The bronchial epithelium is continuously exposed to a multitude of noxious challenges in inhaled air. Cellular contact with most damaging agents is reduced by the action of the mucociliary apparatus ...and by formation of a physical barrier that controls passage of ions and macromolecules. In conjunction with these defensive barrier functions, immunomodulatory cross-talk between the bronchial epithelium and tissue-resident immune cells controls the tissue microenvironment and barrier homeostasis. This is achieved by expression of an array of sensors that detect a wide variety of viral, bacterial, and nonmicrobial (toxins and irritants) agents, resulting in production of many different soluble and cell-surface molecules that signal to cells of the immune system. The ability of the bronchial epithelium to control the balance of inhibitory and activating signals is essential for orchestrating appropriate inflammatory and immune responses and for temporally modulating these responses to limit tissue injury and control the resolution of inflammation during tissue repair. In asthmatic patients abnormalities in many aspects of epithelial barrier function have been identified. We postulate that such abnormalities play a causal role in immune dysregulation in the airways by translating gene-environment interactions that underpin disease pathogenesis and exacerbation.
Exposure to ambient airborne particulate matter is a major risk factor for mortality and morbidity, associated with asthma, lung cancer, heart disease, myocardial infarction, and stroke, and more ...recently type 2 diabetes, dementia and loss of cognitive function. Less is understood about differential effects of particulate matter from different sources. Underground railways are used by millions of people on a daily basis in many cities. Poor air exchange with the outside environment means that underground railways often have an unusually high concentration of airborne particulate matter, while a high degree of railway-associated mechanical activity produces particulate matter which is physicochemically highly distinct from ambient particulate matter. The implications of this for the health of exposed commuters and employees is unclear.
A literature search found 27 publications directly assessing the potential health effects of underground particulate matter, including in vivo exposure studies, in vitro toxicology studies, and studies of particulate matter which might be similar to that found in underground railways. The methodology, findings, and conclusions of these studies were reviewed in depth, along with further publications directly relevant to the initial search results. In vitro studies suggest that underground particulate matter may be more toxic than exposure to ambient/urban particulate matter, especially in terms of endpoints related to reactive oxygen species generation and oxidative stress. This appears to be predominantly a result of the metal-rich nature of underground particulate matter, which is suggestive of increased health risks. However, while there are measureable effects on a variety of endpoints following exposure in vivo, there is a lack of evidence for these effects being clinically significant as may be implied by the in vitro evidence.
There is little direct evidence that underground railway particulate matter exposure is more harmful than ambient particulate matter exposure. This may be due to disparities between in vivo exposures and in vitro models, and differences in exposure doses, as well as statistical under powering of in vivo studies of chronic exposure. Future research should focus on outcomes of chronic in vivo exposure, as well as further work to understand mechanisms and potential biomarkers of exposure.
Airborne particulate matter (PM) is a leading driver of premature mortality and cardiopulmonary morbidity, associated with exacerbations of asthma and chronic obstructive pulmonary disease, ...idiopathic pulmonary fibrosis, and lung cancer. The airway epithelium, as the principal site of PM deposition, is critical to the effects of, and initial response to, PM. A key mechanism by which PM exerts its effects is the generation of reactive oxygen species (ROS), inducing antioxidant and inflammatory responses in exposed epithelial cells. However, much of what is known about the effects of PM is based on research using particulates from urban air. PM from underground railways is compositionally highly distinct from urban PM, being rich in metals associated with wheel, rail and brake wear and electrical arcing and component wear, which endows underground PM with potent ROS-generating capacity. In addition, underground PM appears to be more inflammogenic than urban PM in epithelial cells, but there is a lack of research into effects on exposed individuals, especially those with underlying health conditions. This review summarises current knowledge about the effects of PM on the airway epithelium, how the effects of underground PM may be different to urban PM and the potential health consequences and mitigation strategies for commuters and workers in underground railways.
