Vitamin D supplementation has been suggested to enhance immunity during respiratory infection season. We tested the effect of active vitamin D (calcitriol) supplementation on key airway innate immune ...mechanisms in vitro.
Primary human airway epithelial cells (hAECs) grown at the air liquid interface were supplemented with 10-7 M calcitriol for 24 hours (or a time course) and their antimicrobial airway surface liquid (ASL) was tested for pH, viscoscity, and antibacterial and antiviral properties. We also tested hAEC ciliary beat frequency (CBF). Next, we assessed alterations to hAEC gene expression using RNA sequencing, and based on results, we measured neutrophil migration across hAECs.
Calcitriol supplementation enhanced ASL bacterial killing of Staphylococcus aureus (p = 0.02) but did not enhance its antiviral activity against 229E-CoV. It had no effect on ASL pH or viscosity at three timepoints. Lastly, it did not affect hAEC CBF or neutrophil migration, although there was a trend of enhanced migration in the presence of a neutrophil chemokine (p = 0.09). Supplementation significantly altered hAEC gene expression, primarily of AMP-related genes including CAMP and TREM1.
While vitamin D supplementation did not have effects on many airway innate immune mechanisms, it may provide a useful tool to resolve respiratory bacterial infections.
Pro‐inflammatory fungal β‐d‐glucan (BDG) polysaccharides cause respiratory pathology. However, specific immunological effects of unique BDG structures on pulmonary inflammation are understudied. We ...characterized the effect of four unique fungal BDGs with unique branching patterns, solubility, and molecular weights in murine airways. Scleroglucan (1 → 3)(1 → 6)‐highly branched BDG, laminarin (1 → 3)(1 → 6)‐branched BDG, curdlan (1 → 3)‐linear BDG, and pustulan (1 → 6)‐linear BDG were assessed by nuclear magnetic resonance spectroscopy. Each BDG was tested by inhalation model with C3HeB/FeJ mice and compared to saline‐exposed control mice and unexposed sentinels (n = 3–19). Studies were performed ±heat‐inactivation (1 h autoclave) to increase BDG solubility. Outcomes included bronchoalveolar lavage (BAL) differential cell counts (macrophages, neutrophils, lymphocytes, eosinophils), cytokines, serum IgE, and IgG2a (multiplex and ELISA). Ex vivo primary cells removed from lungs and plated at monolayer were stimulated (BDG, lipopolysaccharide (LPS), anti‐CD3), and cytokines compared to unstimulated cells. Right lung histology was performed. Inhalation of BDGs with distinct branching patterns exhibited varying inflammatory potency and immunogenicity. Lichen‐derived (1 → 6)‐linear pustulan was the most pro‐inflammatory BDG, increasing inflammatory infiltrate (BAL), serum IgE and IgG2a, and cytokine production. Primed lung cells responded to secondary LPS stimulation with a T‐cell‐specific response to pustulan. Glucan source and solubility should be considered in exposure and toxicological studies.
Vitamin D deficiency is a risk factor for exacerbation of obstructive airway disease, a hallmark of which is mucus dehydration and plugging. Calcitriol (the active form of vitamin D) deficiency in ...cultured human airway epithelia resulted in increased
and
mRNAs encoding subunits of ENaC and the Na-K pump compared with supplemented epithelia. These drive the absorption of airway surface liquid. Consistently, calcitriol-deficient epithelia absorbed liquid faster than supplemented epithelia. Calcitriol deficiency also increased amiloride-sensitive
and
without altering Na-K pump activity, indicating the changes in amiloride-sensitivity arose from ENaC. ENaC activity can be regulated by trafficking, proteases, and channel abundance. We found the effect was likely not induced by changes to endocytosis of ENaC given that calcitriol did not affect the half-lives of amiloride-sensitive
and
. Furthermore, trypsin nominally increased
produced by epithelia ± calcitriol, suggesting calcitriol did not affect proteolytic activation of ENaC. Consistent with mRNA and functional data, calcitriol deficiency resulted in increased γENaC protein. These data indicate that the vitamin D receptor response controls ENaC function and subsequent liquid absorption, providing insight into the relationship between vitamin D deficiency and respiratory disease.
