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Nootkatone (NKT) exhibits potential pharmacological activities including anti-oxidation and anti-inflammation. Nevertheless, little is known about the roles of NKT in asthmatic airway inflammation. In the study, mice were sensitized and challenged with ovalbumin (OVA) to establish experimental allergic asthma model. After treatment with NKT, lung tissues, peripheral blood, and bronchoalveolar lavage fluid (BALF) were collected to assess inflammatory cytokines, oxidative stress, and pathological alternations. The effects of NKT on regulating reactive oxygen species (ROS)-induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation was assessed in IL-13-treated BEAS-2B cell model. We found that NKT treatment decreased the production of Th2 inflammatory cytokines (IL-4, IL-5, and IL-13) in BALF and IgE levels in serum, and alleviated inflammatory cell penetration, goblet cell proliferation, collagen accumulation, and mucus hypersecretion in lung tissues. NKT treatment mitigated oxidative stress and NLRP3 inflammasome activation in asthmatic mice. IL-13 treatment induced oxidative stress and NLRP3-mediated pyroptosis in BEAS-2B bronchial epithelial cells, whereas these effects were blocked by NKT. NKT protected against airway remodeling, as indicated by decreased epithelial-mesenchymal transition. Taken together, these results demonstrate that NKT mitigates asthmatic airway inflammation by inhibiting ROS-triggered NLRP3 activation and may be a potential agent for treating asthma., Competing Interests: The authors declare that there are no competing interests.

Background: It is as fact that dual-specificity phosphatase 1 (DUSP1) regulates the T cell activation, pro-allergic response, and inflammation to engage with the pathogenesis of asthma, but its clinical role in children with asthma is unclear. The present study aimed to explore the expression of DUSP1, its association with exacerbation risk, severity, and inflammatory cytokines in children with asthma., Method: Around 52 children with asthma-exacerbation, 50 children in asthma-remission, and 50 healthy children were chosen for the study. The serum levels of DUSP1, as well as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-17 were detected by the enzyme-linked immunosorbent assay., Results: The levels of DUSP1 was the highest in healthy children (median (IQR)=34.305 (25.892- 43.693) ng/mL), the second highest in children in asthma-remission (median (IQR)=21.471 (18.581-27.934) ng/mL), and the lowest in children with asthma-exacerbation (median (IQR)=13.982 (7.901-21.624) ng/mL) ( P <0.001). At the same time, DUSP1 was also related to decreased asthma risk with area under curve (AUC) (95%CI) of 0.847 (0.780-0.914), and correlated with its lower exacerbation risk with AUC (95%CI) of 0.755 (0.661-0.849). Besides, DUSP1 was negatively linked with exacerbation severity ( r s =-0.338, P =0.014), immunoglobulin E ( r s =-0.277, P =0.047), TNF-α ( r s =-0.423, P =0.002), IL-1β ( r s =-0.389, P =0.004), and IL-17 ( r s =-0.293, P =0.035), but not related with other disease features in children with asthma-exacerbation. Meanwhile, DUSP1 was only negatively associated with TNF-α (rs=-0.300, P=0.034) and IL-1β ( r s =-0.309, P =0.029) in children in asthma-remission. However, no correlation was found in DUSP1 with inflammatory cytokines or other disease features in healthy children (all P >0.05)., Conclusion: DUSP1 reflects the reduced exacerbation risk, and associates with lower exacerbation severity and inflammatory cytokines in children with asthma-exacerbation; it also associates with inflammatory cytokines in children in asthma-remission. These findings suggest that DUSP1 may help to improve the management of asthmatic children., Competing Interests: The authors declare no potential conflicts of interest with respect to research, authorship, and/or publication of this article.

The role of Dectin-2 (gene symbol, Clec4n) in house dust mite (HDM) induced Th2 immune response and the exact mechanism remains controversial. In this study, we illustrated that, Clec4n -/- mice had decreased Th2 immune response following HDM challenge, which may ascribe to dramatically reduced type 2 conventional dendritic cells (cDC2s) in lung of Clec4n -/- mice, as cDC2s from lung of Clec4n -/- mice after challenging had less ability to induce Th2 response with decreased production of IL-4/IL-13. Further in vitro experiments showed the activation of Clec4n -/- -BMDCs significantly decreased after HDM stimulation accompanied with decreased activation of Syk-NF-κB and Syk-JNK signal pathway. Importantly, Dectin-2 expression in PBMCs from asthmatic patients was significantly higher than that in healthy controls. Taken together, these results demonstrated that Dectin-2 could promote cDC2s activation in lung, which polarizes Th2 immune response outlining a novel mechanism of asthma development., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: The present study aimed to investigate the prevalence and associated factors of suboptimal daily peak inspiratory flow (PIF) and technical misuse of three commonly used dry powder inhalers (DPIs) in outpatients with stable chronic airway diseases., Patients and Methods: Included in this study were 85 outpatients with stable asthma, chronic obstructive pulmonary disease (COPD), or asthma-COPD Overlap (ACO) and had previously used any of Turbuhaler ® (TUR), Diskus ® (DIS), HandiHaler ® (HAN) between December 2018 and September 2019. The patient's daily PIF against the resistance of a specific DPI and operation technique was investigated by two pharmacists by using In-Check DIAL G16 and a checklist., Results: Of the 85 patients, the proportion of patients with a suboptimal daily PIF and technical misuse was 38.8% and 65.9%, respectively. In logistic regression, we observed that the factors that increase the risk for suboptimal daily PIF were age (OR=1.06) and combination with respiratory diseases (OR = 6.59). The factor that decreases the risk for misuse was the higher education level (OR =0.63)., Conclusion: Even if patients have received training at the time of initial prescription, the standardization of the use of DPIs by patients in our center was still unoptimistic. Age and combined with respiratory diseases were associated with suboptimal PIF. Higher education level decreased the incidence of technique misuse., Competing Interests: The authors have no conflicts of interest in this work., (© 2021 Ding et al.)

