205 results found
Guinart A, Perry HL, Wilton-Ely JDET, et al., 2020, Gold nanomaterials in the management of lung cancer, Emerging Topics in Life Sciences, Vol: 4, Pages: 627-643, ISSN: 2397-8554
Lung cancer (LC) is one of the most deadly cancers worldwide, with very low survival rates, mainly due to poor management, which has barely changed in recent years. Nanomedicines, especially gold nanomaterials, with their unique and size-dependent properties offer a potential solution to many challenges in the field. The versatility afforded by the shape, size, charge and surface chemistry of gold nanostructures allows them to be adapted for many applications in the diagnosis, treatment and imaging of LC. In this review, a survey of the most recent advances in the field is presented with an emphasis on the optical properties of gold nanoscale materials and their use in cancer management. Gold nanoparticle toxicology has also been a focus of interest for many years but the studies have also sometimes arrived at contradictory conclusions. To enable extrapolation and facilitate the development of medicines based on gold nanomaterials, it must be assumed that each design will have its own unique characteristics that require evaluation before translation to the clinic. Advances in the understanding and recognition of the molecular signatures of LC have aided the development of personalised medicines. Tailoring the treatment to each case should, ideally increase the survival outcomes as well as reduce medical costs. This review seeks to present the potential of gold nanomaterials in LC management and to provide a unified view, which will be of interest to those in the field as well as researchers considering entering this highly important area of research.
Michaeloudes C, Seiffert J, Chen S, et al., 2020, Effect of silver nanospheres and nanowires on human airway smooth muscle cells: role of sulfidation, NANOSCALE ADVANCES, Vol: 2, Pages: 5635-5647, ISSN: 2516-0230
Contera S, de la Serna JB, Tetley TD, 2020, Biotechnology, nanotechnology and medicine, Emerging Topics in Life Sciences, Vol: 4, Pages: 551-554, ISSN: 2397-8554
The 1980s mark the starting point of nanotechnology: the capacity to synthesise, manipulate and visualise matter at the nanometre scale. New powers to reach the nanoscale brought us the unprecedented possibility to directly target at the scale of biomolecular interactions, and the motivation to create smart nanostructures that could circumvent the hurdles hindering the success of traditional pharmacological approaches. Forty years on, the progressive integration of bio- and nanotechnologies is starting to produce a transformation of the way we detect, treat and monitor diseases and unresolved medical problems [ 1]. While much of the work remains in research laboratories, the first nano-based treatments, vaccines, drugs, and diagnostic devices, are now receiving approval for commercialisation and clinical use. In this special issue we review recent advances of nanomedical approaches to combat antibiotic resistance, treatment and detection of cancers, targeting neurodegerative diseases, and applications as diverse as dentistry and the treatment of tuberculosis. We also examine the use of advanced smart nanostructured materials in areas such as regenerative medicine, and the controlled release of drugs and treatments. The latter is currently poised to bring ground-breaking changes in immunotherapy: the advent of ‘vaccine implants’ that continuously control and improve immune responses over time. With the increasingly likely prospect of ending the COVID 19 pandemic with the aid of a nanomedicine-based vaccine (both Moderna and BioNTech/Pfizer vaccines are based on lipid nanoparticle formulations), we are witnessing the coming of age of nanomedicine. This makes it more important than ever to concentrate on safety: in parallel to pursuing the benefits of nanomedine, we must strengthen the continuous focus on nanotoxicology and safety regulation of nanomedicines that can deliver the medical revolution that is within our grasp.
