A Muscarinic Antagonist Reduces Airway Inflammation and Bronchoconstriction Induced by Ambient Particulate Matter in a Mouse Model of Asthma.

Ambient particulate matter (PM) can increase airway inflammation and induce bronchoconstriction in asthma. This study aimed to investigate the effect of tiotropium bromide, a long-acting muscarinic antagonist, on airway inflammation and bronchoconstriction induced by ambient PM in a mouse model of asthma. We compared the effect of tiotropium bromide to that of fluticasone propionate and formoterol fumarate. BALB/c mice were sensitized to ovalbumin (OVA) via the airways and then administered tiotropium bromide, fluticasone propionate, or formoterol fumarate. Mice were also sensitized to ambient PM via intranasal instillation. Differential leukocyte counts and the concentrations of interferon (IFN)-γ, interleukin (IL)-5, IL-6, IL-13, and keratinocyte-derived chemokine (KC/CXCL1) were measured in bronchoalveolar lavage fluid (BALF). Diacron-reactive oxygen metabolites (dROMs) were measured in the serum. Airway resistance and airway inflammation were evaluated in lung tissue 24 h after the OVA challenge. Ambient PM markedly increased neutrophilic airway inflammation in mice with OVA-induced asthma. Tiotropium bromide improved bronchoconstriction, and reduced neutrophil numbers, decreased the concentrations of IL-5, IL-6, IL-13, and KC/CXCL1 in BALF. However, tiotropium bromide did not decrease the levels of dROMs increased by ambient PM. Though eosinophilic airway inflammation was reduced with fluticasone propionate, neutrophilic airway inflammation was unaffected. Bronchoconstriction was improved with formoterol fumarate, but not with fluticasone propionate. In conclusion, tiotropium bromide reduced bronchoconstriction, subsequently leading to reduced neutrophilic airway inflammation induced by ambient PM.

Association between transported Asian dust and outdoor fungal concentration during winter in a rural area of western Japan.

BACKGROUND: Recently, Asian dust (AD) has become a serious health problem and several studies have clearly proven that AD can aggravate asthma. However, it remains unclear as to which components of AD have a strong effect on the asthma exacerbation caused by AD exposure. Outdoor fungi can increase emergency department visits and hospitalization for asthma exacerbation and can aggravate asthma symptoms. Therefore, this study was aimed at investigating the relationship between AD and outdoor fungi and determining the potential of fungi to cause airborne particulate matter (PM)-related inflammatory responses. METHODS: Airborne PM was collected each day from January 26, 2015 to February 27, 2015. Daily levels of outdoor fungi-associated PM were calculated using a culture-based method. Production of cytokines such as interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α was assessed in THP1 cells stimulated by the collected airborne PM each day. RESULTS: Daily levels of AD particles were assessed using Light Detection and Ranging and did not correlate with outdoor fungi (r = -0.17, P = 0.94). There was also no association between outdoor fungi and the daily production of IL-6 (r = 0.16, P = 0.37), IL-8 (r = 0.19, P = 0.30), or TNF-α induced by collected PM (r = 0.07, P = 0.70). However, the daily levels of AD particles were significantly associated with IL-6 (r = 0.91, P < 0.0001), IL-8 (r = 0.64, P = 0.0004), and TNF-α (r = 0.72, P < 0.0001) production. CONCLUSION: AD did not increase the acute levels of outdoor fungi and outdoor fungi did not affect the cytokine production induced by airborne PM. These results suggest that outdoor fungi do not have any detectable effect on the asthma exacerbation caused by AD exposure.

Association of Short-Term Exposure to Ambient Fine Particulate Matter with Skin Symptoms in Schoolchildren: A Panel Study in a Rural Area of Western Japan.

Numerous studies have unmasked the deleterious effects of particulate matter less than 2.5 µm (PM2.5) on health. However, epidemiologic evidence focusing on the effects of PM2.5 on skin health remains limited. An important aspect of Asian dust (AD) in relationship to health is the amount of PM2.5 contained therein. Several studies have demonstrated that AD can aggravate skin symptoms. The current study aimed to investigate the effects of short-term exposure to PM2.5 and AD particles on skin symptoms in schoolchildren. A total of 339 children recorded daily skin symptom scores during February 2015. Light detection and ranging were used to calculate AD particle size. Generalized estimating equation logistic regression analyses were used to estimate the associations among skin symptoms and the daily levels of PM2.5 and AD particles. Increases in the levels of PM2.5 and AD particles were not related to an increased risk of skin symptom events, with increases of 10.1 µg/m³ in PM2.5 and 0.01 km-1 in AD particles changing odds ratios by 1.03 and 0.99, respectively. These results suggest that short-term exposure to PM2.5 and AD does not impact skin symptoms in schoolchildren.

