies ER, Calderwood CJ, Thatcher TH, Jones MG, Smart DE, Mahajan S, Alzetani A, Havelock T, Maher TM, Molyneaux PL, Thorley AJ, Tetley TD, Warner JA, Packham G, Ganesan A, Skipp PJ, Marshall BJ, Richeldi L, Sime PJ, O'Reilly KMA, Davies DE, Conforti F, Davies ER, Calderwood CJ, Thatcher TH, Jones MG, Smart DE, Mahajan S, Alzetani A, Havelock T, Maher TM, Molyneaux PL, Thorley AJ, Tetley TD, Warner JA, Packham G, Ganesan A, Skipp PJ, Marshall BJ, Richeldi L, Sime PJ, O'Reilly KMA, Davies DE, Conforti F, Davies ER, Calderwood CJ, Thatcher TH, Jones MG, Smart DE, Mahajan S, Alzetani A, Havelock T, Maher TM, Molyneaux PL, Thorley AJ, Tetley TD, Warner JA, Packham G, Ganesan A, Skipp PJ, Marshall BJ, Richeldi L, Sime PJ, O'Reilly KMA, Davies DE, Conforti F, Davies ER, Calderwood CJ, Thatcher TH, Jones MG, Smart DE, Mahajan S, Alzetani A, Havelock T, Maher TM, Molyneaux PL, Thorley AJ, Tetley TD, Warner JA, Packham G, Ganesan A, Skipp PJ, Marshall BJ, Richeldi L, Sime PJ, O'Reilly KMA, Davies DE, Conforti F, Davies ER, Calderwood CJ, Thatcher TH, Jones MG, Smart DE, Mahajan S, Alzetani A, Havelock T, Maher TM, Molyneaux PL, Thorley AJ, Tetley TD, Warner JA, Packham G, Ganesan A, Skipp PJ, Marshall BJ, Richeldi L, Sime PJ, OReilly KMA, Davies DE, Conforti F, Davies ER, Calderwood CJ, Thatcher TH, Jones MG, Smart DE, Mahajan S, Alzetani A, Havelock T, Maher TM, Molyneaux PL, Thorley AJ, Tetley TD, Warner JA, Packham G, Ganesan A, Skipp PJ, Marshall BJ, Richeldi L, Sime PJ, O'Reilly KMA, Davies DEet 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.

JOURNAL ARTICLE

Mohamed NA, Davies RP, Lickiss PD, Ahmetaj-Shala B, Reed DM, Gashaw HH, Saleem H, Freeman GR, George PM, Wort SJ, Morales-Cano D, Barreira B, Tetley TD, Chester AH, Yacoub MH, Kirkby NS, Moreno L, Mitchell JA, Mohamed NA, Davies RP, Lickiss PD, Ahmetaj-Shala B, Reed DM, Gashaw HH, Saleem H, Freeman GR, George PM, Wort SJ, Morales-Cano D, Barreira B, Tetley TD, Chester AH, Yacoub MH, Kirkby NS, Moreno L, Mitchell JA, Mohamed NA, Davies RP, Lickliss PD, Ahmetaj-Shala B, Reed DM, Gashaw HH, Saleem H, Freeman GR, George PM, Wort J, Morales-Cano D, Barreira B, Tetley TD, Chester AH, Yacoub M, Kirkby NS, Moreno L, Mitchell JA, Mohamed NA, Davies RP, Lickiss PD, Ahmetaj-Shala B, Reed DM, Gashaw HH, Saleem H, Freeman GR, George PM, Wort SJ, Morales-Cano D, Barreira B, Tetley TD, Chester AH, Yacoub MH, Kirkby NS, Moreno L, Mitchell JAet 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., Pulm Circ, Vol: 7, Pages: 2045893217710224-204589321771022, ISSN: 2045-8932

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.

JOURNAL ARTICLE

Robinson RK, Birrell MA, Adcock JJ, Wortley MA, Dubuis ED, Chen S, McGilvery CM, Hu S, Shaffer MSP, Bonvini SJ, Maher SA, Mudway IS, Porter AE, Carlsten C, Tetley TD, Belvisi MG, Robinson RK, Birrell MA, Adcock JJ, Wortley MA, Dubuis ED, Chen S, McGilvery CM, Hu S, Shaffer MSP, Bonvini SJ, Maher SA, Mudway IS, Porter AE, Carlsten C, Tetley TD, Belvisi MG, Robinson RK, Birrell MA, Adcock JJ, Wortley MA, Dubuis ED, Chen S, McGilvery CM, Hu S, Shaffer MSP, Bonvini SJ, Maher SA, Mudway IS, Porter AE, Carlsten C, Tetley TD, Belvisi MG, Robinson RK, Birrell MA, Adcock JJ, Wortley MA, Dubuis ED, Chen S, McGilvery CM, Hu S, Shaffer MSP, Bonvini SJ, Maher SA, Mudway IS, Porter AE, Carlsten C, Tetley TD, Belvisi MG, Robinson RK, Birrell MA, Adcock JJ, Wortley MA, Dubuis ED, Chen S, McGilvery CM, Hu S, Shaffer MSP, Bonvini SJ, Maher SA, Mudway IS, Porter AE, Carlsten C, Tetley TD, Belvisi MGet al., 2017, Mechanistic link between diesel exhaust particles and respiratory reflexes., J Allergy Clin Immunol, ISSN: 0091-6749

BACKGROUND: Diesel 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. OBJECTIVE: We sought to identify the mechanisms involved in activation of airway sensory afferents by DEPs. METHODS: In 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. RESULTS: We 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. CONCLUSIONS: This 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.