Exposure to ambient particulate matter (PM) air pollution is a leading risk factor for morbidity and mortality, associated with up to 8.9 million deaths/year worldwide. Measurement of personal ...exposure to PM is hindered by poor spatial resolution of monitoring networks. Low-cost PM sensors may improve monitoring resolution in a cost-effective manner but there are doubts regarding data reliability. PM sensor boxes were constructed using four low-cost PM micro-sensor models. Three boxes were deployed at each of two schools in Southampton, UK, for around one year and sensor performance was analysed. Comparison of sensor readings with a nearby background station showed moderate to good correlation (0.61 < r < 0.88, p < 0.0001), but indicated that low-cost sensor performance varies with different PM sources and background concentrations, and to a lesser extent relative humidity and temperature. This may have implications for their potential use in different locations. Data also indicates that these sensors can track short-lived events of pollution, especially in conjunction with wind data. We conclude that, with appropriate consideration of potential confounding factors, low-cost PM sensors may be suitable for PM monitoring where reference-standard equipment is not available or feasible, and that they may be useful in studying spatially localised airborne PM concentrations.
Airborne particulate matter (PM) exposure has been identified as a key environmental risk factor, associated especially with diseases of the respiratory and cardiovascular system and with almost 9 ...million premature deaths per year. Low-cost optical sensors for PM measurement are desirable for monitoring exposure closer to the personal level and particularly suited for developing spatiotemporally dense city sensor networks. However, questions remain over the accuracy and reliability of the data they produce, particularly regarding the influence of environmental parameters such as humidity and temperature, and with varying PM sources and concentration profiles. In this study, eight units each of five different models of commercially available low-cost optical PM sensors (40 individual sensors in total) were tested under controlled laboratory conditions, against higher-grade instruments for: lower limit of detection, response time, responses to sharp pollution spikes lasting <1 min , and the impact of differing humidity and PM source. All sensors detected the spikes generated with a varied range of performances depending on the model and presenting different sensitivity mainly to sources of pollution and to size distributions with a lesser impact of humidity. The sensitivity to particle size distribution indicates that the sensors may provide additional information to PM mass concentrations. It is concluded that improved performance in field monitoring campaigns, including tracking sources of pollution, could be achieved by using a combination of some of the different models to take advantage of the additional information made available by their differential response.
Air Quality (AQ) is a very topical issue for many cities and has a direct impact on citizen health. The AQ of a large UK city is being investigated using low-cost Particulate Matter (PM) sensors, and ...the results obtained by these sensors have been compared with government operated AQ stations. In the first pilot deployment, six AQ Internet of Things (IoT) devices have been designed and built, each with four different low-cost PM sensors, and they have been deployed at two locations within the city. These devices are equipped with LoRaWAN wireless network transceivers to test city scale Low-Power Wide Area Network (LPWAN) coverage. The study concludes that (i) the physical device developed can operate at a city scale; (ii) some low-cost PM sensors are viable for monitoring AQ and for detecting PM trends; (iii) LoRaWAN is suitable for city scale sensor coverage where connectivity is an issue. Based on the findings from this first pilot project, a larger LoRaWAN enabled AQ sensor network is being deployed across the city of Southampton in the UK.
Low-cost Particulate Matter (PM) sensors offer an excellent opportunity to improve our knowledge about this type of pollution. Their size and cost, which support multi-node network deployment, along ...with their temporal resolution, enable them to report fine spatio-temporal resolution for a given area. These sensors have known issues across performance metrics. Generally, the literature focuses on the PM mass concentration reported by these sensors, but some models of sensors also report Particle Number Concentrations (PNCs) segregated into different PM size ranges. In this study, eight units each of Alphasense OPC-R1, Plantower PMS5003 and Sensirion SPS30 have been exposed, under controlled conditions, to short-lived peaks of PM generated using two different combustion sources of PM, exposing the sensors’ to different particle size distributions to quantify and better understand the low-cost sensors performance across a range of relevant environmental ranges. The PNCs reported by the sensors were analysed to characterise sensor-reported particle size distribution, to determine whether sensor-reported PNCs can follow the transient variations of PM observed by the reference instruments and to determine the relative impact of different variables on the performances of the sensors. This study shows that the Alphasense OPC-R1 reported at least five size ranges independently from each other, that the Sensirion SPS30 reported two size ranges independently from each other and that all the size ranges reported by the Plantower PMS5003 were not independent of each other. It demonstrates that all sensors tested here could track the fine temporal variation of PNCs, that the Alphasense OPC-R1 could closely follow the variations of size distribution between the two sources of PM, and it shows that particle size distribution and composition are more impactful on sensor measurements than relative humidity.