A panel study of airborne particulate matter composition versus concentration: Potential for inflammatory response and impaired pulmonary function in children.

BACKGROUND: The relationship between airborne particulate matter (PM) and pulmonary function in children has not been consistent among studies, potentially owing to differences in the inflammatory response to PM, based on PM types and sources. The objective of this study was to investigate the effect of airborne PM on pulmonary function in schoolchildren and its potential for an inflammatory response. METHODS: Daily morning peak expiratory flow (PEF) was measured in 339 schoolchildren in February 2015. Interleukin (IL)-8 production was assessed in THP1 cells stimulated by airborne PM collected every day during the study period, and these IL-8 concentrations are described as the daily IL-8 levels. A linear mixed model was used to estimate the association between PEF values and the daily levels of suspended PM (SPM), PM diameters smaller than 2.5 µm (PM2.5), and IL-8. RESULTS: The daily IL-8 levels were significantly associated with those of SPM and PM2.5. A 0.83 µg/mL increase in IL-8 levels was significantly associated with a -1.07 L/min (95% confidence interval, -2.05 to -0.08) decrease in PEF. A 12.0 µg/m3 increase in SPM and a 10.0 µg/m3 increase in PM2.5 were associated with a -1.36 L/min (-2.93 to 0.22) and -1.72 L/min (-3.82 to 0.36) decreases in PEF, respectively. There were no significant relationships between PEF, SPM, and PM2.5. CONCLUSIONS: These findings suggest that the effects of airborne PM on pulmonary function in schoolchildren might depend more on the pro-inflammatory response than the mass concentration of the PM.

Effects of Asian Dust Particles on the Early-Stage Antigen-Induced Immune Response of Asthma in NC/Nga Mice.

Asian dust (AD) can aggravate airway inflammation in asthma, but the association between AD and the development of asthma remains unclear. This study aimed to investigate the effects of AD on the early stage of antigen sensitization using a mouse model of asthma, as well as the role of leukotrienes (LTs) in antigen-induced airway inflammation potentiated by AD particles. NC/Nga mice were co-sensitized by intranasal instillation of AD particles and/or Dermatophagoides farinae (Df) for five consecutive days. Df-sensitized mice were stimulated with an intranasal Df challenge at seven days. Mice were treated with the type 1 cysteinyl LT (CysLT1) receptor antagonist orally 4 h before and 1 h after the allergen challenge. At 24 h post-challenge, the differential leukocyte count, inflammatory cytokines, and LTs in bronchoalveolar lavage fluid were assessed, and airway inflammation was evaluated histopathologically. AD augmented neutrophilic and eosinophilic airway inflammation with increased CysLTs and dihydroxy-LT in a mouse model of asthma. The CysLT1 receptor antagonist was shown to attenuate both neutrophilic and eosinophilic airway inflammation augmented by AD. Therefore, exposure to AD may be associated with the development of asthma and LTs may play important roles in airway inflammation augmented by AD.

Effects of Short-Term Exposure to Particulate Air Pollutants on the Inflammatory Response and Respiratory Symptoms: A Panel Study in Schoolchildren from Rural Areas of Japan.

The relationship between particulate air pollutants and respiratory symptoms in children has not been consistent among studies, potentially owing to differences in the inflammatory response to different particulate air pollutants. This study aimed to investigate the effect of particulate air pollutants on respiratory symptoms and the inflammatory response in schoolchildren. Three hundred-and-sixty children were included in the study. The children recorded daily respiratory symptom scores for October 2015. In addition, the daily amount of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α production was assessed in THP1 cells stimulated with suspended particulate matter (SPM), which was collected every day during the study period. Generalized estimating equation logistic regression analyses were used to estimate the associations among respiratory symptoms and the daily levels of SPM, IL-6, IL-8, and TNF-α. Daily SPM levels were not associated with respiratory symptoms or the daily IL-6, IL-8, and TNF-α levels. Conversely, there was a significant association between respiratory symptoms and the daily IL-6, IL-8, and TNF-α levels. These results suggested that the effects of particulate air pollutants on respiratory symptoms in schoolchildren might depend more on the pro-inflammatory response to them than on their mass concentration.

