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Eosinophilic chronic rhinosinusitis (ECRS) is a refractory airway disease accompanied by eosinophilic inflammation, the mechanisms of which are unknown. We recently found that CCL4/MIP-1β—a specific ligand for CCR5 receptors—was implicated in eosinophil recruitment into the inflammatory site and was substantially released from activated eosinophils. Moreover, it was found in nasal polyps from patients with ECRS, primarily in epithelial cells. In the present study, the role of epithelial cell-derived CCL4 in eosinophil activation was investigated. First, CCL4 expression in nasal polyps from patients with ECRS as well as its role of CCL4 in eosinophilic airway inflammation were investigated in an in vivo model. Furthermore, the role of CCL4 in CD69 expression—a marker of activated eosinophils—as well as the signaling pathways involved in CCL4-mediated eosinophil activation were investigated. Notably, CCL4 expression, but not CCL5, CCL11, or CCL26, was found to be significantly increased in nasal polyps from patients with ECRS associated with eosinophil infiltration as well as in BEAS-2B cells co-incubated with eosinophils. In an OVA-induced allergic mouse model, CCL4 increased eosinophil accumulation in the nasal mucosa and the bronchoalveolar lavage (BALF). Moreover, we found that CD69 expression was upregulated in CCL4-stimulated eosinophils; similarly, phosphorylation of several kinases, including platelet-derived growth factor receptor (PDGFR)β, SRC kinase family (Lck, Src, and Yes), and extracellular signal-regulated kinase (ERK), was upregulated. Further, CCR5, PDGFRβ, and/or Src kinase inhibition partially restored CCL4-induced CD69 upregulation. Thus, CCL4, which is derived from airway epithelial cells, plays a role in the accumulation and activation of eosinophils at inflammatory sites. These findings may provide a novel therapeutic target for eosinophilic airway inflammation, such as ECRS.

Stone minerals are a partially ignored environmental challenge but a significant contributor to urban air pollution. We examined if short-term exposure to two stone minerals - quartz diorite and rhomb porphyry - commonly used in asphalt pavement would affect lung function, promote pulmonary inflammation, and affect bronchial reactivity differently. Our randomized crossover study included 24 healthy, non-smoking young adults exposed to the stone minerals quartz diorite, rhomb porphyry, and control dust (lactose). Exposure occurred in an exposure chamber, in three separate 4-hour exposure sessions. Fractional exhaled nitric oxide (FeNO) and lung function were monitored before exposure, then immediately following exposure, and 4 and 24 hours after exposure. In addition, methacholine was administered 4 hours following exposure, and exhaled breath condensate (EBC) was collected before exposure, then immediately and 4 hours after exposure. EBC was analyzed for pH, thiobarbituric acid reactive substances (TBARS), intercellular adhesion molecule 1 (ICAM-1), interleukin-6 (IL-6), IL-10, P-Selectin, surfactant protein D (SP-D), and tumor necrosis factor-α (TNF-α). Our results showed significantly elevated concentrations of FeNO after exposure to quartz diorite compared to rhomb porphyry, suggesting that quartz diorite is more likely to trigger pulmonary inflammation after short-term exposure. Moreover, short-term exposure to rhomb porphyry was associated with a modest but statistically significant decline in forced vital capacity (FVC) compared to quartz diorite. These results emphasize that using stone material in asphalt road construction should be reconsidered as it may affect lung inflammation and lung function in exposed subjects.

Purpose ADAMTS7 is a secreted metalloproteinase enzyme and proteoglycan associated with the early progression of coronary artery disease. However, there is limited information regarding the role of ADAMTS7 in lung adaptive immunity and inflammation. Thus, we sought to assess whether ADAMTS7 expression in the lung modulates house dust mite (HDM)-induced airway inflammation and Th2 immune response. Methods The role of ADAMTS7 in HDM-induced airway disease was assessed in ADAMTS7-deficient (ADAMTS7 −/− ) mice and compared with the wild-type control mice by flow cytometry, ELISA, and histopathology. Furthermore, the antigen priming capability of dendritic cells (DC) was determined ex vivo by employing coculture with CD4 + OT-II cells. Results ADAMTS7 −/− mice develop an augmented eosinophilic airway inflammation, mucous cell metaplasia, and increased Th2 immune response to inhaled HDM. In addition, allergen uptake by lung DC and migration to draining mediastinal lymph node were significantly increased in ADAMTS7 −/− mice, which shows an enhanced capacity to mount allergen-specific T-cell proliferation and effector Th2 cytokine productions. We propose that the mechanism by which ADAMTS7 negatively regulates DC function involves attenuated antigen uptake and presentation capabilities, which reduces allergic sensitization and Th2 immune responses in the lung. Conclusion In aggregate, we provide compelling evidence that ADAMTS7 plays a pivotal role in allergic airway disease and Th2 immunity and would be an attractive target for asthma.