Background: Asthma is one of the most common noninfectious chronic diseases characterized by type II inflammation. This study aimed to investigate the effects of molecular hydrogen on the pathogenesis of asthma., Methods: OVA sensitized asthma mouse model and house dust mite treated 16HBE cellular model were established and hydrogen/oxygen mixture was used to treat asthmatic mice and 16HBE cells. Serum and BALF cytokines were measured with specific ELISA assays. E-cadherin and ZO-1 were detected by immunohistochemical staining and expression of caspase 3 and 9, NF-κB, IL-33 and ST2 was assessed by quantitative real-time PCR, western blot and/or immunofluorescence. IL-33 promoter activity was analyzed by dual-luciferase assay. ILC2 population was assayed by flow cytometry and differentially expressed miRNAs were detected using miRNA array., Results: Serum and BALF levels of IL-33 and other alarmin and type II cytokines were greatly increased by OVA and inhibited by H 2 in asthmatic mice. The expression of NF-κB (p65) and ST2 was upregulated by OVA and suppressed by H 2 . ILC2 population was markedly increased in OVA-induced asthmatic mice, and such increase was inhibited by H 2 . E-cadherin and ZO-1 levels in airway tissues of asthmatic mice were significantly lower than that of control mice, and the reduction was recovered by H 2 treatment. H 2 alleviated HDM induced apoptosis of 16HBE cells, upregulation of IL-33 and ST2, and elevation of IL-33 promoter activity. A group of miRNAs differentially expressed in HDM and HDM + H 2 treated 16HBE cells were identified., Conclusions: These data demonstrated that H 2 is efficient in suppressing allergen-induced asthma and could be developed as a therapeutics for asthma and other conditions of type II inflammation.

Background: The association between body mass index (BMI) status and childhood asthma control is not well understood. The aim of this study was to explore the association between BMI status and childhood asthma control. Methods: Two hundred forty-two children, aged 6-11 years, with asthma were included. The outcome variables were asthma control levels assessed by the Chinese version of the childhood asthma control test (C-ACT), asthma-related hospitalizations or emergency department (ED) visits in the past 12 months, and forced expiratory volume in 1 second (FEV 1 ) as a percentage of the predicted value. The associations between BMI status (underweight, overweight, or obese, relative to normal weight) and the three outcome variables were estimated by ordinal logistic regression, binary logistic regression, and multiple linear regression analyses. Results: No significant association was found between BMI status and asthma control levels assessed by C-ACT, and between BMI status and asthma-related hospitalizations or ED visits in the past 12 months, after adjustment for age, sex, father's education level, mother's education level, per capita family monthly income, medical insurance, passive smoking, allergic rhinitis, course of disease, and medication compliance. A significant association between underweight and FEV 1 as a percentage of the predicted value was found after adjustment for the above covariates. However, no significant association between overweight or obese and FEV 1 as a percentage of the predicted value was found. Conclusions: This study shows that BMI status may not be associated with childhood asthma control. Given the inconsistency in current evidence, more studies are needed in the future to investigate this association.

