Summary
Background
Autophagy and neutrophil extracellular DNA traps (NETs) are implicated in asthma; however, their roles in asthma pathogenesis have not been elucidated.
Objectives
We compared ...autophagy and NET production levels from peripheral blood neutrophils (PBNs) of patients with severe asthma (SA) and non‐severe asthma (NSA). Additionally, we investigated the inflammatory effects of NETs on human airway epithelial cells (AECs) and peripheral blood eosinophils (PBEs).
Methods
Peripheral blood neutrophils from patients with SA (n = 30) and NSA (n = 38) were treated with interleukin (IL)‐8 (100 ng/mL). Autophagy (light chain 3‐II expression) and NET production levels were evaluated by Western blot, immunofluorescence microscopy, and PicoGreen assay. The effects of NETs on AECs were assessed by investigating cell death, cell detachment, expression of occludin and claudin‐1, and IL‐8 production; the effects of NETs on PBEs were examined by investigating the activation and release of eosinophil cationic protein (ECP) and eosinophil‐derived neurotoxin (EDN).
Results
Untreated and IL‐8‐treated PBNs from the SA group produced higher autophagy and NET levels compared with those from the NSA group (P < 0.01). IL‐8 increased autophagy and NET levels in PBNs from the SA group, but not from the NSA group. NET levels were correlated with autophagy levels in PBNs (P < 0.001). IL‐8‐induced NET production levels negatively were correlated with FEV1/FVC (r = −0.700, P = 0.016). NETs induced cell death, detachment, degradation of occludin and claudin‐1, and IL‐8 production from AECs. Higher levels of NET‐induced ECP and EDN were released from PBEs in SA compared with NSA groups.
Conclusions and Clinical Relevance
Neutrophil autophagy and NETs could enhance asthma severity by damaging airway epithelium and triggering inflammatory responses of AECs and PBEs. Modulating neutrophil autophagy and NET production may be a new target therapy for SA.
Modeling the climate of urban areas is of interest for studying urban heat islands (UHIs). Reliable assessment of the primary causes of UHIs and the efficacy of various heat mitigation strategies ...requires accurate prediction of urban temperatures and realistic representation of land surface physical characteristics in models. In this study, we expand the capabilities of the Weather Research and Forecasting (WRF) model by implementing high‐resolution, real‐time satellite observations of green vegetation fraction (GVF) and albedo. Satellite‐based GVF and albedo replace constant values that are assumed for urban pixels in the default version of WRF. Simulations of urban meteorology in Los Angeles using the improved model show marked improvements relative to the default model. The largest improvements are for nocturnal air temperatures, with a reduction in root‐mean‐square deviation between simulations and observations from 3.8 to 1.9°C. Utilizing the improved model, we quantify relationships between surface and 2 m air temperatures versus urban fraction, GVF, albedo, distance from the ocean, and elevation. Distance from the ocean is found to be the main contributor to variations in temperatures around Los Angeles. After conditionally sampling pixels to minimize the influence of distance from the ocean and elevation, we find that variations in GVF and urban fraction are responsible for up to 58 and 27% of the variance in temperatures. The satellite‐supported meteorological modeling framework reported here can be used for studying UHIs in other cities and can serve as a foundation for testing the efficacy of various heat mitigation strategies.
Key Points
Satellite‐supported WRF‐UCM is developed using MODIS observed GVF and albedo
Satellite observations are implemented over both urban and vegetated pixels
Urban heat island in Los Angeles is related to surface characteristics
Summary
Background
Autophagy and genetic predisposition have been suggested to potentially play roles in the development of asthma. However, little is known about the role of autophagy in the ...pathogenesis of severe asthma.
Objective
We compared autophagy in the sputum granulocytes, peripheral blood cells (PBCs) and peripheral blood eosinophils (PBEs) between patients with severe asthma and those with non‐severe asthma and investigated the functional effects of autophagy.
Methods
We enrolled 36 patients with severe asthma, 14 with non‐severe asthma and 23 normal healthy controls in this study. Sputum granulocytes, PBCs and PBEs were isolated from each subject. Autophagy was evaluated based on the expression of microtubule‐associated protein light chain 3 (LC3) by Western blot, confocal microscopy, transmission electron microscopy and flow cytometry. IL‐8 levels were measured by ELISA. To induce autophagy, HL‐60 cells, human primary small airway epithelial cells (SAECs) and A549 cells were treated with IL‐5, IL‐1β and TNF‐α. To inhibit autophagy, PI3K inhibitors (LY29400 and 3‐methyladenine 3‐MA) and hydroxychloroquine (HCQ) were used. Knockdown of ATG5 and Beclin‐1 was performed in A549 cells, and the therapeutic effects of dexamethasone were evaluated.