JOURNAL ARTICLE

Smyth E, Solomon A, Birrell MA, Smallwood MJ, Winyard PG, Tetley TD, Emerson M, Smyth E, Solomon A, Birrell MA, Smallwood MJ, Winyard PG, Tetley TD, Emerson M, Smyth E, Solomon A, Birrell MA, Smallwood MJ, Winyard PG, Tetley TD, Emerson M, Smyth E, Solomon A, Birrell MA, Smallwood MJ, Winyard PG, Tetley TD, Emerson M, Smyth E, Solomon A, Birrell MA, Smallwood MJ, Winyard PG, Tetley TD, Emerson M, Smyth E, Solomon A, Birrell MA, Smallwood MJ, Winyard PG, Tetley TD, Emerson Met 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.

JOURNAL ARTICLE

Thorley A, Ogger P, Legorburo-Schofield M, Tetley T, Wollin Let 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

CONFERENCE PAPER

Botelho DJ, Leo BF, Massa CB, Sarkar S, Tetley TD, Chung KF, Chen S, Ryan MP, Porter AE, Zhang J, Schwander SK, Gow AJ, Botelho DJ, Leo BF, Massa CB, Sarkar S, Tetley TD, Chung KF, Chen S, Ryan MP, Porter AE, Zhang J, Schwander SK, Gow AJ, Botelho DJ, Leo BF, Massa CB, Sarkar S, Tetley TD, Chung KF, Chen S, Ryan MP, Porter AE, Zhang J, Schwander SK, Gow AJ, Botelho DJ, Leo BF, Massa CB, Sarkar S, Tetley TD, Chung KF, Chen S, Ryan MP, Porter AE, Zhang J, Schwander SK, Gow AJ, Botelho DJ, Leo BF, Massa CB, Sarkar S, Tetley TD, Chung KF, Chen S, Ryan MP, Porter AE, Zhang J, Schwander SK, Gow AJet 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

Multiple studies have examined the direct cellular toxicity of silver nanoparticles (AgNPs). However, the lung is a complex biological system with multiple cell types and a lipid-rich surface fluid; therefore, organ level responses may not depend on direct cellular toxicity. We hypothesized that interaction with the lung lining is a critical determinant of organ level responses. Here, we have examined the effects of low dose intratracheal instillation of AgNPs (0.05 μg/g body weight) 20 and 110 nm diameter in size, and functionalized with citrate or polyvinylpyrrolidone. Both size and functionalization were significant factors in particle aggregation and lipid interaction in vitro. One day post-intratracheal instillation lung function was assessed, and bronchoalveolar lavage (BAL) and lung tissue collected. There were no signs of overt inflammation. There was no change in surfactant protein-B content in the BAL but there was loss of surfactant protein-D with polyvinylpyrrolidone (PVP)-stabilized particles. Mechanical impedance data demonstrated a significant increase in pulmonary elastance as compared to control, greatest with 110 nm PVP-stabilized particles. Seven days post-instillation of PVP-stabilized particles increased BAL cell counts, and reduced lung function was observed. These changes resolved by 21 days. Hence, AgNP-mediated alterations in the lung lining and mechanical function resolve by 21 days. Larger particles and PVP stabilization produce the largest disruptions. These studies demonstrate that low dose AgNPs elicit deficits in both mechanical and innate immune defense function, suggesting that organ level toxicity should be considered.

JOURNAL ARTICLE

Chen S, Goode AE, Skepper JN, Thorley AJ, Seiffert JM, Chung KF, Tetley TD, Shaffer MSP, Ryan MP, Porter AE, Chen S, Goode AE, Skepper JN, Thorley AJ, Seiffert JM, Chung KF, Tetley TD, Shaffer MSP, Ryan MP, Porter AE, Chen S, Goode AE, Skepper JN, Thorley AJ, Seiffert JM, Chung KF, Tetley TD, Shaffer MSP, Ryan MP, Porter AE, Chen S, Goode AE, Skepper JN, Thorley AJ, Seiffert JM, Chung KF, Tetley TD, Shaffer MSP, Ryan MP, Porter AE, Chen S, Goode AE, Skepper JN, Thorley AJ, Seiffert JM, Chung KF, Tetley TD, Shaffer MSP, Ryan MP, Porter AE, CHEN S, GOODE AE, SKEPPER JN, THORLEY AJ, SEIFFERT JM, CHUNG KF, TETLEY TD, SHAFFER MSP, RYAN MP, PORTER AE, Chen S, Goode AE, Skepper JN, Thorley AJ, Seiffert JM, Chung KF, Tetley TD, Shaffer MSP, Ryan MP, Porter AEet al., 2016, Avoiding artefacts during electron microscopy of silver nanomaterials exposed to biological environments, JOURNAL OF MICROSCOPY, Vol: 261, Pages: 157-166, ISSN: 0022-2720

Electron microscopy has been applied widely to study the interaction of nanomaterials with proteins, cells and tissues at nanometre scale. Biological material is most commonly embedded in thermoset resins to make it compatible with the high vacuum in the electron microscope. Room temperature sample preparation protocols developed over decades provide contrast by staining cell organelles, and aim to preserve the native cell structure. However, the effect of these complex protocols on the nanomaterials in the system is seldom considered. Any artefacts generated during sample preparation may ultimately interfere with the accurate prediction of the stability and reactivity of the nanomaterials. As a case study, we review steps in the room temperature preparation of cells exposed to silver nanomaterials (AgNMs) for transmission electron microscopy imaging and analysis. In particular, embedding and staining protocols, which can alter the physicochemical properties of AgNMs and introduce artefacts thereby leading to a misinterpretation of silver bioreactivity, are scrutinized. Recommendations are given for the application of cryogenic sample preparation protocols, which simultaneously fix both particles and diffusible ions. By being aware of the advantages and limitations of different sample preparation methods, compromises or selection of different correlative techniques can be made to draw more accurate conclusions about the data.