Background: Asthma is a common chronic airway disease worldwide. Despite its large population size, China has had no comprehensive study of the national prevalence, risk factors, and management of asthma. We therefore aimed to estimate the national prevalence of asthma in a representative sample of the Chinese population., Methods: A representative sample of 57 779 adults aged 20 years or older was recruited for the national cross-sectional China Pulmonary Health (CPH) study using a multi-stage stratified sampling method with parameters derived from the 2010 census. Ten Chinese provinces, representative of all socioeconomic settings, from six geographical regions were selected, and all assessments were done in local health centres. Exclusion criteria were temporary residence, inability to take a spirometry test, hospital treatment of cardiovascular conditions or tuberculosis, and pregnancy and breastfeeding. Asthma was determined on the basis of a self-reported history of diagnosis by a physician or by wheezing symptoms in the preceding 12 months. All participants were assessed with a standard asthma questionnaire and were classed as having or not having airflow limitation through pulmonary function tests before and after the use of a bronchodilator (400 μg of salbutamol). Risk factors for asthma were examined by multivariable-adjusted analyses done in all participants for whom data on the variables of interest were available. Disease management was assessed by the self-reported history of physician diagnosis, treatments, and hospital visits in people with asthma., Findings: Between June 22, 2012, and May 25, 2015, 57 779 participants were recruited into the CPH study. 50 991 (21 446 men and 29 545 women) completed the questionnaire survey and had reliable post-bronchodilator pulmonary function test results and were thus included in the final analysis. The overall prevalence of asthma in our sample was 4·2% (95% CI 3·1-5·6), representing 45·7 million Chinese adults. The prevalence of asthma with airflow limitation was 1·1% (0·9-1·4), representing 13·1 million adults. Cigarette smoking (odds ratio [OR] 1·89, 95% CI 1·26-2·84; p=0·004), allergic rhinitis (3·06, 2·26-4·15; p<0·0001), childhood pneumonia or bronchitis (2·43, 1·44-4·10; p=0·002), parental history of respiratory disease (1·44, 1·02-2·04; p=0·040), and low education attainment (p=0·045) were associated with prevalent asthma. In 2032 people with asthma, only 28·8% (95% CI 19·7-40·0) reported ever being diagnosed by a physician, 23·4% (13·9-36·6) had a previous pulmonary function test, and 5·6% (3·1-9·9) had been treated with inhaled corticosteroids. Furthermore, 15·5% (11·4-20·8) people with asthma reported at least one emergency room visit and 7·2% (4·9-10·5) at least one hospital admission due to exacerbation of respiratory symptoms within the preceding year., Interpretation: Asthma is prevalent but largely undiagnosed and undertreated in China. It is crucial to increase the awareness of asthma and disseminate standardised treatment in clinical settings to reduce the disease burden., Funding: National Key R&D Program of China, Ministry of Science and Technology of China; the Special Research Foundation for Public Welfare of Health, Ministry of Health of China; the Chinese National Research Program for Key Issues in Air Pollution Control; and the National Natural Science Foundation of China., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Eosinophilia is considered to be associated with allergic disease and may predict asthma exacerbation. Eosinophils contribute to the pathophysiology and pathogenesis of asthma. However, studies on high blood eosinophil counts (BECs) and incident asthma remain scarce., Objective: To examine whether high BECs are positively associated with incident asthma in adults., Methods: Our study included 57975 participants aged from 20 to 79 years from the Shandong multi-center health check-up longitudinal study for Health Management. All patients with determined baseline BECs were ≥20 years old and free from asthma. We defined incident asthma as self-reported new-onset asthma occurring during the 10-year follow-up period. Multivariate modeling employed Poisson regression and Cox proportional hazards models to verify the association between BEC and incident asthma by adjusting demographics and some relevant comorbidities (rhinitis, nasal polyps, pneumonia, bronchitis, and chronic obstructive pulmonary disease)., Results: A BEC ≥110 cells/μL was a risk factor for incident asthma (adjusted IRR = 1.62, 95% CI: 1.05-2.50, P = .028) in the Poisson regression. In the Cox proportional hazards model, the BEC cutoff point for incident asthma was also determined to be 110 cells/μL (HR = 1.59, 95% CI: 1.01-2.51, P = .045)., Conclusion: A high BEC is a risk factor for incident asthma, especially when the BEC exceeds 110 cells/μL. This suggests that adults with high BECs are more likely to develop asthma., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The area of asthma medicine has produced a large volume of important clinical and scientific papers that can be found in those most influential journals. The purpose of our study was to identify the 100 most cited papers in asthma research and to analyze their characteristics., Methods: We used the Institute for Scientific Information Web of Knowledge Database to identify the most frequently cited articles published from 1960 to December 2017. Original articles and reviews were included in the study. The 100 top-cited articles were then analyzed with regard to number of citations, publication year, journals, institution, research type and field, authors and countries of authors of publications., Results: The 100 top-cited articles in asthma were published between 1960 and 2011 with a median of 933 citations per article (range, 701-2947). The number of citations per article was greatest for articles published in the 1990s. The United States of America contributed most of the classic articles, followed by England. The leading institutions were Imperial College London, McMaster University, Erasmus University Rotterdam. The 100 top-cited articles were published in twenty-five journals, led by The New England Journal of Medicine (21 articles), followed by American Journal of Respiratory and Critical Care Medicine (19 articles), Lancet (11 articles), respectively. Among the 100 classics, 50% articles were clinical research articles., Conclusions: Our study provides a historical perspective on the progress of research on asthma. Studies conducted in well-developed European countries and North America, published in high-impact journals had the highest citations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To test the psychometric properties of the Chinese version of the Mini Asthma Quality of Life Questionnaire (MiniAQLQ) and to investigate the differences between the MiniAQLQ completed by patients (p-MiniAQLQ) and by their relatives (r-MiniAQLQ)., Methods: One hundred and two asthmatic patients and 45 relatives were recruited. The reliability was evaluated using Cronbach's alpha and intraclass correlation coefficient (ICC). The validity of the MiniAQLQ was assessed by comparing it with the Sydney Asthma Quality of Life Questionnaire (AQLQ-S) and lung function measurements. The mean quality of life scores were compared by gender and smoking history, and the p-MiniAQLQ scores were then compared with the r-MiniAQLQ scores., Results: The MiniAQLQ showed high internal consistency (Cronbach's alpha = 0.901) and a high two-week reproducibility (ICC = 0.863). The cross-sectional correlations between the MiniAQLQ and the AQLQ-S were strong. Correlations between the MiniAQLQ and lung function (predicted FEV1% and PEF) ranged from poor to weak at the total or domain levels. The MiniAQLQ scores were not significantly associated with gender or smoking history. There was poor agreement between the p-MiniAQLQ and r-MiniAQLQ scores at the total or domain levels., Conclusions: The Chinese version of the MiniAQLQ showed good reliability and validity. It is reliable for evaluating the impact of asthma on patients' quality of life. Relatives of the patients did not have a comprehensive grasp of the patients' conditions. Physicians should be cautious when patients' relatives come to the hospital to seek a modified treatment when the patients are not present.