It is unknown why calcitriol (active vitamin D) deficiency worsens pulmonary disease outcomes. Results from mRNA, immunoblot, Ussing chamber, and absorption experiments indicate that calcitriol deficiency increases ENaC activity in human airway epithelia, decreasing apical hydration. Given that epithelial hydration is required for mucociliary transport and airway innate immune function, the increased ENaC activity observed in calcitriol-deficient epithelia may contribute to respiratory pathology observed in vitamin D deficiency.
Abstract
Air pollution particulate matter (PM) is associated with SARS-CoV-2 infection and severity, although mechanistic studies are lacking. We tested whether airway surface liquid (ASL) from ...primary human airway epithelial cells is antiviral against SARS-CoV-2 and human alphacoronavirus 229E (CoV-229E) (responsible for common colds), and whether PM (urban, indoor air pollution IAP, volcanic ash) affected ASL antiviral activity. ASL inactivated SARS-CoV-2 and CoV-229E. Independently, urban PM also decreased SARS-CoV-2 and CoV-229E infection, and IAP PM decreased CoV-229E infection. However, in combination, urban PM impaired ASL’s antiviral activity against both viruses, and the same effect occurred for IAP PM and ash against SARS-CoV-2, suggesting that PM may enhance SARS-CoV-2 infection.
Primary human airway surface liquid (ASL) inactivates severe acute respiratory syndrome coronavirus 2 and human alphacoronavirus coronavirus 229E in vitro. Air pollution particulate matter (PM) inhibits ASL viral inactivation, suggesting PM may enhance coronavirus infection by impairing airway innate immunity.
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•Tuberculosis is the leading cause of death from infection worldwide.•It is unknown if trees could mitigate the harmful effects of air pollution on tuberculosis patients.•Using ...Kaplan-Meier and Cox survival analyses, we determined the effects of trees on tuberculosis patient mortality.•Those living in neighborhoods with high percent tree cover were less likely to die during treatment.•Trees may provide health benefits to patients undergoing tuberculosis treatment.
Trees can sequester air pollutants, and air pollution is associated with poor tuberculosis outcomes. However, the health impacts of urban trees on tuberculosis patients are unknown. To elucidate the effects of urban tree canopy on mortality during tuberculosis treatment, we evaluated patients diagnosed with active tuberculosis in California from 2000 through 2012, obtaining patient data from the California tuberculosis registry. Our primary outcome was all-cause mortality during tuberculosis treatment. We determined percent tree cover using 1 mresolution color infrared orthoimagery categorized into land cover classes, then linked tree cover to four circular buffer zones of 50–300 m radii around patient residential addresses. We used the Kaplan-Meier method to estimate survival probabilities and Cox regression models to determine mortality hazard ratios, adjusting for demographic, socioeconomic, and clinical covariates. Our cohort included 33,962 tuberculosis patients of median age 47, 59% male, 51% unemployed, and 4.9% HIV positive. Tuberculosis was microbiologically confirmed in 79%, and 1.17% were multi-drug resistant (MDR). Median tree cover was 7.9% (50 m buffer). Patients were followed for 23,280 person-years with 2370 deaths during tuberculosis treatment resulting in a crude mortality rate of 1018 deaths per 10,000 person-years. Increasing tree cover quintiles were associated with decreasing mortality risk during tuberculosis treatment in all buffers, and the magnitude of association decreased incrementally with increasing buffer radius: In the 50 m buffer, patients living in neighborhoods with the highest quintile tree cover experienced a 22% reduction in mortality (HR 0.78, 95%CI 0.68–0.90) compared to those living in lowest quintile tree cover; whereas for 100, 200, and 300 m buffers, a 21%, 13%, and 11% mortality risk reduction was evident. In conclusion, urban tree canopy was associated with decreased mortality during tuberculosis treatment even after adjusting for multiple demographic, socioeconomic, and clinical factors, suggesting that trees might play a role in improving tuberculosis outcomes.
The Southeast Asian tuberculosis burden is high, and it remains unclear if urban indoor air pollution in this setting is exacerbating the epidemic.
To determine the associations of latent ...tuberculosis with common urban indoor air pollution sources (secondhand smoke, indoor motorcycle emissions, and cooking) in Southeast Asia.
We enrolled child household contacts of patients with microbiologically confirmed active tuberculosis in Vietnam, from July 2017 to December 2019. We tested children for latent tuberculosis and evaluated air pollution exposures with questionnaires and personal aerosol sampling. We tested hypotheses using generalized estimating equations.