Results
Higher autophagy levels were noted in sputum granulocytes, PBCs and PBEs from patients with severe asthma than from patients with non‐severe asthma and healthy controls (P < 0.05 for all). IL‐5 increased autophagy levels in both PBCs and PBEs (P < 0.05). 3‐MA attenuated the increased expression of LC3‐II and eosinophil cationic protein in HL‐60 cells induced by IL‐5 (P = 0.034 for both). Dexamethasone did not affect autophagy levels in PBEs. IL‐1β increased LC3‐II expression and IL‐8 production (P < 0.01) in SAECs, and this was attenuated by LY294002, 3‐MA, HCQ and knockdown of ATG5 and Beclin‐1 (in A549 cells) (P < 0.01).
Conclusions and Clinical Relevance
Autophagy could play a role in the pathogenesis of severe asthma. Autophagy modulation may be a novel therapeutic target for conventional therapy‐resistant severe asthma.
During 2012–2014, drought in California resulted in policies to reduce water consumption. One measure pursued was replacing lawns with landscapes that minimize water consumption, such as ...drought‐tolerant vegetation. If implemented at broad scale, this strategy would result in reductions in irrigation and changes in land surface characteristics. In this study, we employ a modified regional climate model to assess the climatic consequences of adopting drought‐tolerant vegetation over the Los Angeles metropolitan area. Transforming lawns to drought‐tolerant vegetation resulted in daytime warming of up to 1.9°C, largely due to decreases in irrigation that shifted surface energy partitioning toward higher sensible and lower latent heat flux. During nighttime, however, adopting drought‐tolerant vegetation caused mean cooling of 3.2°C, due to changes in soil thermodynamic properties and heat exchange dynamics between the surface and subsurface. Our results show that nocturnal cooling effects, which are larger in magnitude and of great importance for public health during heat events, could counterbalance the daytime warming attributed to the studied water conservation strategy. A more aggressive implementation, assuming all urban vegetation was replaced with drought‐tolerant vegetation, resulted in an average daytime cooling of 0.2°C, largely due to strengthened sea breeze patterns, highlighting the important role of land surface roughness in this coastal megacity.
Key Points
Replacing lawns with drought‐tolerant vegetation could result in daytime warming of up to 1.9°C, largely due to decreases in irrigation
Implementing shorter vegetation could prevent this warming via interactions between surface roughness and cooling effects of the sea breeze
Adopting drought vegetation could lead to temperature reductions of ~3°C celsius during night, induced by changes in soil moisture
Rapid urbanization throughout eastern China is imposing an irreversible effect on local climate and air quality. In this paper, we examine the response of a range of meteorological and air quality ...indicators to urbanization. Our study uses the Weather Research and Forecasting model coupled with chemistry (WRF/Chem) to simulate the climate and air quality impacts of four hypothetical urbanization scenarios with fixed surface pollutant emissions during the month of July from 2008 to 2012. An improved integrated process rate (IPR) analysis scheme is implemented in WRF/Chem to investigate the mechanisms behind the forcing-response relationship at the process level. For all years, as urban land area expands, concentrations of CO, elemental carbon (EC), and particulate matter with aerodynamic diameter less than 2.5 microns (PM2.5) tend to decrease near the surface (below ~ 500 m), but increase at higher altitudes (1-3 km), resulting in a reduced vertical concentration gradient. On the other hand, the O3 burden, averaged over all newly urbanized grid cells, consistently increases from the surface to a height of about 4 km. Sensitivity tests show that the responses of pollutant concentrations to the spatial extent of urbanization are nearly linear near the surface, but nonlinear at higher altitudes. Over eastern China, each 10 % increase in nearby urban land coverage on average leads to a decrease of approximately 2 % in surface concentrations for CO, EC, and PM2.5, while for O3 an increase of about 1 % is simulated. At 800 hPa, pollutants' concentrations tend to increase even more rapidly with an increase in nearby urban land coverage. This indicates that as large tracts of new urban land emerge, the influence of urban expansion on meteorology and air pollution would be significantly amplified. IPR analysis reveals the contribution of individual atmospheric processes to pollutants' concentration changes. It indicates that, for primary pollutants, the enhanced sink (source) caused by turbulent mixing and vertical advection in the lower (upper) atmosphere could be a key factor in changes to simulated vertical profiles. The evolution of secondary pollutants is further influenced by the upward relocation of precursors that impact gas-phase chemistry for O3 and aerosol processes for PM2.5. Our study indicates that dense urbanization has a moderate dilution effect on surface primary airborne contaminants, but may intensify severe haze and ozone pollution if local emissions are not well controlled.