Aquaporins (AQPs ) are water channel proteins supposed to facilitating fluid transport in alveolar space, airway humidification, pleural fluid absorption, and submucosal gland secretion . In this chapter, we mainly focus on the expression of 4 AQPs in the lungs which include AQP1, AQP2 , AQP4 and AQP5 in normal and disease status, and the experience of AQPs function from various model and transgenic mice were summarized in detail to improve our understanding of the role of AQPs in fluid balance of respiratory system. It has been suggested that AQPs play important roles in various physiology and pathophysiology conditions of different lung diseases. There still remains unclear the exact role of AQPs in lung diseases, and thus continuous efforts on elucidating the roles of AQPs in lung physiological and pathophysilogical processes are warranted.

Type 2 innate lymphoid cells (ILC2s) have been shown to produce large amounts of type 2 cytokines in a non-antigen-specific manner. These cytokines act upstream and downstream of ILC2 and are increasingly common in asthma drug development, thus warranting a closer investigation of the mechanism-related clinical manifestations of ILC2 in the selection of patients with asthma. We hypothesized that IL-13 + ILC2s in the circulation might correlate with asthma control status as a result of persistent T-helper cell type 2 (Th2) inflammation in the lung. Furthermore, we aimed to explore ILC2s' responsiveness to glucocorticoid. The percentages of ILC2s and IL-13 + ILC2s in different asthma subgroups were checked, and correlation analyses between ILC2s and asthma-related clinical parameters were performed. Dexamethasone treatments in ILC2s and Th2 cells were performed to clarify their response properties. ILC2s were identified as a Lin - CD45 hi IL-7Rα + CRTH2 + cell population distinct from human peripheral blood mononuclear cells. Frequencies of ILC2s were increased dramatically in those with asthma (0.04 ± 0.02%) compared with healthy donors (0.025 ± 0.011%). The percentages of IL-13 + ILC2s were significantly higher in patients in the uncontrolled group (49.7 ± 16.9%) and partly controlled groups (30.8 ± 13.1%) than in those in the well-controlled group (16.7 ± 5.9%) and healthy control subjects (18.7 ± 8.7%). Effective treatment of uncontrolled IL-13 + ILC2-positive patients with asthma resulted in dynamic modulation of IL-13 + ILC2 levels back to baseline. ILC2s were more resistant to glucocorticoid than Th2 cells in vitro. ILC2s are strong responders to IL-25/IL-33 stimulation. IL-13 + ILC2s show a positive correlation with patient asthma control status and are more resistant to glucocorticoid than Th2 cells in humans.

Belching is a common symptom of gastroesophageal reflux disease. If the symptoms are not relieved after anti-reflux treatment, another etiology should be considered. Here, we report a case of a 43-year-old man who presented with belching, regurgitation, chest tightness and dyspnea for 18 mo, which became gradually more severe. Gastroscopic examination suggested superficial gastritis. Twenty-four-hour esophageal pH monitoring showed that the Demeester score was 11.4, in the normal range. High-resolution manometry showed that integrated relaxation pressure and intrabolus pressure were higher than normal (20 mmHg and 22.4 mmHg, respectively), indicating gastroesophageal junction outflow tract obstruction. Pulmonary function test showed severe obstructive ventilation dysfunction [forced expiratory volume in 1 second (FEV1)/forced vital capacity 32%, FEV1 was 1.21 L, occupying 35% predicted value after salbuterol inhalation], and positive bronchial dilation test (∆FEV1 260 mL, ∆FEV1% 27%). Skin prick test showed Dermatophagoides farinae (++), house dust mite (++++), and shrimp protein (++). Fractional exhaled nitric oxide measurement was 76 ppb. All the symptoms were alleviated completely and pulmonary function increased after combination therapy with corticosteroids and long-acting β2-agonist. Bronchial asthma was eventually diagnosed by laboratory tests and the effect of anti-asthmatic treatment, therefore, physicians, especially the Gastrointestinal physicians, should pay attention to the belching symptoms of asthma.

Rationale: Host antioxidant defense, consisting of enzymatic antioxidant activity and nonenzymatic antioxidant micronutrients, is implicated in asthma pathogenesis. Studies of antioxidant defense and adult incident asthma have either used measures of antioxidants estimated from questionnaires or not considered enzymatic aspects of host defense., Objectives: We conducted the first study designed and powered to investigate the association of antioxidant defenses on adult incident asthma., Methods: In a nested case-control study, we followed Shanghai women (aged 40-70 years) without prevalent asthma at baseline, over 8 years. Subjects with incident asthma were ascertained prospectively by gold standard testing of symptomatic women and matched to two asymptomatic control subjects., Measurements and Main Results: Baseline urinary F2-isoprostanes, plasma concentrations of antioxidant micronutrients (tocopherols, xanthines, carotenes, and lycopene), and antioxidant enzyme activity (platelet-activating factor acetylhydrolase [PAF-AH] and superoxide dismutase) were measured from samples collected before disease onset. Among 65,372 women, 150 (0.24%) developed asthma. F2-isoprostane levels before asthma onset were not different between cases and control subjects. Doubling of α-tocopherol concentrations and PAF-AH activity was associated with 50 and 37% decreased risk of incident asthma (α-tocopherol: adjusted odds ratio = 0.52; 95% confidence interval, 0.32-0.84; PAF-AH: adjusted odds ratio = 0.63; 95% confidence interval, 0.42-0.93)., Conclusions: In this prospective study, α-tocopherol, within normal reference ranges, and PAF-AH enzymatic activity were associated with decreased asthma development. These modifiable risk factors may be an effective strategy to test for primary asthma prevention.