JOURNAL ARTICLE

Robinson RK, Birrell MA, Wortley MA, Dubuis ED, Chen S, McGilvery CM, Hu S, Bonvini SJ, Maher SA, Adcock JJ, Mudway I, Porter AE, Tetley TD, Belvisi MGet 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

CONFERENCE PAPER

Ruenraromgsak P, Chen S, Hu S, Melbourne J, Sweeney S, Thorley AJ, Skepper JN, Shaffer MSP, Tetley TD, Porter AE, Ruenraroengsak P, Chen S, Hu S, Melbourne J, Sweeney S, Thorley AJ, Skepper JN, Shaffer MSP, Tetley TD, Porter AE, Ruenraroengsak P, Chen S, Hu S, Melbourne J, Sweeney S, Thorley AJ, Skepper JN, Shaffer MSP, Tetley TD, Porter AE, Ruenraroengsak P, Chen S, Hu S, Melbourne J, Sweeney S, Thorley AJ, Skepper JN, Shaffer MSP, Tetley TD, Porter AE, Ruenraroengsak P, Chen S, Hu S, Melbourne J, Sweeney S, Thorley AJ, Skepper JN, Shaffer MSP, Tetley TD, Porter AE, Ruenraromgsak P, Chen S, Hu S, Melbourne J, Sweeney S, Thorley AJ, Skepper JN, Shaffer MSP, Tetley TD, Porter AEet 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.

JOURNAL ARTICLE

Sarkar S, Carranza C, Theodorou I, Fen LB, Ellis T, Porter A, Ryan M, Zhang J, Tetley T, Schwander S, Sarkar S, Carranza C, Theodorou I, Fen LB, Ellis T, Porter A, Ryan M, Zhang J, Tetley T, Schwander Set 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

CONFERENCE PAPER

Seiffert J, Buckley A, Leo B, Martin NG, Zhu J, Dai R, Hussain F, Guo C, Warren J, Hodgson A, Gong J, Ryan MP, Zhang JJ, Porter A, Tetley TD, Gow A, Smith R, Chung KF, Seiffert J, Buckley A, Leo B, Martin NG, Zhu J, Dai R, Hussain F, Guo C, Warren J, Hodgson A, Gong J, Ryan MP, Zhang JJ, Porter A, Tetley TD, Gow A, Smith R, Chung KF, Seiffert J, Buckley A, Leo B, Martin NG, Zhu J, Dai R, Hussain F, Guo C, Warren J, Hodgson A, Gong J, Ryan MP, Zhang JJ, Porter A, Tetley TD, Gow A, Smith R, Chung KF, Seiffert J, Buckley A, Leo B, Martin NG, Zhu J, Dai R, Hussain F, Guo C, Warren J, Hodgson A, Gong J, Ryan MP, Zhang JJ, Porter A, Tetley TD, Gow A, Smith R, Chung KF, Seiffert J, Buckley A, Leo B, Martin NG, Zhu J, Dai R, Hussain F, Guo C, Warren J, Hodgson A, Gong J, Ryan MP, Zhang J, Porter A, Tetley TD, Gow A, Smith R, Chung KF, Seiffert J, Buckley A, Leo B, Zhu J, Hussain F, Guo C, Warren J, Hodgson A, Gong J, Ryan M, Zhang J, Porter A, Tetley T, Gow A, Smith R, Dai R, Martin NG, Chung KFet 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

BACKGROUND: The increasing use of silver nanoparticles (AgNPs) in consumer products is concerning. We examined the potential toxic effects when inhaled in Brown-Norway (BN) rats with a pre-inflammatory state compared to Sprague-Dawley (SD) rats. METHODS: We determined the effect of AgNPs generated from a spark generator (mass concentration: 600-800 μg/mm(3); 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 after exposure and measurement of lung function. RESULTS: In both strains, there was an increase in neutrophils in bronchoalveolar lavage (BAL) fluid at 24 h at the high dose, with concomitant eosinophilia in BN rats. While BAL inflammatory cells were mostly normalised by Day 7, lung inflammation scores remained increased although not the tissue eosinophil scores. Total protein levels were elevated at both lung doses in both strains. There was an increase in BAL IL-1β, KC, IL-17, CCL2 and CCL3 levels in both strains at Day 1, mostly at high dose. Phospholipid levels were increased at the high dose in SD rats at Day 1 and 7, while in BN rats, this was only seen at Day 1; surfactant protein D levels decreased at day 7 at the high dose in SD rats, but was increased at Day 1 at the low dose in BN rats. There was a transient increase in central airway resistance and in tissue elastance in BN rats at Day 1 but not in SD rats. Positive silver-staining was seen particularly in lung tissue macrophages in a dose and time-dependent response in both strains, maximal by day 7. Lung silver levels were relatively higher in BN rat and present at day 7 in both strains. CONCLUSIONS: Presence of cellular inflammation and increasing silver-positive macrophages in lungs at day 7, associated with significant levels of lung silver indicate that lung toxicity is persistent even with the absence of airway luminal inflammation at that time-point. The high