Eosinophilic airway inflammatory disease is associated with bronchial asthma, with eosinophilic chronic rhinosinusitis (ECRS) typical of refractory type 2 airway inflammation. CCL4 produced at local inflammatory sites is involved in them via the accumulation and activation of type 2 inflammatory cells, including eosinophils. The detailed mechanism of CCL4 production remains unclear, and also the possibility it could function as a biomarker of type 2 airway inflammation remains unresolved. In this study, we evaluated CCL4 mRNA expression and production via the TSLP receptor (TSLPR) and toll-like receptors (TLRs) or proteinase-activated receptor-2 (PAR2) in BEAS-2B bronchial epithelial cells co-incubated with purified eosinophils or eosinophil peroxidase (EPX). We examined serum chemokine (CCL4, CCL11, CCL26, and CCL17) and total IgE serum levels, fractionated exhaled nitrogen oxide (FENO), and CCL4 expression in nasal polyps in patients with severe ECRS and asthma. CCL4 was induced by TSLP under eosinophilic inflammation. Furthermore, CCL4 was released via TLR3 signaling, which was enhanced by TSLP. CCL4 was mainly located in nasal polyp epithelial cells, while serum CCL4 levels were reduced after dupilumab treatment. Serum CCL4 levels were positively correlated with FENO, serum IgE, and CCL17 levels. Thus, CCL4 released from epithelial cells via the innate immune system during type 2 airway inflammation may function as a useful biomarker for the condition.

Background The hygiene hypothesis suggests that early life exposure to helminth infections can reduce hypersensitivity in the immune system. Objective The present study aims to evaluate the effects of Toxocara cati (T. cati) somatic products on allergic airway inflammation. Methods Between 2018 and 2020, T. cati adult worms were collected from stray cats in Mashhad, Iran (31 out of 186 cats), and their somatic extract was collected. Thirty BALB/c mice were equally divided into three groups, including the OVA group (sensitized and challenged with ovalbumin), the somatic administered group (received somatic extract along with ovalbumin sensitization), and the PBS group (sensitized and challenged with phosphate buffer saline). Bronchoalveolar lavage (BAL) fluid was collected to assess the number of cells, and lung homogenates were prepared for cytokine analysis. Histopathological analysis of the lungs was performed, and inflammatory cells and mucus were detected. Cytokine levels (IL‐4, IL‐5, IL‐10) were measured using enzyme‐linked immunosorbent assay (ELISA), and ovalbumin‐specific immunoglobulin E (IgE) levels were determined using a capture ELISA. Results The somatic group significantly decreased regarding the lung pathological changes, including peribronchiolitis, perivasculitis, and eosinophil influx, compared to the group treated with ovalbumin alone. These changes were accompanied by a decrease in proinflammatory cytokines IL‐4 and IL‐5 and an increase in the anti‐inflammatory cytokine IL‐10, indicating a shift toward a more balanced immune response. The number of inflammatory cells in the BAL fluid was also significantly reduced in the somatic group, indicating a decrease in inflammation. Conclusion These preclinical findings suggest that in experimental models, T. cati somatic extract exhibits promising potential as a therapeutic agent for mitigating allergic airway inflammation. Its observed effects on immune response modulation and reduction of inflammatory cell infiltration warrant further investigation in clinical studies to assess its efficacy and safety in human patients. The hygiene hypothesis suggests that helminth infections can reduce hypersensitivity in the immune system. This study aimed to evaluate the effects of Toxocara cati somatic products on allergic airway inflammation. These findings suggest that T. cati somatic extract has the potential as a therapeutic agent for attenuating allergic airway inflammation by modulating immune responses and reducing inflammatory cell infiltration. Highlights Allergic asthma is linked to Th2 cell responses, while corticosteroid side effects discourage patients. The hygiene hypothesis suggests helminth infections could reduce immune hypersensitivity. The administration of Toxocara cati somatic extract significantly decreased lung pathological changes associated with allergic airway inflammation, including peribronchiolitis, perivasculitis, and eosinophil influx. This reduction was accompanied by a shift in cytokine levels, with decreases in proinflammatory cytokines IL‐4 and IL‐5 and an increase in the anti‐inflammatory cytokine IL‐10, suggesting a rebalancing of the immune response. The somatic extract treatment significantly reduced inflammatory cell infiltration in the bronchoalveolar lavage fluid, indicating a decrease in overall inflammation within the airways.