Background: TH2 cells play a critical role in the pathogenesis of allergic asthma. Established TH2 cells have been shown to resist reprogramming into TH1 cells. The inherent stability of TH2 cells poses a significant barrier to treating allergic diseases., Objective: We sought to understand the mechanisms by which CD4(+) T cells from asthmatic patients resist the IL-27-mediated inhibition., Methods: We isolated and cultured CD4(+) T cells from both healthy subjects and allergic asthmatic patients to test whether IL-27 can inhibit IL-4 production by the cultured CD4(+) T cells using ELISA. Culturing conditions that resulted in resistance to IL-27 were determined by using both murine and human CD4(+) T-cell culture systems. Signal transducer and activator of transcription (STAT) 1 phosphorylation was analyzed by means of Western blotting and flow cytometry. Suppressor of cytokine signaling (Socs) mRNA expression was measured by using quantitative PCR. The small interfering RNA method was used to knockdown the expression of Socs3 mRNA., Results: We demonstrated that CD4(+) T cells from asthmatic patients resisted the suppression of IL-4 production mediated by IL-27. We observed that repeated exposure to TH2-inducing conditions rendered healthy human CD4(+) T cells resistant to IL-27-mediated inhibition. Using an in vitro murine culture system, we further demonstrated that repeated or higher doses of IL-4 stimulation, but not IL-2 stimulation, upregulated Socs3 mRNA expression and impaired IL-27-induced STAT1 phosphorylation. The knockdown of Socs3 mRNA expression restored IL-27-induced STAT1 phosphorylation and IL-27-mediated inhibition of IL-4 production., Conclusions: Our findings demonstrate that differentiated TH2 cells can resist IL-27-induced reprogramming toward TH1 cells by downregulating STAT1 phosphorylation and likely explain why the CD4(+) T cells of asthmatic patients are resistant to IL-27-mediated inhibition., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Previous studies proved that bone marrow-derived mesenchymal stem cells (BMSCs) could improve a variety of immune-mediated disease by its immunomodulatory properties. In this study, we investigated the effect on airway remodeling and airway inflammation by administrating BMSCs in chronic asthmatic mice. Forty-eight female BALB/c mice were randomly distributed into PBS group, BMSCs treatment group, BMSCs control group, and asthmatic group. The levels of cytokine and immunoglobulin in serum and bronchoalveolar lavage fluid were detected by enzyme-linked immunosorbent assay. The number of CD4(+) CD25(+) regulatory T cells and morphometric analysis was determined by flow cytometry, hematoxylin-eosin, immunofluorescence staining, periodic-acid Schiff, and masson staining, respectively. We found that airway remodeling and airway inflammation were evident in asthmatic mice. Moreover, low level of IL-12 and high levels of IL-13, IL-4, OVA-specific IgG1, IgE, and IgG2a and the fewer number of CD4(+) CD25(+) regulatory T cells were present in asthmatic group. However, transplantation of BMSCs significantly decreased airway inflammation and airway remodeling and level of IL-4, OVA-specific IgE, and OVA-specific IgG1, but elevated level of IL-12 and the number of CD4 + CD25 + regulatory T cells in asthma (P < 0.05). However, BMSCs did not contribute to lung regeneration and had no significant effect on levels of IL-10, IFN-Y, and IL-13. In our study, BMSCs engraftment prohibited airway inflammation and airway remodeling in chronic asthmatic group. The beneficial effect of BMSCs might involved the modulation imbalance cytokine toward a new balance Th1-Th2 profiles and up-regulation of protective CD4 + CD25 + regulatory T cells in asthma, but not contribution to lung regeneration., (Copyright © 2013 Wiley Periodicals, Inc.)

Mesenchymal stem cells attenuate the severity of lung injury due to their immunomodulatory properties. The effect of bone marrow-derived mesenchymal stem cells on asthma is seldom reported. We have examined the effect of BMSCs on airway inflammation in asthma. Forty female BALB/c mice were equally randomised into PBS group, BMSCs treatment group, BMSCs control group and asthmatic group. Reactivity of the airway to acetylcholine was measured by barometric plethysmography. Cytokine profiles of bronchoalveolar lavage fluid and serum were determined by enzyme-linked immunosorbent assay. Morphometric analysis was done with haematoxylin and periodic-acid Schiff staining. Engraftment of BMSCs in asthmatic mice significantly decreased the number of eosinophils and mononuclear cells in bronchoalveolar lavage fluid and the airway (P < 0.05). Both goblet cell hyperplasia and responsiveness to acetylcholine were significantly reduced in BMSCs treatment groups. Moreover, BMSCs engraftment caused significant increases the ratio of Treg in pulmonary lymph node and interleukin-10 (IL-10) and interleukin-12 levels in BALF and serum. We conclude that BMSCs engraftment ameliorated airway inflammation and improved lung function in asthmatic mouse and the protective effect might be mediated by upregulating Treg and partly involved with increasing IL-10., (© 2013 International Federation for Cell Biology.)