Alzahabi KH, Usmani O, Georgiou TK, et al., 2020, Approaches to treating tuberculosis by encapsulating metal ions and anti-mycobacterial drugs utilizing nano- and microparticle technologies, EMERGING TOPICS IN LIFE SCIENCES, Vol: 4, Pages: 581-600, ISSN: 2397-8554
Katsumiti A, Ruenraroengsak P, Cajaraville MP, et al., 2020, Immortalisation of primary human alveolar epithelial cells using a non-viral vector to study respiratory bioreactivity in vitro, Scientific Reports, Vol: 10, ISSN: 2045-2322
To overcome the scarcity of primary human alveolar epithelial cells for lung research, and the limitations of current cell lines to recapitulate the phenotype, functional and molecular characteristics of the healthy human alveolar epithelium, we have developed a new method to immortalise primary human alveolar epithelial lung cells using a non-viral vector to transfect the telomerase catalytic subunit (hTERT) and the simian virus 40 large-tumour antigen (SV40). Twelve strains of immortalised cells (ICs) were generated and characterised using molecular, immunochemical and morphological techniques. Cell proliferation and sensitivity to polystyrene nanoparticles (PS) were evaluated. ICs expressed caveolin-1, podoplanin and receptor for advanced glycation end-products (RAGE), and most cells were negative for alkaline phosphatase staining, indicating characteristics of AT1-like cells. However, most strains also contained some cells that expressed pro-surfactant protein C, classically described to be expressed only by AT2 cells. Thus, the ICs mimic the cellular heterogeneity in the human alveolar epithelium. These ICs can be passaged, replicate rapidly and remain confluent beyond 15 days. ICs showed differential sensitivity to positive and negatively charged PS nanoparticles, illustrating their potential value as an in vitro model to study respiratory bioreactivity. These novel ICs offer a unique resource to study human alveolar epithelial biology.
Enlo-Scott Z, Akhuemokhan P, Tetley TD, et al., 2020, COMPARISON OF THE PARALLEL ARTIFICIAL MEMBRANE PERMEABILITY ASSAY (PAMPA) TO HUMAN RESPIRATORY EPITHELIAL CELL LINES FOR THE ESTIMATION OF XENOBIOTIC PERMEABILITY IN THE RESPIRATORY TRACT, Publisher: MARY ANN LIEBERT, INC, Pages: A14-A14, ISSN: 1941-2711
van Riet S, Ninaber DK, Mikkers HMM, et al., 2020, In vitro modelling of alveolar repair at the air-liquid interface using alveolar epithelial cells derived from human induced pluripotent stem cells, Scientific Reports, Vol: 10, ISSN: 2045-2322
Research on acute and chronic lung diseases would greatly benefit from reproducible availability of alveolar epithelial cells (AEC). Primary alveolar epithelial cells can be derived from human lung tissue but the quality of these cells is highly donor dependent. Here, we demonstrated that culture of EpCAM+ cells derived from human induced pluripotent stem cells (hiPSC) at the physiological air-liquid interface (ALI) resulted in type 2 AEC-like cells (iAEC2) with alveolar characteristics. iAEC2 cells expressed native AEC2 markers (surfactant proteins and LPCAT-1) and contained lamellar bodies. ALI-iAEC2 were used to study alveolar repair over a period of 2 weeks following mechanical wounding of the cultures and the responses were compared with those obtained using primary AEC2 (pAEC2) isolated from resected lung tissue. Addition of the Wnt/β-catenin activator CHIR99021 reduced wound closure in the iAEC2 cultures but not pAEC2 cultures. This was accompanied by decreased surfactant protein expression and accumulation of podoplanin-positive cells at the wound edge. These results demonstrated the feasibility of studying alveolar repair using hiPSC-AEC2 cultured at the ALI and indicated that this model can be used in the future to study modulation of alveolar repair by (pharmaceutical) compounds.