JOURNAL ARTICLE

Serrano-Mollar A, Gay-Jordi G, Guillamat-Prats R, Closa D, Hernandez-Gonzalez F, Marin P, Burgos F, Martorell J, Sanchez M, Arguis P, Soy D, Bayas JM, Ramirez J, Tetley TD, Molins L, Puig de la Bellacasa J, Rodriguez-Villar C, Rovira I, Jose Fibla J, Xaubet A, Serrano-Mollar A, Gay-Jordi G, Guillamat-Prats R, Closa D, Hernandez-Gonzalez F, Marin P, Burgos F, Martorell J, Sánchez M, Arguis P, Soy D, Bayas JM, Ramirez J, Tetley TD, Molins L, de la Bellacasa JP, Rodríguez-Villar C, Rovira I, Fiblà JJ, Xaubet A, Pneumocyte Study Group, Serrano-Mollar A, Gay-Jordi G, Guillamat-Prats R, Closa D, Hernandez-Gonzalez F, Marin P, Burgos F, Martorell J, Sánchez M, Arguis P, Soy D, Bayas JM, Ramirez J, Tetley TD, Molins L, de la Bellacasa JP, Rodríguez-Villar C, Rovira I, Fiblà JJ, Xaubet A, Serrano-Mollar A, Gay-Jordi G, Guillamat-Prats R, Closa D, Hernandez-Gonzalez F, Marin P, Burgos F, Martorell J, Sánchez M, Arguis P, Soy D, Bayas JM, Ramirez J, Tetley TD, Molins L, de la Bellacasa JP, Rodríguez-Villar C, Rovira I, Fiblà JJ, Xaubet A, Pneumocyte Study Group, Serrano-Mollar A, Gay-Jordi G, Guillamat-Prats R, Closa D, Hernandez-Gonzalez F, Marin P, Burgos F, Martorell J, Sánchez M, Arguis P, Soy D, Bayas JM, Ramirez J, Tetley TD, Molins L, de la Bellacasa JP, Rodríguez-Villar C, Rovira I, Fiblà JJ, Xaubet A, Serrano-Mollar A, Gay-Jordi G, Guillamat-Prats R, Closa D, Hernandez-Gonzalez F, Marin P, Burgos F, Martorell J, Sánchez M, Arguis P, Soy D, Bayas JM, Ramirez J, Tetley TD, Molins L, de la Bellacasa JP, Rodríguez-Villar C, Rovira I, Fiblà JJ, Xaubet A, Pneumocyte Study Groupet 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.

JOURNAL ARTICLE

Sweeney S, Hu S, Ruenraroengsak P, Chen S, Gow A, Schwander S, Zhang JJ, Chung KF, Ryan MP, Porter AE, Shaffer MS, Tetley TD, Sweeney S, Hu S, Ruenraroengsak P, Chen S, Gow A, Schwander S, Zhang J, Chung KF, Ryan MP, Porter AE, Shaffer MS, Tetley TD, Sweeney S, Hu S, Ruenraroengsak P, Chen S, Gow A, Schwander S, Zhang JJ, Chung KF, Ryan MP, Porter AE, Shaffer MS, Tetley TDet 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

© The Royal Society of Chemistry 2016. 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 par

JOURNAL ARTICLE

Sweeney S, Leo BF, Chen S, Abraham-Thomas N, Thorley AJ, Gow A, Schwander S, Zhang JJ, Shaffer MSP, Chung KF, Ryan MP, Porter AE, Tetley TD, Sweeney S, Leo BF, Chen S, Abraham-Thomas N, Thorley AJ, Gow A, Schwander S, Zhang JJ, Shaffer MSP, Chung KF, Ryan MP, Porter AE, Tetley TD, Sweeney S, Leo BF, Chen S, Abraham-Thomas N, Thorley AJ, Gow A, Schwander S, Zhang JJ, Shaffer MSP, Chung KF, Ryan MP, Porter AE, Tetley TD, Sweeney S, Leo BF, Chen S, Abraham-Thomas N, Thorley AJ, Gow A, Schwander S, Zhang JJ, Shaffer MSP, Chung KF, Ryan MP, Porter AE, Tetley TD, Sweeney S, Leo BF, Chen S, Abraham-Thomas N, Thorley AJ, Gow A, Schwander S, Zhang JJ, Shaffer MSP, Chung KF, Ryan MP, Porter AE, Tetley TD, Sweeney S, Leo BF, Chen S, Abraham-Thomas N, Thorley AJ, Gow A, Schwander S, Zhang JJ, Shaffer MS, Chung KF, Ryan MP, Porter AE, Tetley TDet 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: 0927-7765

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.

