Establishment of an asthma model by sensitization with mite antigen alone in C57BL/6J mice

Bronchial asthma is characterized by the bronchial hyperresponsiveness and airway obstruction related to airway smooth muscle contraction. Eosinophilic airway inflammation is involved in its pathogenesis. To reproduce the condition, various animal models have been prepared. However, there are many models that do not reflect the spontaneous history of bronchial asthma onset in humans due to the mouse strain, sensitizing antigen, or administration method. In this study, we prepared a mouse model of which the mechanism is similar to that of human bronchial asthma. Mite Extract-Dermatophagoides farinae (Derf) antigen was transnasally administered to wild-type C57BL/6J mice (WT) 13 times. Subsequently, an airway hypersensitivity test (Mch PC_200), specific antigen exposure test (ΔSRaw), bronchoalveolar lavage (BAL), and blood collection were performed to examine the presence or absence of asthma acquisition and differences in the local pulmonary levels of cytokines/chemokines in comparison with the physiological saline-treated group. In the mite antigen-treated mice (WT/-Derf), bronchial hyperresponsiveness was enhanced, antigen-specific was increased airway resistance in comparison with physiological salinetreated mice (WT/-Saline). In addition, the number of eosinophils in BAL fluid (BALF) was greater. Furthermore, there was a correlation among leukotrienes, eotaxin, and tissue inhibitors of metalloproteinase 1 in BALF, suggesting that the mechanism concerning eosinophilic airway inflammation involving in human bronchial asthma was reproduced. In this study, we successfully established a mouse bronchial asthma model in which the pathogenesis resembles that in humans in comparison with conventional models, using Derf antigen alone and C57BL/6J mice

Fatal Asthma with Rhabdomyolysis Induced by Hair Dye

Hair dyes have been reported to cause exacerbation of asthma in hairdressers through occupational exposure. We report a 54-year-old housewife who developed a fatal asthma attack following the use of a hair dye at home. She was admitted semiconscious with multiple organ failure. Laboratory findings were indicative of rhabdomyolysis. Skin prick and interdermal tests with hair dyes were performed. Hair dyes can be nonspecific stimuli that cause an asthma attack. But in our case, we cannot deny the possibility that the attack resulted from antigen-antibody reaction by the hair dye. We should warn that hair dyes can cause an asthma attack not only through occupational exposure but also through occasional domestic use

Associations of chemical composition and sources of PM2.5 with lung function of severe asthmatic adults in a low air pollution environment of urban Nagasaki, Japan

Previous studies have linked ambient PM2.5 to decreased pulmonary function, but the influence of specific chemical elements and emission sources on the severe asthmatic is not well understood. We examined the mass, chemical constituents, and sources of PM2.5 for short-term associations with the pulmonary function of adults with severe asthma in a low air pollution environment in urban Nagasaki, Japan. We recruited 35 asthmatic adults and obtained the daily record of morning peak expiratory flow (PEF) in spring 2014–2016. PM2.5 filters were extracted from an air quality monitoring station (178 days) and measured for 27 chemical elements. Source apportionment was performed using Positive Matrix Factorization (PMF). We fitted generalized linear model with generalized estimating equation (GEE) method to estimate changes in PEF (from personal monthly maximum) and odds of severe respiratory deterioration (first ≥ 15% PEF reduction within a 1-week interval) associated with mass, constituents, and sources of PM2.5, with adjustment for temperature and relative humidity. Constituent sulfate (SO42−) and PM2.5 from oil combustion and traffic were associated with reduced PEF. An interquartile range (IQR) increase in SO42− (3.7 μg/m3, average lags 0–1) was associated with a decrease of 0.38% (95% confidence interval = −0.75% to −0.001%). An IQR increase in oil combustion and traffic-sourced PM2.5 (2.64 μg/m3, lag 1) was associated with a decrease of 0.33% (−0.62% to −0.002%). We found a larger PEF decrease associated with PM2.5 from dust/soil on Asian Dust days. There was no evidence linking total mass and metals to reduced pulmonary function. The ventilatory capacity of adults with severe asthma is susceptible to specific constituents/sources of PM2.5 such as sulfate and oil combustion and traffic despite active self-management of asthma and low air pollution levels in the study location

The exacerbation risk prediction by fractional exhaled nitric oxide in younger and elder children with bronchial asthma

The usefulness of the Fractional exhaled nitric oxide (FeNO) measurements for asthma exacerbation risk prediction in asthmatic children is controversial. Fifty-seven asthmatic children who were regularly treated and had previously been stable for at least 3 months were enrolled. The asthma excerbations risk prediction by the FeNO levels and age contribution on it were investigated. As analyzed all the patients, FeNO cut off value for the significant risk of asthma exacerbation was 36.9 ppb (risk odds was 5.1 [95% C.I., 1.8 to 15.0], chi square valve = 9.0, p=0.0028). However, sensitivity and specificity were not adequate for predicting asthma exacerbation (Sensitivity, 77.8%; Specificity, 59.9%; Area under the curve [AUC], 0.674). These parameters were improved only when 6-10 year old children were assessed (FeNO threshold=39.9 ppb, risk odds=10.2 [3.1 to 33.1], chi square valve 14.8, p=0.0001); Sensitivity, 80.8%; Specificity, 71.8%; AUC, 0.758). High value of FeNO is a risk factor for the asthma exacerbation, and FeNO measurement may be more useful for asthma control in younger children than elder asthmatic children