Meldrum K, Robertson S, Romer I, et al., 2020, Diesel exhaust particle and dust mite induced airway inflammation is modified by cerium dioxide nanoparticles, ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY, Vol: 73, ISSN: 1382-6689
Hiemstra PS, Tetley TD, Janes SM, 2019, Airway and alveolar epithelial cells in culture, EUROPEAN RESPIRATORY JOURNAL, Vol: 54, ISSN: 0903-1936
Nyga A, Hart A, Tetley TD, 2019, Molecular analysis of HIF activation as a potential biomarker for adverse reaction to metal debris (ARMD) in tissue and blood samples, JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS, Vol: 107, Pages: 1352-1362, ISSN: 1552-4973
Cryer AM, Chan C, Eftychidou A, et al., 2019, Tyrosine kinase inhibitor gold nanoconjugates for the treatment of non-small cell lung cancer, ACS Applied Materials and Interfaces, Vol: 11, Pages: 16336-16346, ISSN: 1944-8244
Gold nanoparticles (AuNPs) have emerged as promising drug delivery candidates that can be leveraged for cancer therapy. Lung cancer (LC) is a heterogeneous disease that imposes a significant burden on society, with an unmet need for new therapies. Chemotherapeutic drugs such as afatinib (Afb), which is clinically approved for the treatment of epidermal growth factor receptor positive LC, is hydrophobic and has low bioavailability leading to spread around the body, causing severe side effects. Herein, we present a novel afatinib-AuNP formulation termed Afb-AuNPs, with the aim of improving drug efficacy and biocompatibility. This was achieved by synthesis of an alkyne-bearing Afb derivative and reaction with azide functionalized lipoic acid using copper catalyzed click chemistry, then conjugation to AuNPs via alkylthiol-gold bond formation. The Afb-AuNPs were found to possess up to 3.7-fold increased potency when administered to LC cells in vitro and were capable of significantly inhibiting cancer cell proliferation, as assessed by MTT assay and electric cell-substrate impedance sensing respectively. Furthermore, when exposed to Afb-AuNPs, human alveolar epithelial type I-like cells, a model of the healthy lung epithelium, maintained viability and were found to release less pro-inflammatory cytokines when compared to free drug, demonstrating the biocompatibility of our formulation. This study provides a new platform for the development of non-traditional AuNP conjugates which can be applied to other molecules of therapeutic or diagnostic utility, with potential to be combined with photothermal therapy in other cancers.
Diez MM, Buckley A, Tetley TD, et al., 2019, The method of depositing CeO2 nanoparticles onto a DPPC monolayer affects surface tension behaviour, NANOIMPACT, Vol: 16, ISSN: 2452-0748
Moore AJS, Dean LSN, Fraceto LF, et al., 2018, THE EFFECTS OF A NOVEL POLY(EPSILON-CAPROLACTONE) NANOCAPSULE CONTAINING THE PESTICIDE ATRAZINE ON HUMAN ALVEOLAR EPITHELIUM, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A20-A21, ISSN: 0040-6376
Meldrum K, Robertson SB, Gant TW, et al., 2018, Transcriptional changes underlying cerium dioxide nanoparticle modulation of allergen induced type II airway inflammation, 54th Congress of the European-Societies-of-Toxicology (EUROTOX) - Toxicology Out of the Box, Publisher: ELSEVIER IRELAND LTD, Pages: S213-S213, ISSN: 0378-4274
Bolaji JA, Adcock JJ, Sandstrom T, et al., 2018, Biodiesel: is it any safer to use?, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Ellis T, Chiappi M, García-Trenco A, et al., 2018, Multimetallic microparticles increase the potency of rifampicin against intracellular mycobacterium tuberculosis, ACS Nano, Vol: 12, Pages: 5228-5240, ISSN: 1936-0851
Mycobacterium tuberculosis ( M.tb) has the extraordinary ability to adapt to the administration of antibiotics through the development of resistance mechanisms. By rapidly exporting drugs from within the cytosol, these pathogenic bacteria diminish antibiotic potency and drive the presentation of drug-tolerant tuberculosis (TB). The membrane integrity of M.tb is pivotal in retaining these drug-resistant traits. Silver (Ag) and zinc oxide (ZnO) nanoparticles (NPs) are established antimicrobial agents that effectively compromise membrane stability, giving rise to increased bacterial permeability to antibiotics. In this work, biodegradable multimetallic microparticles (MMPs), containing Ag NPs and ZnO NPs, were developed for use in pulmonary delivery of antituberculous drugs to the endosomal system of M.tb-infected macrophages. Efficient uptake of MMPs by M.tb-infected THP1 cells was demonstrated using an in vitro macrophage infection model, with direct interaction between MMPs and M.tb visualized with the use of electron FIB-SEM tomography. The release of Ag NPs and ZnO NPs within the macrophage endosomal system increased the potency of the model antibiotic rifampicin by as much as 76%, realized through an increase in membrane disorder of intracellular M.tb. MMPs were effective at independently driving membrane destruction of extracellular bacilli located at the exterior face of THP1 macrophages. This MMP system presents as an effective drug delivery vehicle that could be used for the transport of antituberculous drugs such as rifampicin to infected alveolar macrophages, while increasing drug potency. By increasing M.tb membrane permeability, such a system may prove effectual in improving treatment of drug-susceptible TB in addition to M.tb strains considered drug-resistant.