Regulation of cutaneous immunity is severely compromised in inflammatory skin disease. To investigate the molecular crosstalk underpinning tolerance versus inflammation in atopic dermatitis, we ...utilise a human in vivo allergen challenge study, exposing atopic dermatitis patients to house dust mite. Here we analyse transcriptional programmes at the population and single cell levels in parallel with immunophenotyping of cutaneous immunocytes revealed a distinct dichotomy in atopic dermatitis patient responsiveness to house dust mite challenge. Our study shows that reactivity to house dust mite was associated with high basal levels of TNF-expressing cutaneous Th17 T cells, and documents the presence of hub structures where Langerhans cells and T cells co-localised. Mechanistically, we identify expression of metallothioneins and transcriptional programmes encoding antioxidant defences across all skin cell types, that appear to protect against allergen-induced inflammation. Furthermore, single nucleotide polymorphisms in the MTIX gene are associated with patients who did not react to house dust mite, opening up possibilities for therapeutic interventions modulating metallothionein expression in atopic dermatitis.
Extracellular matrix (ECM) stiffening with downstream activation of mechanosensitive pathways is strongly implicated in fibrosis. We previously reported that altered collagen nanoarchitecture is a ...key determinant of pathogenetic ECM structure-function in human fibrosis (Jones et al., 2018). Here, through human tissue, bioinformatic and ex vivo studies we provide evidence that hypoxia-inducible factor (HIF) pathway activation is a critical pathway for this process regardless of the oxygen status (pseudohypoxia). Whilst TGFβ increased the rate of fibrillar collagen synthesis, HIF pathway activation was required to dysregulate post-translational modification of fibrillar collagen, promoting pyridinoline cross-linking, altering collagen nanostructure, and increasing tissue stiffness. In vitro, knockdown of Factor Inhibiting HIF (FIH), which modulates HIF activity, or oxidative stress caused pseudohypoxic HIF activation in the normal fibroblasts. By contrast, endogenous FIH activity was reduced in fibroblasts from patients with lung fibrosis in association with significantly increased normoxic HIF pathway activation. In human lung fibrosis tissue, HIF-mediated signalling was increased at sites of active fibrogenesis whilst subpopulations of human lung fibrosis mesenchymal cells had increases in both HIF and oxidative stress scores. Our data demonstrate that oxidative stress can drive pseudohypoxic HIF pathway activation which is a critical regulator of pathogenetic collagen structure-function in fibrosis.
Sensitization and exposure to the allergenic fungus Alternaria alternata has been associated with increased risk of asthma and asthma exacerbations. The first cells to encounter inhaled allergens are ...epithelial cells at the airway mucosal surface. Epithelial barrier function has previously been reported to be defective in asthma. This study investigated the contribution of proteases from Alternaria alternata on epithelial barrier function and inflammatory responses and compared responses of in vitro cultures of differentiated bronchial epithelial cells derived from severely asthmatic donors with those from non-asthmatic controls. Polarised 16HBE cells or air-liquid interface (ALI) bronchial epithelial cultures from non-asthmatic or severe asthmatic donors were challenged apically with extracts of Alternaria and changes in inflammatory cytokine release and transepithelial electrical resistance (TER) were measured. Protease activity in Alternaria extracts was characterised and the effect of selectively inhibiting protease activity on epithelial responses was examined using protease inhibitors and heat-treatment. In 16HBE cells, Alternaria extracts stimulated release of IL-8 and TNFα, with concomitant reduction in TER; these effects were prevented by heat-treatment of the extracts. Examination of the effects of protease inhibitors suggested that serine proteases were the predominant class of proteases mediating these effects. ALI cultures from asthmatic donors exhibited a reduced IL-8 response to Alternaria relative to those from healthy controls, while neither responded with increased thymic stromal lymphopoietin (TSLP) release. Only cultures from asthmatic donors were susceptible to the barrier-weakening effects of Alternaria. Therefore, the bronchial epithelium of severely asthmatic individuals may be more susceptible to the deleterious effects of Alternaria.
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