We enrolled 72 patients with tuberculosis (27% with cavitary disease) and 109 of their child household contacts. Latent tuberculosis was diagnosed in 58 (53%) household contacts at baseline visit. Children experienced a 2.56-fold increased odds of latent tuberculosis for each additional household member who smoked (95% confidence interval, 1.27-5.16). Odds were highest among children exposed to indoor smokers and children <5 years old exposed to household smokers. Each residential floor above street-level pollution decreased the odds of latent tuberculosis by 36% (adjusted odds ratio, 0.64; 95% confidence interval, 0.42-0.96). Motorcycles parked inside children's homes and cooking with liquid petroleum gas compared with electricity increased the odds of latent tuberculosis, whereas kitchen ventilation decreased the effect, but these findings were not statistically significant.
Common urban indoor air pollution sources were associated with increased odds of latent tuberculosis infection in child household contacts of patients with active tuberculosis.
Biomass fuels (wood) are commonly used indoors in underventilated environments for cooking in the developing world, but the impact on lung physiology is poorly understood. Quantitative computed ...tomography (qCT) can provide sensitive metrics to compare the lungs of women cooking with wood vs. liquified petroleum gas (LPG). We prospectively assessed (qCT and spirometry) 23 primary female cooks (18 biomass, 5 LPG) with no history of cardiopulmonary disease in Thanjavur, India. CT was obtained at coached total lung capacity (TLC) and residual volume (RV). qCT assessment included texture-derived ground glass opacity GGO: Adaptive Multiple Feature Method (AMFM), air-trapping (expiratory voxels ≤ -856HU) and image registration-based assessment Disease Probability Measure (DPM) of emphysema, functional small airways disease (%AirTrap
), and regional lung mechanics. In addition, within-kitchen exposure assessments included particulate matter <2.5 μm(PM
), black carbon, β-(1, 3)-d-glucan (surrogate for fungi), and endotoxin. Air-trapping went undetected at RV via the threshold-based measure (voxels ≤ -856HU), possibly due to density shifts in the presence of inflammation. However, DPM, utilizing image-matching, demonstrated significant air-trapping in biomass vs. LPG cooks (
= 0.049). A subset of biomass cooks (6/18), identified using k-means clustering, had markedly altered DPM-metrics: greater air-trapping (
< 0.001), lower TLC-RV volume change (
< 0.001), a lower mean anisotropic deformation index (ADI;
< 0.001), and elevated % GGO (
< 0.02). Across all subjects, a texture measure of bronchovascular bundles was correlated to the log-transformed β-(1, 3)-d-glucan concentration (
= 0.026,
= 0.46), and black carbon (
= 0.04,
= 0.44). This pilot study identified environmental links with qCT-based lung pathologies and a cluster of biomass cooks (33%) with significant small airways disease.
Quantitative computed tomography has identified a cluster of women (33%) cooking with biomass fuels (wood) with image-based markers of functional small airways disease and associated alterations in regional lung mechanics. Texture and image registration-based metrics of lung function may allow for early detection of potential inflammatory processes that may arise in response to inhaled biomass smoke, and help identify phenotypes of chronic lung disease prevalent in nonsmoking women in the developing world.
The observed deficit of lung cancer in farmers has been partly attributed to exposure to organic dusts and endotoxins based largely on surrogate metrics. To move beyond these surrogates for ...etiological studies, we characterized task-based and time-weighted average (TWA) exposure to inhalable endotoxin, (1 → 3)-β-D-glucan, and dust in Iowa farmers.
We collected 320 personal inhalable dust samples from 32 farmers during 69 sample days in 2015 and 2016. Samples were collected using Button aerosol samplers and analyzed for endotoxin using a kinetic chromogenic amebocyte lysate assay, and for (1 → 3)-β-D-glucan using a Limulus endpoint assay. We assessed relationships between bioaerosol concentrations and selected tasks and farm characteristics using linear mixed-effects models.
Bedding work, hog handling, and working in barn/confinement buildings, grain bins, and grain elevators were associated with higher endotoxin exposure. We found a monotonic trend between higher endotoxin concentrations and increasing number of animals. Bedding work, cleaning, and feed/grain storage work were associated with higher (1 → 3)-β-D-glucan concentrations. The median concentrations by task spanned one order of magnitude for inhalable dust and two orders of magnitude for endotoxin and (1 → 3)-β-D-glucan. Pearson correlations between endotoxin and glucan concentrations were 0.22 for TWA exposure and 0.56 for task samples.