Meldrum K, Robertson SB, Roemer I, et al., 2018, Cerium dioxide nanoparticles exacerbate house dust mite induced type II airway inflammation, PARTICLE AND FIBRE TOXICOLOGY, Vol: 15, ISSN: 1743-8977
BackgroundNanomaterial inhalation represents a potential hazard for respiratory conditions such as asthma. Cerium dioxide nanoparticles (CeO2NPs) have the ability to modify disease outcome but have not been investigated for their effect on models of asthma and inflammatory lung disease. The aim of this study was to examine the impact of CeO2NPs in a house dust mite (HDM) induced murine model of asthma.ResultsRepeated intranasal instillation of CeO2NPs in the presence of HDM caused the induction of a type II inflammatory response, characterised by increased bronchoalveolar lavage eosinophils, mast cells, total plasma IgE and goblet cell metaplasia. This was accompanied by increases in IL-4, CCL11 and MCPT1 gene expression together with increases in the mucin and inflammatory regulators CLCA1 and SLC26A4. CLCA1 and SLC26A4 were also induced by CeO2NPs + HDM co-exposure in air liquid interface cultures of human primary bronchial epithelial cells. HDM induced airway hyperresponsiveness and airway remodelling in mice were not altered with CeO2NPs co-exposure. Repeated HMD instillations followed by a single exposure to CeO2NPs failed to produce changes in type II inflammatory endpoints but did result in alterations in the neutrophil marker CD177. Treatment of mice with CeO2NPs in the absence of HDM did not have any significant effects. RNA-SEQ was used to explore early effects 24 h after single treatment exposures. Changes in SAA3 expression paralleled increased neutrophil BAL levels, while no changes in eosinophil or lymphocyte levels were observed. HDM resulted in a strong induction of type I interferon and IRF3 dependent gene expression, which was inhibited with CeO2NPs co-exposure. Changes in the expression of genes including CCL20, CXCL10, NLRC5, IRF7 and CLEC10A suggest regulation of dendritic cells, macrophage functionality and IRF3 modulation as key early events in how CeO2NPs may guide pulmonary responses to HDM towards type II inflammation.Conclusi
Cui X, Gong J, Han H, et al., 2018, Relationship between free and total malondialdehyde, a well-established marker of oxidative stress, in various types of human biospecimens, JOURNAL OF THORACIC DISEASE, Vol: 10, Pages: 3088-+, ISSN: 2072-1439
Jarvis IWH, Enlo-Scott Z, Nagy E, et al., 2018, Genotoxicity of fine and coarse fraction ambient particulate matter in immortalised normal (TT1) and cancer-derived (A549) alveolar epithelial cells, ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Vol: 59, Pages: 290-301, ISSN: 0893-6692
Katsumiti A, Thorley AJ, Arostegui I, et al., 2018, Cytotoxicity and cellular mechanisms of toxicity of CuO NPs in mussel cells in vitro and comparative sensitivity with human cells, TOXICOLOGY IN VITRO, Vol: 48, Pages: 146-158, ISSN: 0887-2333
There is a need to assess human and ecosystem health effects of copper oxide nanoparticles (CuO NPs), extensively used in many industrial products. Here, we aimed to determine the cytotoxicity and cellular mechanisms involved in the toxicity of CuO NPs in mussel cells (hemocytes and gill cells) in parallel with exposures to ionic Cu and bulk CuO, and to compare the sensitivity of mussel primary cells with a well-established human cell line (pulmonary TT1 cells). At similar doses, CuO NPs promoted dose-dependent cytotoxicity and increased reactive