Background
Surfactant protein D (SPD) is a member of the collectin family that lines the airway epithelial cells with host defense. However, the role of SPD in the pathogenesis of aspirin‐exacerbated ...respiratory disease (AERD) is still unclear.
Methods
The serum SPD level was measured in patients with AERD (n = 336), those with aspirin‐tolerant asthma (ATA, n = 442), and healthy controls (HC, n = 104). Polymorphisms of SFTPD in the study subjects were analyzed. The effect of LTE4 on SPD production through eosinophil infiltration was investigated in BALB/c mice. The protective function of SPD against eosinophils inducing inflammation and remodeling was assessed in vitro/vivo. The potential efficacy of nintedanib against airway remodeling through the production of SPD was evaluated.
Results
The serum SPD level was significantly lower (P < .001) in AERD compared with ATA patients, and negatively correlated with fall in FEV1 (%) after lysine‐aspirin bronchoprovocation test and/or the urinary LTE4 level. In addition, polymorphism of SFTPD at rs721917 was significantly different in the study subjects (odds ratio, 2.124; 95% confidence intervals, 1.310‐3.446; P = .002). LTE4‐exposed mice showed an increased eosinophil count with a decreased SPD level in bronchoalveolar lavage fluid. Eosinophils increased α‐smooth muscle actin expression in airway epithelial cells, which was attenuated by SPD treatment. Furthermore, nintedanib protected the airway epithelial cells against eosinophils by enhancing the production of SPD.
Conclusion
The decreased level of SPD in AERD was associated with airway inflammation/remodeling under the eosinophilic condition, suggesting that modulation of SPD may provide a potential benefit in AERD.
High level of leukotriene E4 induces eosinophil infiltration in the lungs, leading to the reduction of surfactant protein D in patients with AERD. Decreased level of surfactant protein D and increased number of eosinophils enhance airway inflammation/remodeling. Modulation of surfactant protein D may provide a potential benefit in airway epithelium against eosinophils.
Summary
Background
A multidrug regimen including isoniazid, rifampicin, pyrazinamide and ethambutol is commonly used as first‐line treatment for tuberculosis. However, this regimen can occasionally ...result in severe adverse drug reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome and drug‐induced liver injury. The culprit drug and mechanistic basis for the hypersensitive reaction are unknown.
Objectives
To investigate drug‐specific T‐cell responses in patients with antituberculosis drug (ATD)‐induced cutaneous hypersensitivity and its underlying mechanism.
Methods
We enrolled eight patients with ATD‐induced maculopapular exanthema and DRESS and performed a lymphocyte transformation test. Subsequently, drug‐specific T‐cell clones were generated from four of the patients who showed proliferation in response to ATDs. We measured the drug‐specific proliferative responses and counted the drug‐specific interferon (IFN)‐γ/granzyme B‐producing cells after drug stimulation. Antihuman leukocyte antigen (HLA) class I and class II blocking antibodies were used to analyse human leukocyte antigen‐restricted T‐cell responses.
Results
Positive proliferative responses to ATDs were mostly found in patients with cutaneous hypersensitivity. Furthermore, we isolated isoniazid/rifampicin‐specific T cells from patients, which consisted primarily of CD4+ T cells. Drug‐specific CD4+ T cells proliferated and secreted IFN‐γ/granzyme B when stimulated with isoniazid or rifampicin, respectively. Isoniazid‐responsive T‐cell clones did not proliferate in the presence of rifampicin and vice versa. Drug‐specific T‐cell responses were blocked in the presence of anti‐HLA class II antibodies.
Conclusions
This study identifies the presence of isoniazid/rifampicin‐specific T cells in patients with ATD‐induced maculopapular exanthema and DRESS. Furthermore, it highlights the important role of drug‐specific T‐cell immune responses in the pathogenesis of these reactions.
What's already known about this topic?
Antituberculosis drug (ATD) treatment often induces severe adverse drug reactions including hepatotoxicity, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome and maculopapular exanthema.
What does this study add?
This study identified an isoniazid/rifampicin‐specific T‐cell response in patients with ATD‐induced maculopapular exanthema and DRESS.
This study describes the nature of isoniazid/rifampicin‐specific CD4+ T cells and the mechanism of drug‐specific T‐cell activation in ATD‐induced maculopapular exanthema and DRESS syndrome.
What is the translational message?
As the first‐line treatment for tuberculosis is a combination regimen, the culprit drug is frequently not identified.