Objective: Current dry powder inhalers (DPIs), introduced to overcome problems associated with pressurized metered dose inhalers (pMDIs), possess not only difficulties originating from their designs but also other barriers that prevent their correct usage. The authors of this study investigated the ease and correctness of use of Swinghaler, a new device in the form of multidose DPI, as well as the preference of the study participants for either a Swinghaler or a Turbuhaler., Methods: A total of 260 patients from Korea, China, Indonesia, the Philippines, Taiwan, and Thailand were prospectively recruited. Patients who had stable asthma, were more than 12 years old, had no experience with DPIs, and provided informed consents were included, whereas those with limited physical or intellectual ability and prior experience with any DPIs were excluded., Results: There were no group or time effects between the patients who were assigned to use a Swinghaler or a Turbuhaler first. Forty-one (16.1%) participants correctly performed the inhalation maneuver with a Swinghaler, whereas 28 (10.9%) did so with a Turbuhaler; the difference was not statistically significant. The overall assessment on the precise use of the devices indicated that there were no differences between Swinghaler and Turbuhaler usage. Comparing the preference scales between the two devices, the participants gave higher scores to the Swinghaler for all assessment items and were more satisfied with the Swinghaler compared with the Turbuhaler (78.5% vs. 55.0%, p < .001)., Conclusions: The participants showed no difference in their ability to correctly use a Swinghaler when compared with a Turbuhaler and preferred the Swinghaler. These results suggest that the Swinghaler may be an effective and valuable tool for the management of airway diseases.

Salmeterol is a long-acting β2-agonist that activates adenylate cyclase, causing long-lasting bronchodilation and has been used for many years to control asthma. However, little information is available about the immunoregulatory effects of salmeterol. We found that salmeterol decreases the production of pro-inflammatory cytokines in a model of allergen-challenged mice that expressed tumor-necrosis factor-alpha, interleukin-1 and interleukin-6. Dendritic cells (DCs) are antigen-presenting cells and act as sentinels in the airway. We found that salmeterol (10(-5) mol/l) reduced the inflammation caused by lipopolysaccharide (0.1 µg/ml) in activated murine bone marrow-derived DCs. Moreover, western blots demonstrated that this protective effect was mediated partially by inhibiting signaling through the nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) pathways and dramatically decreased levels of p-ERK. We suggest that salmeterol regulates the inflammation of allergen-induced asthma by modulating DCs. In conclusion, we provide evidence that DCs are the target immune cells responsible for the action of salmeterol against asthma.

Ovalbumin (OVA)-induced asthma in mouse lungs causes changes in the mRNA and protein levels of aquaporins (AQPs). AQP expression was examined in the presence of various anti-asthmatic agents, including dexamethasone, ambroxol, and terbutaline. The influence of these agents on OVA-induced airway inflammation was also evaluated. The mRNA expression levels of AQP1, 4, and 5 were significantly reduced and that of AQP3 was significantly increased 24h after the last OVA exposure. The protein levels of AQP1, 3, and 5 mirrored the mRNA expression profiles, but AQP4 did not exhibit any changes. Only the mRNA and protein expression levels of AQP1 and AQP5 were significantly increased by these three anti-asthmatic agents. Dexamethasone and ambroxol improved the eosinophil infiltration, mucus secretion, and pulmonary edema caused by OVA, but terbutaline only alleviated pulmonary edema. These results indicate that AQP1 and AQP5 are closely related to pulmonary edema but not to eosinophil infiltration or mucus secretion during asthma. Anti-asthmatic agents could alleviate pulmonary edema through upregulating the expression of AQP1 and AQP5 in mouse lungs that have OVA-induced asthma., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: Multiple genetic and environmental factors impact the pathogenesis of asthma. ADAM33 (a disintegrin and metalloproteinase domain 33) represents a novel susceptibility gene for asthma in several diverse populations. The aim of this study was to determine whether single nucleotide polymorphisms (SNPs) of the ADAM33 gene associate with asthma susceptibility and severity in the Chinese Han population., Methods: A total of 224 subjects were enrolled, including 74 normal controls and 150 asthmatic patients. The asthmatic enrollees were further categorized into high- or low-severity groups according to the percentage of forced expiratory volume in 1 second of predicted value, symptoms, nighttime awakening, requirement for short-acting β2-agonist, and interference with normal activities. Six SNPs (F + 1, ST + 4, S1, S2, T1, and T2) in ADAM33 were genotyped using the polymerase chain restriction fragment length polymorphism method., Results: Three SNPs (F + 1, T1, and T2) of ADAM33 were found to have significant associations with asthma in the study population (p = .0058-.0067). The allele frequencies of two SNPs (F + 1, T1) in both the low- and high-severity groups were significantly different from the allele frequency in the control group. The allelic frequency of the T2 SNP was significantly different from that of the control group only in the high-severity group (p = .0081). Haplotype analysis demonstrated that the frequency of 7575G, 12433T, and 12462C (GTC haplotype) is higher in healthy controls than amongst asthma patients (78.4% vs. 61.8%, p = .0004)., Conclusions: Polymorphisms of the ADAM33 gene associate with asthma susceptibility in the east China Han population, and the genetic association is stronger in high-severity asthmatics.