JOURNAL ARTICLE

Theodorou IG, Ruenraroengsak P, Gow A, Schwander S, Zhang JJ, Chung KF, Tetley TD, Ryan MP, Porter AE, Theodorou IG, Ruenraroengsak P, Gow A, Schwander S, Zhang JJ, Chung KF, Tetley TD, Ryan MP, Porter AE, Theodorou IG, Ruenraroengsak P, Gow A, Schwander S, Zhang J, Chung KF, Tetley TD, Ryan MP, Porter AE, Theodorou IG, Ruenraroengsak P, Gow A, Schwander S, Zhang JJ, Chung KF, Tetley TD, Ryan MP, Porter AE, Theodorou IG, Ruenraroengsak P, Gow A, Schwander S, Zhang JJ, Chung KF, Tetley TD, Ryan MP, Porter AE, Theodorou IG, Ruenraroengsak P, Gow A, Schwander S, Zhang JJ, Chung KF, Tetley TD, Ryan MP, Porter AEet 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: 1743-5390

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.

JOURNAL ARTICLE

Zhang JJ, Lee K-B, He L, Seiffert J, Subramaniam P, Yang L, Chen S, Maguire P, Mainelis G, Schwander S, Tetley T, Porter A, Ryan M, Shaffer M, Hu S, Gong J, Chung KF, Zhang JJ, Lee K-B, He L, Seiffert J, Subramaniam P, Yang L, Chen S, Maguire P, Mainelis G, Schwander S, Tetley T, Porter A, Ryan M, Shaffer M, Hu S, Gong J, Chung KF, Zhang J, Lee KB, He L, Seiffert J, Subramaniam P, Yang L, Chen S, Maguire P, Mainelis G, Schwander S, Tetley T, Porter A, Ryan M, Shaffer M, Hu S, Gong J, Chung KF, Zhang JJ, Lee K-B, He L, Seiffert J, Subramaniam P, Yang L, Chen S, Maguire P, Mainelis G, Schwander S, Tetley T, Porter A, Ryan M, Shaffer M, Hu S, Gong J, Chung KF, Zhang JJ, Lee K-B, He L, Seiffert J, Subramaniam P, Yang L, Chen S, Maguire P, Mainelis G, Schwander S, Tetley T, Porter A, Ryan M, Shaffer M, Hu S, Gong J, Chung KF, Zhang JJ, Lee KB, He L, Seiffert J, Subramaniam P, Yang L, Chen S, Maguire P, Mainelis G, Schwander S, Tetley T, Porter A, Ryan M, Shaffer M, Hu S, Gong J, Chung KFet 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

JOURNAL ARTICLE

Botelho D, Shaffer M, Porter A, Chung KF, Tetley T, Zhang J, Gow Aet al., 2015, Lung Lining Interaction Determines the Fate of Multi-Walled Carbon Nanotubes (MWCNTs) in vivo, Experimental Biology Meeting, Publisher: FEDERATION AMER SOC EXP BIOL, ISSN: 0892-6638

CONFERENCE PAPER

Cryer AM, Ruenraroengsak P, Tetley TD, Thorley AJ, Cryer AM, Ruenraroengsak P, Tetley TD, Thorley AJet 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

CONFERENCE PAPER

Marchetti M, Shaffer MSP, Zambianchi M, Chen S, Superti F, Schwander S, Gow A, Zhang JJ, Chung KF, Ryan MP, Porter AE, Tetley TD, Marchetti M, Shaffer MSP, Zambianchi M, Chen S, Superti F, Schwander S, Gow A, Zhang JJ, Chung KF, Ryan MP, Porter AE, Tetley TD, Marchetti M, Shaffer MSP, Zambianchi M, Chen S, Superti F, Schwander S, Gow A, Zhang JJI, Chung KFA, Ryan MP, Porter AE, Tetley TD, Marchetti M, Shaffer MSP, Zambianchi M, Chen S, Superti F, Schwander S, Gow A, Zhang JJ, Chung KF, Ryan MP, Porter AE, Tetley TD, Marchetti M, Shaffer MSP, Zambianchi M, Chen S, Superti F, Schwander S, Gow A, Zhang JJ, Chung KF, Ryan MP, Porter AE, Tetley TD, Marchetti M, Shaffer MSP, Zambianchi M, Chen S, Superti F, Schwander S, Gow A, Zhang J, Chung KF, Ryan MP, Porter AE, Tetley TDet 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, Pages: 20140038-20140038, ISSN: 0962-8436

The alveolar respiratory unit constitutes one of the main targets of inhaled nanoparticles; the effect of engineered nanomaterials (NMs) on human health is largely unknown. Surfactant protein D (SP-D) is synthesized by alveolar type II epithelial cells and released into respiratory secretions; its main function is in immune defence, notably against inhaled microbes. SP-D also plays an important role in modulating an appropriate inflammatory response in the lung, and reduced SP-D is associated with a number of inflammatory lung diseases. Adsorption of SP-D to inhaled NMs may facilitate their removal via macrophage phagocytosis. This study addresses the hypothesis that the chemistry, size and surface modification of engineered NMs will impact on their interaction with, and adsorption of, SP-D. To this purpose, we have examined the interactions between SP-D in human lung lavage and two NMs, carbon nanotubes and polystyrene nanoparticles, with different surface functionalization. We have demonstrated that particle size, functionalization and concentration affect the adsorption of SP-D from human lung lavage. Functionalization with negatively charged groups enhanced the amount of SP-D binding. While SP-D binding would be expected to enhance macrophage phagocytosis, these results suggest that the degree of binding is markedly affected by the physicochemistry of the NM and that deposition of high levels of some nanoparticles within the alveolar unit might deplete SP-D levels and affect alveolar immune defence mechanisms.