oxygen species (ROS) production in mussel and human cells. In mussel cells, ionic Cu was more toxic than CuO NPs and the latter more than bulk CuO. Ionic Cu and CuO NPs increased catalase and acid phosphatase activities in both mussel cells and decreased gill cells Na-K-ATPase activity. All Cu forms produced DNA damage in hemocytes, whereas in gill cells only ionic Cu and CuO NPs were genotoxic. Induction of the MXR transport activity was found in gill cells exposed to all forms of Cu and in hemocytes exposed to ionic Cu and CuO NPs. Phagocytosis increased only in hemocytes exposed to CuO NPs, indicating a nanoparticle-specific immunostimulatory effect. In conclusion, toxicity of CuO NPs is driven by ROS in human and mussel cells. Mussel cells respond to CuO NP exposure by triggering an array of defensive mechanisms.
Botelho D, Leo BF, Massa C, et al., 2018, Exposure to silver nanospheres leads to altered respiratory mechanics and delayed immune response in an in vivo Murine model, Frontiers in Pharmacology, Vol: 9, ISSN: 1663-9812
Here we examine the organ level toxicology of both carbon black (CB) and silver nanoparticles (AgNP). We aim to determine metal-specific effects to respiratory function, inflammation and potential interactions with lung lining fluid (LLF). C57Bl6/J male mice were intratracheally instilled with saline (control), low (0.05 μg/g) or high (0.5 μg/g) doses of either AgNP or CB 15 nm nanospheres. Lung histology, cytology, surfactant composition and function, inflammatory gene expression, and pulmonary function were measured at 1, 3, and 7 days post-exposure. Acutely, high dose CB resulted in an inflammatory response, increased neutrophilia and cytokine production, without alteration in surfactant composition or respiratory mechanics. Low dose CB had no effect. Neither low nor high dose AgNPs resulted in an acute inflammatory response, but there was an increase in work of breathing. Three days post-exposure with CB, a persistent neutrophilia was noted. High dose AgNP resulted in an elevated number of macrophages and invasion of lymphocytes. Additionally, AgNP treated mice displayed increased expression of IL1B, IL6, CCL2, and IL10. However, there were no significant changes in respiratory mechanics. At day 7, inflammation had resolved in AgNP-treated mice, but tissue stiffness and resistance were significantly decreased, which was accompanied by an increase in surfactant protein D (SP-D) content. These data demonstrate that the presence of metal alters the response of the lung to nanoparticle exposure. AgNP-surfactant interactions may alter respiratory function and result in a delayed immune response, potentially due to modified airway epithelial cell function.
Smyth E, Solomon A, Birrell MA, et al., 2017, Effects of diesel exhaust particles on coagulation., British Journal of Pharmacology, Vol: 174, Pages: 4200-4200, ISSN: 1476-5381
Katsumiti A, Ruenraroengsak P, Cajaraville MP, et al., 2017, Immortalisation of human alveolar epithelial cells to investigate the mechanistic effects of inhaled airborne materials in vitro, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Dean L, Chen S, Shaffer M, et al., 2017, Effect of surface functionalisation on the interaction of carbon nanotubes with primary human alveolar cells in vitro, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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
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.
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