Airway inflammation and mucus hyperproduction play the central role in the development of asthma, although the mechanisms remain unclear. The aquaporin (AQP)-5 may be involved in the process due to its contribution to the volume of liquid secreted from the airways. The present study firstly found the overexpression of AQP5 in the airway epithelium and submucosal glands of asthmatics. Furthermore, we aimed at evaluating the role of AQP5 in airway inflammation and mucous hyperproductions during chronic allergic responses to house dust mite (HDM). Bronchoalveolar lavage levels of interleukin (IL)-2, IL-4, IL-10, interferon-γ and Mucin 5AC (MUC5AC), and number of peribronchial and perivascular cells were measured in AQP5 wild-type and AQP5 knockout (KO) mice. We found that HDM induced airway inflammation, lung Th2 cell accumulation and mucin hypersecretion in C57BL/6 mice rather than AQP5 KO mice. Expression of MUC5AC and MUC5B proteins and genes in the lung tissue was significantly lower in AQP5 KO mice. Thus, our results implicate involvement of AQP5 in the development of airway inflammation and mucous hyperproduction during chronic asthma., (© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

Background: The criteria used to identify persons with asthma in epidemiologic studies are varying and, depending on the method used, can be challenging and resource consuming., Objective: To develop a nomogram (scoring system) to identify adult patients with asthma using a combination of variables collected via a validated questionnaire., Methods: We studied the first 268 women aged 40 to 69 years in the Shanghai Women's Asthma and Allergy Study who reported signs and symptoms of asthma and underwent either methacholine challenge testing or test of reversibility during the asthma screening survey between 2003 and 2007. These women were defined as having definite asthma (n=106) or not (n=162). Multivariable logistic regression analysis was performed to develop a predictive model for identifying asthma using survey information alone., Results: Clinically relevant questions were used for the predictive multivariable logistic regression model and included the following: ever wheezing or whistling in the chest, current medication use for asthma, self-reported ever asthma, self-reported ever allergic rhinitis, family history of allergy, and age. The area under the receiver operating characteristic curve of the prediction model was 0.75 (95% confidence interval, 0.69-0.81). A nomogram was developed to assess the individual probability of asthma based on individually weighted variables in the predictive model., Conclusions: In clinical or epidemiologic studies, this asthma nomogram could be used as a tool to assess the probability of asthma for an individual patient by incorporating asthma-related predictor variables obtained through a field questionnaire., (Copyright © 2010 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Vaccination with allergen-encoding DNA has been proposed as having potential for allergen-specific immunotherapy. In this study, we examine the therapeutic effect of allergen-encoding DNA vaccination directly to dendritic cells (DCs) on allergen-induced allergic airway inflammation in a mouse model and explore potential mechanism. Ovalbumin (OVA)-sensitized and challenged mice were immunized with DNA vaccine and received bronchoalveolar lavage (BAL) 1 day after the last challenge, to measure BAL levels of interleukin (IL)-4, IL-5, interferon (IFN)-gamma and differential cell count. Pulmonary DCs and Spleen DCs were purified and sorted according to the expression of CD(11c) (+)CD(80) (+) and CD(11c) (+)CD(86) (+) co-stimulatory molecules. Our data demonstrated that DNA vaccine therapy with OVA-Fc-pcDNA(3.1) significantly prevented OVA-increased levels of IL-4, IL-5 and the percentage of eosinophils and OVA-decreased level of IFN-gamma. OVA-Fc-pcDNA(3.1)-treated mice had less severity of airway inflammation, and lower expression of CD(11c) (+)CD(80) (+) and CD(11c) (+)CD(86) (+) on pulmonary DCs, as compared with animals with OVA-pcDNA(3.1,) pcDNA(3.1) and OVA respectively. DNA vaccine encoding both Fc and OVA was shown to be more effective than DNA vaccine encoding OVA alone. Our data indicate that Fc-antigen combination-encoding DNA vaccination has better preventive effects on antigen-induced airway inflammation by regulating DCs, and may be a new alternative therapy for asthma.

Aquaporin 5 (AQP5) is one of the water channel proteins which participate in a wide array of physiological processes and are primary determinants of membrane osmotic water permeability. The AQP5 gene is located in human chromosome 12q, the same region as the location of the major asthma susceptibility loci. In this study we try to determine whether the AQP5 knock-out has some effect on allergen-induced asthma. With a mouse asthma model induced by ovalbumin (OVA), we found that deletion of AQP5 reduced some major characteristic features of asthma, such as less inflammation cell infiltration in lung tissues, lower cytokine expression and fewer inflammation cells in bronchoalveolar lavage fluids compared with those from wild-type (WT) mice. Because it was found that mice injected intratracheally with OVA-pulsed dendritic cells (DCs), the AQP5 gene knock-out (AQP5(-/-)) ones presented fewer inflammation cells. Because DCs are major antigen-presenting cells that play an important role in antigen-induced asthma, we also probed into the possible effect of gene knock-out on DCs. Surprisingly, reverse transcription-polymerase chain reaction and fluorescence activated cell sorter analysis showed high levels of AQP5 on the surface of DCs from in vivo or bone marrow monocyte-derived DCs (mDC) in vitro. Immature mDC from AQP5 knock-out mice (AQP5(-/-)) showed decreased expression of CD80 and CD86 and endocytosis ability compared with that from WT, but the difference disappeared after mDCs matured with lipopolysaccharide. AQP5-mediated water transmembrane may play some role in the function of DCs. However, the mechanism of the effect of AQP5 on the DCs' function needs to be investigated further.