Background： The effects of near-road pollution on lung function in China have not been well studied. We aimed to investigate the effects of long-term exposure to traffic-related air pollution on lung function, airway inflammation, and respiratory symptoms. Methods： We enrolled 1003 residents aged 57.96 ± 8.99 years living in the Shichahai Community in Beijing. Distances between home addresses and the nearest major roads were measured to calculate home-road distance. We used the distance categories 1, 2, and 3, representing 〈100 m, 100-200 m, and 〉200 m, respectively, as the dose indicator for traffic-related air pollution exposure. Lung function, exhaled breath condensate （EBC） pH, and interleukin 6 levels were measured. As a follow-up, 398 participants had a second lung function assessment about 3 years later, and lung function decline was also examined as an outcome. We used regression analysis to assess the impacts of home-road distance on lung function and respiratory symptoms. As the EBC biomarker data were not normally distributed, we performed correlation analysis between home-road distance categories and EBC biomarkers. Results： Participants living a shorter distance from major roads had lower percentage of predicted value of forced expiratory volume in 1 s （FEV1% -1.54, 95% confidence interval [CI]： -0.20 to -2.89）. The odds ratio for chronic cough was 2.54 （95% CI： 1.57-4.10） for category 1 and 1.97 （95% CI： 1.16-3.37） for category 2, compared with category 3. EBC pH was positively correlated with road distance （rank correlation coefficient of Spearman [rs] = 0.176, P 〈 0.001 ）. Conclusions： Long-term exposure to traffic-related air pollution in people who live near major roads in Beijing is associated with lower lung function, airway acidification, and a higher prevalence of chronic cough. EBC pH is a potential useful biomarker for evaluating air pollution exposure.

Pulmonary iron levels are increased in chronic obstructive pulmonary disease (COPD) patients. Iron causes oxidative stress and is a nutrient for pathogenic bacteria. Iron may therefore play an important role in the pathophysiology of COPD. The CD163-haptglobin axis plays a central role in the regulation of iron bioavailability. The aim of this study was to examine dysregulation of the CD163-haptglobin axis in COPD. We measured soluble CD163 (sCD163) and haptoglobin levels in sputum supernatants by enzyme-linked immunosorbent assay (ELISA) and sputum macrophage CD163 and haptoglobin expression by flow cytometry in COPD patients and controls. SCD163 levels were lower in COPD patients compared to controls (p = 0.02), with a significant correlation to forced expiratory volume in 1 s (FEV1)% predicted (rho = 0.5, p = 0.0007). Sputum macrophage CD163 expression was similar between COPD patients and controls. SCD163 levels and macrophage CD163 expression were lower in COPD current smokers compared to COPD ex-smokers. Haptoglobin levels were not altered in COPD patients but were regulated by genotype. Macrophage CD163 and haptolgobin expression were significantly correlated, supporting the role of CD163 in the cellular uptake of haptoglobin. Our data implicates a dysfunctional CD163-haptoglobin axis in COPD, which may contribute to disease pathophysiology, presumably due to reduced clearance of extracellular iron.

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.

COPD is characterized by chronic bronchitis, chronic airway obstruction, and emphysema, leading to a progressive and irreversible decline in lung function. Inflammation is central for the development of COPD. Chronic inflammation in COPD mainly involves the infiltration of neutrophils, macrophages, lymphocytes, and other inflammatory cells into the small airways. The contribution of resident airway structural cells to the inflammatory process is also important in COPD. Airway remodeling consists of detrimental changes in structural tissues and cells including airway wall thickening, epithelial metaplasia, goblet cell hypertrophy, and smooth muscle hyperplasia. Persistent airway inflammation might contribute to airway remodeling and small airway obstruction. However, the underlying mechanisms remain unclear. In this review, we will provide an overview of recent insights into the role of major immunoinflammatory cells in COPD airway remodeling.

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.