JOURNAL ARTICLE

McKenzie Z, Kendall M, Mackay R-M, Tetley TD, Morgan C, Griffiths M, Clark HW, Madsen J, McKenzie Z, Kendall M, Mackay R-M, Tetley TD, Morgan C, Griffiths M, Clark HW, Madsen J, McKenzie Z, Kendall M, Mackay RM, Tetley TD, Morgan C, Griffiths M, Clark HW, Madsen J, McKenzie Z, Kendall M, Mackay RM, Tetley TD, Morgan C, Griffiths M, Clark HW, Madsen J, McKenzie Z, Kendall M, Mackay R-M, Tetley TD, Morgan C, Griffiths M, Clark HW, Madsen J, McKenzie Z, Kendall M, Mackay R-M, Tetley TD, Morgan C, Griffiths M, Clark HW, Madsen J, McKenzie Z, Kendall M, Mackay R-M, Tetley TD, Morgan C, Griffiths M, Clark HW, Madsen Jet al., 2015, Nanoparticles modulate surfactant protein A and D mediated protection against influenza A infection in vitro, PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 370, Pages: 20140049-20140049, ISSN: 0962-8436

Numerous epidemiological and toxicological studies have indicated that respiratory infections are exacerbated following enhanced exposure to airborne particulates. Surfactant protein A (SP-A) and SP-D form an important part of the innate immune response in the lung and can interact with nanoparticles to modulate the cellular uptake of these particles. We hypothesize that this interaction will also affect the ability of these proteins to combat infections. TT1, A549 and differentiated THP-1 cells, representing the predominant cell types found in the alveolus namely alveolar type I (ATI) epithelial cells, ATII cells and macrophages, were used to examine the effect of two model nanoparticles, 100 nm amine modified (A-PS) and unmodified polystyrene (U-PS), on the ability of SP-A and SP-D to neutralize influenza A infections in vitro. Pre-incubation of low concentrations of U-PS with SP-A resulted in a reduction of SP-A anti-influenza activity in A549 cells, whereas at higher concentrations there was an increase in SP-A antiviral activity. This differential pattern of U-PS concentration on surfactant protein mediated protection against IAV was also shown with SP-D in TT1 cells. On the other hand, low concentrations of A-PS particles resulted in a reduction of SP-A activity in TT1 cells and a reduction in SP-D activity in A549 cells. These results indicate that nanoparticles can modulate the ability of SP-A and SP-D to combat viral challenges. Furthermore, the nanoparticle concentration, surface chemistry and cell type under investigation are important factors in determining the extent of these modulations.

JOURNAL ARTICLE

Melbourne J, Clancy A, Seiffert J, Skepper J, Tetley TD, Shaffer MS, Porter A, Melbourne J, Clancy A, Seiffert J, Skepper J, Tetley TD, Shaffer MSP, Porter A, Melbourne J, Clancy A, Seiffert J, Skepper J, Tetley TD, Shaffer MSP, Porter A, Melbourne J, Clancy A, Seiffert J, Skepper J, Tetley TD, Shaffer MSP, Porter A, Melbourne J, Clancy A, Seiffert J, Skepper J, Tetley TD, Shaffer MSP, Porter A, Melbourne J, Clancy A, Seiffert J, Skepper J, Tetley TD, Shaffer MSP, Porter Aet 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.

JOURNAL ARTICLE

Mukherjee D, Porter A, Ryan M, Schwander S, Chung KF, Tetley T, Zhang J, Georgopoulos P, Mukherjee D, Porter A, Ryan M, Schwander S, Chung KF, Tetley T, Zhang J, Georgopoulos P, Mukherjee D, Porter A, Ryan M, Schwander S, Chung KF, Tetley T, Zhang J, Georgopoulos P, Mukherjee D, Porter A, Ryan M, Schwander S, Chung KF, Tetley T, Zhang J, Georgopoulos P, Mukherjee D, Porter A, Ryan M, Schwander S, Chung K, Tetley T, Zhang J, Georgopoulos P, Mukherjee D, Porter A, Ryan M, Schwander S, Chung KF, Tetley T, Zhang J, Georgopoulos Pet 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.

JOURNAL ARTICLE

Nyga A, Hart A, Tetley TD, Nyga A, Hart A, Tetley TD, Nyga A, Hart A, Tetley TD, Nyga A, Hart A, Tetley TD, Nyga A, Hart A, Tetley TDet al., 2015, Importance of the HIF pathway in cobalt nanoparticle-induced cytotoxicity and inflammation in human macrophages, NANOTOXICOLOGY, Vol: 9, Pages: 905-917, ISSN: 1743-5390

Recent, unexpected high failure rates of metal-on-metal hip implants have reintroduced the issue of cobalt toxicity. An adverse reaction to cobalt ions and cobalt-induced lung injury occurs during environmental exposure and is now strictly controlled. Currently adverse reaction occurs to cobalt nanoparticles during wear and tear of metal-on-metal hip implants of which the underlying mechanism is not fully understood. The putative role of the hypoxia-inducible factor (HIF) pathway in the mechanism of cobalt nanoparticle (Co-NPs) toxicity was examined using the U937 cell line, human alveolar macrophages and monocyte-derived macrophages. Co-NPs (5-20 μg/ml)-induced cytotoxicity (viability ranged from 75% to <20% of control, respectively) and reactive oxygen species (ROS), whereas a comparable concentration of cobalt ions (Co(II); up to 350 μM) did not. Co-NPs induced HIF-1α stabilization. Addition of ascorbic acid (100 µM) and glutathione (1 mM) both prevented the increased ROS. However, only treatment with ascorbic acid reduced HIF-1α levels and prevented cell death, indicating that a ROS-independent pathway is involved in Co-NPs-induced cytotoxicity. Replenishing intracellular ascorbate, which is crucial in preventing HIF pathway activation, modified Co-induced HIF target gene expression and the inflammatory response, by decreasing interleukin-1 beta (IL-1β) mRNA and protein expression. Addition of glutathione had no effect on Co-NPs-induced HIF target gene expression or inflammatory response. Thus, Co-NPs induce the HIF pathway by depleting intracellular ascorbate, leading to HIF stabilization and pathway activation. This suggests a strong, ROS-independent role for HIF activation in Co-NPs-induced cytotoxicity and a possible role for HIF in metal-on-metal hip implant pathology.