Asthma and allergic rhinitis frequently coexist in the same patient. There is a similarity and variation as well as potential relationship between asthma and allergic rhinitis. There is an increasing evidence to suggest a major involvement of airway epithelial cells in the pathogenesis of asthma and allergic rhinitis. The present review describes the importance of the airway epithelial cell in the development of allergic airway diseases, its role as the primary airway defense against exposure of the airway and lung to inflammatory stimuli and antigens and as an important player through activation of epithelial Toll-like receptors (TLRs) to provide an important link between innate immunity and allergic disease. Additionally, airway epithelial cells can act as inflammatory promoters capable of directing dendritic cells (DCs) towards a T helper 2 (Th2) response, and as active producers of several inflammatory/anti-inflammatory mediators. It is hypothesized that airway epithelial cells may play as both inflammatory initiator and immuno-pathological feedback regulation between allergic rhinitis and asthma via release of systemic inflammatory mediators. Thus, airway epithelial cells may be valuable therapeutic targets for discovery and development of new drugs and/or new therapeutic strategies to treat asthma and allergic rhinitis.

The Shanghai Women's Asthma and Allergy Study is the first population-based incidence study designed to assess the associations of dietary antioxidant intake and measures of oxidative stress and antioxidant enzyme activity with development of adult-onset asthma and allergic rhinitis. A total of 65,732 participants in the Shanghai Women's Health Study, an ongoing cohort study in seven districts of Shanghai, People's Republic of China, were recruited to the Shanghai Women's Asthma and Allergy Study from 2003 to 2007. Dietary intake was assessed in the parent study by using a validated and quantitative food frequency questionnaire at baseline recruitment and at the first biennial follow-up survey. Blood and urine samples were collected to measure baseline oxidative stress, antioxidant enzyme activity, and nutrient levels at the baseline survey. Incident asthma and allergic rhinitis were assessed by using a modification of the International Study of Asthma and Allergies in Childhood questionnaire during the biennial in-person survey of the Shanghai Women's Health Study. Diagnosis of asthma was confirmed by either methacholine challenge testing or test of reversibility to beta-agonists. Dietary antioxidant intake, plasma antioxidants, antioxidant enzymes, and urinary isoprostanes, a marker of oxidative stress, were measured prior to disease onset. This paper describes the study objectives, design, population demographics, and recruitment results.

Cysteinyl-leukotrienes are important pro-inflammatory mediators in bronchial asthma (BA) and are derived from arachidonic acid by the action of 5-lipoxygenase. We identified a novel polymorphism, c.760 G>A (E254K), in exon 6 of the 5-lipoxygenase gene (5-LO). This substitution was detected in 11 out of 180 patients with BA, but not in any of the 150 non-allergic subjects. The frequency of c.760 G>A showed a significant difference between BA and non-allergic subjects (P=0.0007). The c.760 G>A polymorphism existed at the surface edge of the C-terminal catalytic domain, and the E-to-K substitution changed the charge of the side chain from negative to positive. Thus, our results suggest that E254K in the 5-LO might be associated with BA.

Aim: We aimed to observe the clinical practicing value of radial endobronchial ultrasonography evaluating airway wall thickness before and after bronchial thermoplasty. Methods: We selected two patients who received bronchial thermoplasty in our hospital. We measured the thickness of each segmental airway wall of each patient by radial endobronchial ultrasonography, and observed the difference before and after the therapy. All the treatments and measurement were performed by a designated bronchoscopist and the locations and depths of the ultrasound probe were relatively fixed, to reduce the operational error. Results: In both two patients, the mean thicknesses of all segmental airway walls was 4.9 ± 0.7 mm before the first session of BT; the mean thickness was 4.13 ± 0.92 mm before the second session; the mean thickness was 2.69 ± 0.68 mm before the third session; the mean thickness was 2.7 ± 0.5 mm in the follow-up measurement at six months after the BT treatment; all thicknesses of airway wall were significantly reduced comparing with those before treatment; all the thicknesses of the airway walls were stable without any tendency of thickening after six months. Although the airways in the right middle lobe of both two patients were not received BT, their thicknesses were also decreased comparing with those before the treatment; both upper lobes bronchus of both two patients were not activated in the first and second sessions, but their thicknesses were also decreased at the third measurement. Conclusion: Radial endobronchial ultrasonography is a simple and practical method to measure the thickness of patient's airway wall. Bronchial thermoplasty can effectively reduce the thickness of airway wall. It can reduce airway smooth muscle by direct activation and other possible more complicated mechanism, which need further research.