A lymphocyte transformation test for ATDs would be beneficial to assess the risk of drug hypersensitivity reaction.
Linked Comment: Pavlos et al. Br J Dermatol 2017; 176:292–293.
The climate warming effects of accelerated urbanization along with projected global climate change raise an urgent need for sustainable mitigation and adaptation strategies to cool urban climates. ...Our modeling results show that historical urbanization in the Los Angeles and San Diego metropolitan areas has increased daytime urban air temperature by 1.3 °C, in part due to a weakening of the onshore sea breeze circulation. We find that metropolis-wide adoption of cool roofs can meaningfully offset this daytime warming, reducing temperatures by 0.9 °C relative to a case without cool roofs. Residential cool roofs were responsible for 67% of the cooling. Nocturnal temperature increases of 3.1 °C from urbanization were larger than daytime warming, while nocturnal temperature reductions from cool roofs of 0.5 °C were weaker than corresponding daytime reductions. We further show that cool roof deployment could partially counter the local impacts of global climate change in the Los Angeles metropolitan area. Assuming a scenario in which there are dramatic decreases in greenhouse gas emissions in the 21st century (RCP2.6), mid- and end-of-century temperature increases from global change relative to current climate are similarly reduced by cool roofs from 1.4 °C to 0.6 °C. Assuming a scenario with continued emissions increases throughout the century (RCP8.5), mid-century warming is significantly reduced by cool roofs from 2.0 °C to 1.0 °C. The end-century warming, however, is significantly offset only in small localized areas containing mostly industrial/commercial buildings where cool roofs with the highest albedo are adopted. We conclude that metropolis-wide adoption of cool roofs can play an important role in mitigating the urban heat island effect, and offsetting near-term local warming from global climate change. Global-scale reductions in greenhouse gas emissions are the only way of avoiding long-term warming, however. We further suggest that both climate mitigation and adaptation can be pursued simultaneously using 'cool photovoltaics'.
We report on a search for ultralow-mass axionlike dark matter by analyzing the ratio of the spin-precession frequencies of stored ultracold neutrons and Hg199 atoms for an axion-induced oscillating ...electric dipole moment of the neutron and an axion-wind spin-precession effect. No signal consistent with dark matter is observed for the axion mass range 10−24≤ma≤10−17eV . Our null result sets the first laboratory constraints on the coupling of axion dark matter to gluons, which improve on astrophysical limits by up to 3 orders of magnitude, and also improves on previous laboratory constraints on the axion coupling to nucleons by up to a factor of 40.
Improving the ability of global models to predict concentrations of black carbon (BC) over the Pacific Ocean is essential to evaluate the impact of BC on marine climate. In this study, we tag BC ...tracers from 13 source regions around the globe in a global chemical transport model, Model for Ozone and Related Chemical Tracers, version 4 (MOZART-4). Numerous sensitivity simulations are carried out varying the aging timescale of BC emitted from each source region. The aging timescale for each source region is optimized by minimizing errors in vertical profiles of BC mass mixing ratios between simulations and HIAPER Pole-to-Pole Observations (HIPPO). For most HIPPO deployments, in the Northern Hemisphere, optimized aging timescales are less than half a day for BC emitted from tropical and midlatitude source regions and about 1 week for BC emitted from high-latitude regions in all seasons except summer. We find that East Asian emissions contribute most to the BC loading over the North Pacific, while South American, African and Australian emissions dominate BC loadings over the South Pacific. Dominant source regions contributing to BC loadings in other parts of the globe are also assessed. The lifetime of BC originating from East Asia (i.e., the world's largest BC emitter) is found to be only 2.2 days, much shorter than the global average lifetime of 4.9 days, making the contribution from East Asia to the global BC burden only 36 % of that from the second largest emitter, Africa. Thus, evaluating only relative emission rates without accounting for differences in aging timescales and deposition rates is not predictive of the contribution of a given source region to climate impacts. Our simulations indicate that the lifetime of BC increases nearly linearly with aging timescale for all source regions. When the aging rate is fast, the lifetime of BC is largely determined by factors that control local deposition rates (e.g., precipitation). The sensitivity of lifetime to aging timescale depends strongly on the initial hygroscopicity of freshly emitted BC. Our findings suggest that the aging timescale of BC varies significantly by region and season and can strongly influence the contribution of source regions to BC burdens around the globe. Therefore, improving parameterizations of the aging process for BC is important for enhancing the predictive skill of global models. Future observations that investigate the evolution of the hygroscopicity of BC as it ages from different source regions to the remote atmosphere are urgently needed.
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