JOURNAL ARTICLE

Ruenraroengsak P, Tetley TD, Ruenraroengsak P, Tetley TD, Ruenraroengsak P, Tetley TD, Ruenraroengsak P, Tetley TD, Ruenraroengsak P, Tetley TD, Tetley TD, Ruenraroengsak Pet al., 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

BACKGROUND: Engineered 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. METHODS: Amine- (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). RESULTS: ANP-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. CONCLUSION: ANP induced marked oxidative d

JOURNAL ARTICLE

Sarkar S, Leo BF, Carranza C, Chen S, Rivas-Santiago C, Porter AE, Ryan MP, Gow A, Chung KF, Tetley TD, Zhang JJ, Georgopoulos PG, Ohman-Strickland PA, Schwander S, Sarkar S, Leo BF, Carranza C, Chen S, Rivas-Santiago C, Porter AE, Ryan MP, Gow A, Chung KF, Tetley TD, Zhang JJ, Georgopoulos PG, Ohman-Strickland PA, Schwander S, Sarkar S, Leo BF, Carranza C, Chen S, Rivas-Santiago C, Porter AE, Ryan MP, Gow A, Chung KF, Tetley TD, Zhang JJ, Georgopoulos PG, Ohman-Strickland PA, Schwander S, Sarkar S, Leo BF, Carranza C, Chen S, Rivas-Santiago C, Porter AE, Ryan MP, Gow A, Chung KF, Tetley TD, Zhang JJ, Georgopoulos PG, Ohman-Strickland PA, Schwander S, Sarkar S, Leo BF, Carranza C, Chen S, Rivas-Santiago C, Porter AE, Ryan MP, Gow A, Chung KF, Tetley TD, Zhang JJ, Georgopoulos PG, Ohman-Strickland PA, Schwander S, Sarkar S, Leo BF, Carranza C, Chen S, Rivas-Santiago C, Porter AE, Ryan MP, Gow A, Chung KF, Tetley TD, Zhang JJ, Georgopoulos PG, Ohman-Strickland PA, Schwander Set al., 2015, Modulation of Human Macrophage Responses to Mycobacterium tuberculosis by Silver Nanoparticles of Different Size and Surface Modification, PLOS ONE, Vol: 10, Pages: e0143077-e0143077, 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.

JOURNAL ARTICLE

Seiffert J, Hussain F, Wiegman C, Li F, Bey L, Baker W, Porter A, Ryan MP, Chang Y, Gow A, Zhang J, Zhu J, Tetley TD, Chung KF, Seiffert J, Hussain F, Wiegman C, Li F, Bey L, Baker W, Porter A, Ryan MP, Chang Y, Gow A, Zhang J, Zhu J, Tetley TD, Chung KF, Seiffert J, Hussain F, Wiegman C, Li F, Bey L, Baker W, Porter A, Ryan MP, Chang Y, Gow A, Zhang J, Zhu J, Tetley TD, Chung KF, Seiffert J, Hussain F, Wiegman C, Li F, Bey L, Baker W, Porter A, Ryan MP, Chang Y, Gow A, Zhang J, Zhu J, Tetley TD, Chung KF, Seiffert J, Hussain F, Wiegman C, Li F, Bey L, Baker W, Porter A, Ryan MP, Chang Y, Gow A, Zhang J, Zhu J, Tetley TD, Chung KFet al., 2015, Pulmonary Toxicity of Instilled Silver Nanoparticles: Influence of Size, Coating and Rat Strain, PLOS ONE, Vol: 10, Pages: e0119726-e0119726, ISSN: 1932-6203

Particle size and surface chemistry are potential determinants of silver nanoparticle (AgNP) respiratory toxicity that may also depend on the lung inflammatory state. We compared the effects of intratracheally-administered AgNPs (20 nm and 110 nm; polyvinylpyrrolidone (PVP) and citrate-capped; 0.1 mg/Kg) in Brown-Norway (BN) and Sprague-Dawley (SD) rats. In BN rats, there was both a neutrophilic and eosinophilic response, while in SD rats, there was a neutrophilic response at day 1, greatest for the 20 nm citrate-capped AgNPs. Eosinophilic cationic protein was increased in bronchoalveolar lavage (BAL) in BN and SD rats on day 1. BAL protein and malondialdehyde levels were increased in BN rats at 1 and 7 days, and BAL KC, CCL11 and IL-13 levels at day 1, with increased expression of CCL11 in lung tissue. Pulmonary resistance increased and compliance decreased at day 1, with persistence at day 7. The 20 nm, but not the 110 nm, AgNPs increased bronchial hyperresponsiveness on day 1, which continued at day 7 for the citrate-capped AgNPs only. The 20 nm versus the 110 nm size were more proinflammatory in terms of neutrophil influx, but there was little difference between the citrate-capped versus the PVP-capped AgNPs. AgNPs can induce pulmonary eosinophilic and neutrophilic inflammation with bronchial hyperresponsiveness, features characteristic of asthma.