Determining Response to Treatment for Drug-Induced Bronchocentric Granulomatosis by the Forced Oscillation Technique

Anti-tumor necrosis factor alpha (TNFα) therapy is widely used to treat various inflammatory conditions. Paradoxically, there are several case reports describing the development of bronchocentric granulomatosis treated with TNFα inhibitors, and it is difficult to determine the effect of treatment using conventional spirometry because the lesions are located in small airways. However, it has been reported that the forced oscillation technique (FOT) is useful in the evaluation of small airway disease in bronchial asthma or chronic obstructive pulmonary disease. We performed the FOT to determine the effect of treatment on bronchocentric granulomatosis and found it to be useful. We report the case of a 55-year-old female with ulcerative colitis who was treated with golimumab and who developed bronchocentric granulomatosis as a sarcoid-like reaction to golimumab. She was successfully treated with prednisone, and the treatment efficacy was confirmed by the FOT. The FOT may be useful in the evaluation of small airway disease in bronchocentric granulomatosis. This case may help inform clinicians of the usefulness of the FOT to assess small airway disease in various diseases

Comparison of T-Cell Interferon-γ Release Assays for Mycobacterium tuberculosis-Specific Antigens in Patients with Active and Latent Tuberculosis

Through the use of QuantiFERON-TB Gold, a commercial IFN-γ assay, we compared differences in quantitative T-cell responses to Mycobacterium tuberculosis (MTB)-specific antigens [QuantiFERON TB-2G (QFT-2G)] between patients with active tuberculosis (TB) disease and those with latent TB infection (LTBI). The patient group consisted of 180 patients with active TB disease (culture-positive for MTB) and 50 screening contacts with LTBI-positive response to the QFT-2G test. We prospectively performed a tuberculin skin test (TST) and a QFT-2G test for all subjects. The median IFN-γ levels upon the application of both antigens, ESAT-6 and CFP-10, were significantly higher in patients with active TB disease than in those with LTBI. A combined positive response to both antigens occurred at a higher rate in patients with active TB disease than in those with LTBI. There were no significant relationships between the quantitative responses of IFN-γ to both antigens and the maximum induration on TST in both patient groups. We demonstrated significant differences in the quantitative responses of IFN-γ to MTB between patients with active TB disease and those with LTBI in this study. However, there was an overlap in the IFN-γ levels between active TB disease and LTBI groups. Therefore, it would be difficult to use the QFT-2G test to completely discriminate active TB disease from LTBI

Serum Cytokines Usefulness for Understanding the Pathology in Allergic Bronchopulmonary Aspergillosis and Chronic Pulmonary Aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA) are important fungal infections caused by Aspergillus species. An overlap of ABPA and CPA has been reported; therefore, it is critical to determine whether the main pathology is ABPA or CPA and whether antifungals are required. In this study, we investigated whether the serum cytokine profile is useful for understanding the pathology and for differentiating between these diseases. We compared the various serum cytokine levels among healthy subjects and patients diagnosed with asthma, ABPA, or CPA at Nagasaki University Hospital between January 2003 and December 2018. In total, 14 healthy subjects, 19 patients with asthma, 11 with ABPA, and 10 with CPA were enrolled. Interleukin (IL) -5 levels were significantly higher in patients with ABPA than in those with CPA, and IL-33 and tumor necrosis factor (TNF) levels were significantly higher in patients with CPA than in those with asthma (p < 0.05, Dunn’s multiple comparison test). The sensitivity and specificity of the IL-10/IL-5 ratio (cutoff index 2.47) for diagnosing CPA were 70% and 100%, respectively. The serum cytokine profile is useful in understanding the pathology of ABPA and CPA, and the IL-10/IL-5 ratio may be a novel supplemental biomarker for indicating the pathology of CPA

Novel SPEF2 Variant in a Japanese Patient with Primary Ciliary Dyskinesia: A Case Report and Literature Review

Primary ciliary dyskinesia (PCD) is a genetic and congenital disease associated with an abnormal ciliary ultrastructure and function and is estimated to affect 1 in 15,000–20,000 individuals. A PCD diagnosis can be achieved by genotyping. Here, we performed whole-exome analysis for the diagnosis of PCD and described the detailed clinical characteristics of the case. A 39-year-old Japanese woman with sinusitis and bronchiectasis without situs inversus had had upper and lower respiratory symptoms since childhood and had received long-term macrolide therapy without an accurate diagnosis. A moderate deterioration of cilia function was observed by high-speed video microscopy analysis; additionally, the number of cells with moving cilia was fewer than that in patients without PCD. Electron microscopy revealed no apparent structural abnormalities. We performedwhole-exome analysis and identified novel biallelic variants of SPEF2 in the homozygous state (c.1860_1861insCT).We confirmed the absence of SPEF2 protein expression in the cilia of the nasal mucosa using fluorescent immunostaining. Accordingly, she was diagnosed as having PCD with the SPEF2 variant. The present case suggests that the deterioration of cilia function is moderate, the number of respiratory cells with moving cilia might be reduced, and the respiratory condition could be severe in patients with PCD with the SPEF2 variant

多剤耐性カンジダおよび細菌に対するカスポファンギンの新たな抗微生物活性

長崎大学学位論文 [学位記番号]博（医歯薬）甲第1326号 [学位授与年月日]令和3年3月22