This characterization of exposure factors that influence bioaerosol concentrations can support the development of refined bioaerosol exposure metrics for future etiologic analyses of cancer and other health outcomes in farmers.
Cooks exposed to biomass fuel experience increased risk of respiratory disease and mortality. We sought to characterize lung function and environmental exposures of primary cooking women using two ...fuel-types in southeastern India, as well as to investigate the effect of particulate matter (PM) from kitchens on human airway epithelial (HAE) cells in vitro.
We assessed pre- and post-bronchodilator lung function on 25 primary female cooks using wood biomass or liquified petroleum gas (LPG), and quantified exposures from 34 kitchens (PM2.5, PM < 40 μm, black carbon, endotoxin, and PM metal and bacterial content). We then challenged HAE cells with PM, assessing its cytotoxicity to small-airway cells (A549) and its effect on: transepithelial conductance and macromolecule permeability (NuLi cells), and antimicrobial activity (using airway surface liquid, ASL, from primary HAE cells).
Lung function was impaired in cooks using both fuel-types. 60% of participants in both fuel-types had respiratory restriction (post bronchodilator FEV1/FVC>90). The remaining 40% in the LPG group had normal spirometry (post FEV1/FVC = 80–90), while only 10% of participants in the biomass group had normal spirometry, and the remaining biomass cooks (30%) had respiratory obstruction (post FEV1/FVC<80). Significant differences were found in environmental parameters, with biomass kitchens containing greater PM2.5, black carbon, zirconium, arsenic, iron, vanadium, and endotoxin concentrations. LPG kitchens tended to have more bacteria (p = 0.14), and LPG kitchen PM had greater sulphur concentrations (p = 0.02). In vitro, PM induced cytotoxicity in HAE A549 cells in a dose-dependent manner, however the effect was minimal and there were no differences between fuel-types. PM from homes of participants with a restrictive physiology increased electrical conductance of NuLi HAE cells (p = 0.06) and decreased macromolar permeability (p ≤ 0.05), while PM from homes of those with respiratory obstruction tended to increase electrical conductance (p = 0.20) and permeability (p = 0.07). PM from homes of participants with normal spirometry did not affect conductance or permeability. PM from all homes tended to inhibit antimicrobial activity of primary HAE cell airway surface liquid (p = 0.06).
Biomass cooks had airway obstruction, and significantly greater concentrations of kitchen environmental contaminants than LPG kitchens. PM from homes of participants with respiratory restriction and obstruction altered airway cell barrier function, elucidating mechanisms potentially responsible for respiratory phenotypes observed in biomass cooks.
•PM from two cookstove fuel types had distinct combustion and bioaerosol properties.•30% of women cooking with wood had respiratory obstruction, none using LPG did.•Respiratory restriction was common in both groups (60%).•PM from homes of subjects with obstruction or restriction altered cell permeability.•PM from all homes tended to inhibit innate immunity.
Myopericytoma is an emerging class of neoplasm originating from the perivascular myoid cellular environment, previously classified as a variant of hemangiopericytoma. Most reported myopericytomas are ...found in soft tissues of the extremities; however, infrequent cases are described involving the central nervous system. Intracranial myopericytoma remains rare. Here, we describe the first report of myopericytoma occurring at the cervicomedullary junction in close proximity to the vertebral artery, mimicking a vascular lesion.
A 64-yr-old woman presented with radiating neck pain. Magnetic resonance imaging revealed a well-circumscribed enhancing lesion adjacent to the vertebral artery-accessory nerve complex. She underwent a far lateral craniotomy and cervical laminectomy to obtain proximal vertebral artery control and adequate exposure of the lesion, which appeared most consistent with neoplasm at surgery. Histopathology revealed a grade I myopericytoma. A gross total resection was achieved, and the patient has no evidence of recurrence 3 yr after surgery.
Tumors of perivascular origin include hemangiopericytoma, glomus tumor, myofibroma, and myopericytoma and are uncommon lesions intracranially. Consideration of and distinction among these perivascular tumors is critically important, as they each have distinct clinical behaviors and management. Myopericytoma can mimic other neoplastic and cerebrovascular pathologies, but it most commonly has a benign course and can be surgically cured if a gross total resection can be achieved. Rarer myopericytoma variants that adopt a more malignant course have been described, and ongoing molecular studies may identify mutations or activated signaling pathways that can be targeted to offer chemotherapeutic options in the future.
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