JOURNAL ARTICLE

Smyth E, Solomon A, Vydyanath A, Luther PK, Pitchford S, Tetley TD, Emerson M, Smyth E, Solomon A, Vydyanath A, Luther PK, Pitchford S, Tetley TD, Emerson M, Smyth E, Solomon A, Vydyanath A, Luther PK, Pitchford S, Tetley TD, Emerson M, Smyth E, Solomon A, Vydyanath A, Luther PK, Pitchford S, Tetley TD, Emerson M, Smyth E, Solomon A, Vydyanath A, Luther PK, Pitchford S, Tetley TD, Emerson M, Smyth E, Solomon A, Vydyanath A, Luther PK, Pitchford S, Tetley TD, Emerson Met al., 2015, Induction and enhancement of platelet aggregation in vitro and in vivo by model polystyrene nanoparticles, NANOTOXICOLOGY, Vol: 9, Pages: 356-364, ISSN: 1743-5390

Nanoparticles (NPs) may come into contact with circulating blood elements including platelets following inhalation and translocation from the airways to the bloodstream or during proposed medical applications. Studies with model polystyrene latex nanoparticles (PLNPs) have shown that NPs are able to induce platelet aggregation in vitro suggesting a poorly defined potential mechanism of increased cardiovascular risk upon NP exposure. We aimed to provide insight into the mechanisms by which NPs may increase cardiovascular risk by determining the impact of a range of concentrations of PLNPs on platelet activation in vitro and in vivo and identifying the signaling events driving NP-induced aggregation. Model PLNPs of varying nano-size (50 and 100 nm) and surface chemistry [unmodified (uPLNP), amine-modified (aPLNP) and carboxyl-modified (cPLNP)] were therefore examined using in vitro platelet aggregometry and an established mouse model of platelet thromboembolism. Most PLNPs tested induced GPIIb/IIIa-mediated platelet aggregation with potencies that varied with both surface chemistry and nano-size. Aggregation was associated with signaling events, such as granule secretion and release of secondary agonists, indicative of conventional agonist-mediated aggregation. Platelet aggregation was associated with the physical interaction of PLNPs with the platelet membrane or internalization. 50 nm aPLNPs acted through a distinct mechanism involving the physical bridging of adjacent non-activated platelets leading to enhanced agonist-induced aggregation in vitro and in vivo. Our study suggests that should they translocate the pulmonary epithelium, or be introduced into the blood, NPs may increase the risk of platelet-driven events by inducing or enhancing platelet aggregation via mechanisms that are determined by their distinct combination of nano-size and surface chemistry.

JOURNAL ARTICLE

Sweeney S, Berhanu D, Ruenraroengsak P, Thorley AJ, Valsami-Jones E, Tetley TD, Sweeney S, Berhanu D, Ruenraroengsak P, Thorley AJ, Valsami-Jones E, Tetley TD, Sweeney S, Berhanu D, Ruenraroengsak P, Thorley AJ, Valsami-Jones E, Tetley TD, Sweeney S, Berhanu D, Ruenraroengsak P, Thorley AJ, Valsami-Jones E, Tetley TD, Sweeney S, Berhanu D, Ruenraroengsak P, Thorley AJ, Valsami-Jones E, Tetley TDet al., 2015, Nano-titanium dioxide bioreactivity with human alveolar type-I-like epithelial cells: Investigating crystalline phase as a critical determinant, NANOTOXICOLOGY, Vol: 9, Pages: 482-492, ISSN: 1743-5390

There can be significant variability between bioreactivity studies of nanomaterials that are apparently the same, possibly reflecting differences in the models used and differing sources of experimental material. In this study, we have generated two crystal forms of titanium dioxide nanoparticles (nano-TiO2), pure anatase and pure rutile to address the hypothesis that the bioreactivity of these nanoparticles with human alveolar epithelium will depend on their crystal phase. We used a human alveolar type-I-like epithelial cell model (TT1; generated in-house from primary human alveolar epithelial type II cells); these cells cover 95% of the alveolar epithelial surface area and are an important target cell for inhaled nanomaterials. Using literature as a guide, we hypothesised that pure anatase nano-TiO2 would display greater bioreactivity with TT1 cells in comparison to pure rutile nano-TiO2. However, we found the profile and pattern of inflammatory mediator release was similar between these two nano-TiO2 formats, although pure rutile treatment caused a small, but consistently greater, response for IL-6, IL-8 and MCP-1. Interestingly, the temporal induction of oxidative stress (increased reactive oxygen species levels and depleted glutathione) varied markedly between the different nano-TiO2 formats. We have shown that a combination of using nanomaterials synthesised specifically for toxicological study and the use of a highly relevant, reproducible human lung cell model, offers a useful approach to delineating the physicochemical properties of nanomaterials that may be important in their cellular reactivity.

JOURNAL ARTICLE

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

Request URL: http://wlsprd.imperial.ac.uk:80/respub/WEB-INF/jsp/search-html.jsp Request URI: /respub/WEB-INF/jsp/search-html.jsp Query String: respub-action=search.html&id=00165381&limit=30&person=true