The Effect of Seasonal Variations in Airborne Particulate Matter on Asthma-Related Airway Inflammation in Mice.

This study aimed to investigate the effects of winter and spring particulate matter (PM) on airway inflammation and allergies in a mouse asthma model. PM was collected during 7-28 February 2013 (winter) and during 7-28 April 2013 (spring) in Yonago, Japan. NC/Nga mice were co-sensitized using intranasal instillation of the PMs and Dermatophagoides farinae (Df) for 5 consecutive days, and were subsequently challenged using intranasal Df at 7 days after the last sensitization. At 24 h after the challenge, serum immunoglobulin levels, differential leukocyte counts, and inflammatory cytokines levels were measured in the mice's bronchoalveolar lavage fluid (BALF). Compared to co-sensitization using spring PM and Df, winter PM and Df induced greater increases in the BALF neutrophil and eosinophil counts and total serum IgE and IgG2a levels. Furthermore, winter PM-sensitized mice exhibited higher BALF levels of interleukin-5, interleukin-13, interleukin-6, and keratinocyte-derived chemokine. Therefore, we observed seasonal variations in the effects of PM on asthma-related airway inflammation. These findings suggest that the compositions of PM vary according to season, and that it is important to evaluate PM compositions in order to understand the associations between asthma and PM.

Association between Outdoor Fungal Concentrations during Winter and Pulmonary Function in Children with and without Asthma.

Outdoor fungi are important components of airborne particulate matter (PM). However, the associations between pulmonary function and outdoor fungi are less well known compared to other airborne PM constituents. The objective of this study was to investigate the association between outdoor fungi and pulmonary function in children. Morning peak expiratory flow (PEF) rates were measured daily in 339 schoolchildren (including 36 with asthma), aged 10 to 12, 2 to 27 February 2015. Airborne PM was collected on filters, using a high volume air sampler, each day during the study period. The daily concentration of outdoor fungi-associated PM was calculated using a culture-based method. A linear mixed model was used to estimate the association between PEF values and daily concentrations of outdoor fungi, and the daily levels of suspended PM (SPM) and PM ≤ 2.5 µm (PM2.5). An increase in the interquartile range (46.2 CFU/m³) for outdoor fungal concentration led to PEF changes of -1.18 L/min (95% confidence interval, -2.27 to -0.08) in all children, 1.22 L/min (-2.96 to 5.41) in children without asthma, and -1.44 L/min (-2.57 to -0.32) in children with asthma. Outdoor fungi showed a significant negative correlation with PM2.5 levels (r = -0.4, p = 0.04), but not with SPM (r = ‒0.3, p = 0.10) levels. Outdoor fungi may be associated with pulmonary dysfunction in children. Furthermore, children with asthma may show greater pulmonary dysfunction than those without asthma.

VAP-B binds to Rab3GAP1 at the ER: its implication in nuclear envelope formation through the ER-Golgi intermediate compartment.

The vesicle-associated membrane protein-associated protein B (VAP-B) is a tail-anchored protein in the endoplasmic reticulum (ER). VAP-B functions as an adaptor protein to recruit target proteins to the ER and execute various cellular functions, lipid transport, membrane traffic, ER stress etc. Recently, VAP-B has been shown to regulate the nuclear envelope protein transport through the ER-Golgi intermediate compartment (ERGIC). We showed here that VAP-B directly binds to Rab3 GTPase activating protein 1 (Rab3GAP1), the catalytic subunit of Rab3GAP, through the two phenylalanines (FF) in an acidic tract (FFAT)-like motif of Rab3GAP1. Rab3GAP consists of two subunits, the catalytic subunit Rab3GAP1 and the non-catalytic subunit Rab3GAP2. VAP-B binds to Rab3GAP1 even in the Rab3GAP1/2 heterodimer complex. A single amino acid substitution of the FFAT-like motif reduces the binding activity of Rab3GAP1 to VAP-B. On the other hand, the FFAT-like motif mutation increases the binding activity of Rab3GAP1 to ERGIC-53, the ERGIC marker protein. Overexpression of Rab3GAP1 affects nuclear envelope formation more potently than that of Rab3GAP1 FFAT-like motif mutant. These results suggest that the binding of VAP-B to Rab3GAP1 is implicated in the regulation of nuclear envelope formation through ERGIC.