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Here we report a rare case of immunoglobulin G4 (IgG4)–related pleural disease diagnosed using a thoracoscopic pleural biopsy. A 66‐year‐old man was admitted to our hospital with right‐dominant bilateral pleural effusions and gradually worsening dyspnoea. Chest radiographs revealed right‐dominant pleural effusions, while chest computed tomography showed bilateral pleural effusions without parenchymal lesions. Although the bilateral pleural effusions were exudative with an increased number of lymphocytes, the definitive diagnosis was initially elusive. High IgG4 levels in the serum and pleural effusions were observed. A pathological evaluation of a right pleural biopsy specimen collected via video‐assisted thoracoscopic surgery showed fibrosis‐associated lymphoplasmacytic infiltration, 45–60 IgG4‐positive plasma cells per high‐power field, and an IgG4/immunoglobulin G ratio of 40%. Consequently, the patient was diagnosed with IgG4‐related pleural disease. The bilateral pleural effusions improved after corticosteroid therapy. [ABSTRACT FROM AUTHOR]

This article explores the role of the STING/RANTES pathway in airway inflammation induced by Der p1, a common allergen. The study found that STING, a pattern recognition receptor, is highly expressed in airway epithelial cells and is involved in neutrophilic inflammation. RANTES, a chemokine, was shown to enhance eosinophilic inflammation in the presence of Der p1. These findings suggest that the STING/RANTES axis may play a role in connecting different types of airway inflammation. The study was supported by various grants and the authors declare no conflicts of interest. [Extracted from the article]

A 46‐year‐old male was treated with corticosteroids for nonspecific interstitial pneumonia (NSIP). He was referred to our hospital and admitted for worsening dyspnea and diffuse ground‐glass opacity on chest computed tomography (CT) during corticosteroid treatment. Gottron's sign was observed, and the patient was diagnosed with clinically amyopathic dermatomyositis on skin biopsy. We increased the corticosteroid dose and added immunosuppressive agents; however, the opacity on the chest CT worsened. Based on periodic‐acid‐Schiff‐positive granular material in the bronchoalveolar lavage fluid and the presence of anti‐GM‐CSF antibodies, the patient was diagnosed with autoimmune pulmonary alveolar proteinosis (APAP). The concentration of anti‐GM‐CSF antibodies in preserved serum was also elevated when the patient was diagnosed with NSIP. Thus, we assumed that NSIP and APAP coexisted, and that APAP manifested during immunosuppressive therapy. When exacerbation is observed during the treatment of interstitial pneumonia with immunosuppressive agents, it is necessary to consider APAP. [ABSTRACT FROM AUTHOR]

Introduction: Eosinophilic pneumonia (EP) is characterized by a marked accumulation of eosinophils in the lungs and blood. Eosinophils and mast cells play an important role in the pathogenesis of EP via release of biomarkers such as tryptase and interleukin (IL)-33. However, the potential role of these biomarkers is not fully understood. Objectives: We aimed to evaluate the differences among the levels of tryptase and IL-33 in bronchoalveolar lavage fluid (BALF) from several types of EP. We evaluated the differences between the levels of these biomarkers in the recurrent and nonrecurrent cases. Method: We prospectively collected the clinical data of patients with EP, diagnosed between 2006 and 2015 in our institution. Bronchoscopy was performed before steroid treatment; BALF was collected. The clinical characteristics of EP patients and the levels of tryptase and IL-33 in BALF were evaluated. Results: We enrolled 15 patients with chronic EP (CEP), 5 with acute EP (AEP), 10 with drug-induced EP, and 6 with angiitis-related EP. Tryptase levels in the CEP group were significantly higher than that in the drug-induced EP group (p = 0.048), while the AEP group had the highest IL-33 levels. Recurrence of EP was noted in 67% of patients with CEP. The levels of tryptase and IL-33 were notably higher in the recurrent cases than that in the nonrecurrent CEP group (p = 0.004, p = 0.04, respectively). Furthermore, there was a positive correlation between the levels of tryptase and IL-33 in the BALF of patients with CEP (ρ = 0.69, p = 0.004). Conclusions: Tryptase and IL-33 in BALF are useful biomarkers for the assessment of EP types. These biomarkers could be used to predict disease recurrence. [ABSTRACT FROM AUTHOR]

To examine the effect of adenosine [A.sub.3] receptor stimulation on airway mucociliary clearance, we measured transport of Evans blue dye in rabbit trachea in vivo and ciliary motility of epithelium by the photoelectric method in vitro. Mucociliary transport was enhanced dose dependently by the selective [A.sub.3] agonist [N.sup.6]-(3-iodobenzyl)-5'-N-methylcarbamoyladenosine (IB-MECA) and to a lesser extent by the less-selective [N.sup.6]-2-(4-amino-3-iodophenyl)ethyladenosine, whereas the [A.sub.1] agonist N-cyclopentyladenosine (CPA) and the [A.sub.2] agonist CGS-21680 had no effect. The effect of IB-MECA was abolished by pretreatment with the selective [A.sub.3] antagonist MRS-1220 but not by the [A.sub.1] antagonist 1,3-dipropyly-8-cyclopentylxanthine or the [A.sub.2] antagonist 3,7-dimethyl-L-propargylxanthine. Epithelial ciliary beat frequency was increased by IB-MECA in a concentration-dependent manner, the maximal increase being 33%, and this effect was inhibited by MRS-1220. The IB-MECA-induced ciliary stimulation was not altered by the Rp diastereomer of cAMP but was greatly inhibited by [Ca.sup.2+]-free medium containing BAPTAAM. Incubation with IB-MECA increased intracellular [Ca.sup.2+] contents. Therefore, [A.sub.3] agonist enhances airway mucociliary clearance probably through [Ca.sup.2+]-mediated stimulation of ciliary motility of airway epithelium. airway epithelium; adenine nucleotide; ciliary beat frequency; calcium

A study was conducted to demonstrate Ca2+ oscillations induced by exogenous adenosine triphosphate and its inhibition by FK506 in fura 2-loaded cow tracheal epithelial cells. Previous studies have reported that airway epithelial cells exhibit Ca2+ oscillations when responding to mechanical stimulation. Cow tracheal epithelial cells were used and later subjected to a Ca2+ image analysis. Findings reveal that FK506 has an inhibitory action on the Ca2+ response via intracellular FK-binding proteins, but not via calcineurin.

Experimental evidence shows that the antiallergic agent azelastine inhibits platelet-activating factor-induced microvascular leakage in airways in pathogen-free rats. This observation was confirmed in an experiment that assessed the amount of vascular leakage in rat airways by measuring the percent area occupied by Monastral blue-labeled blood vessels in the mucosae of the rat trachea and bronchus with a stereological point-counting technique. Findings showed that azelastine suppresses platelet-activating factor-induced airway inflammation, probably by attenuating the release of neutrophil elastase from activated neutrophils.

Guinea pig trachea tissue sections stained with alcian blue and Schiff acid were analyzed to determine the effects of lipopolysaccharides (LPS) on the rate of goblet cell secretion. Administration of LPS promoted the accumulation of neutrophils in the guinea pig airway mucosa and induced the secretory activity of goblet cells. Furthermore, time-dependent reductions in mucus score was detected after the inhalation of LPS by guinea pigs indicating the role of LPS in stimulating neutrophil chemotaxis.

Endogenous nitric oxide (NO) in the respiratory tract takes part in many biological processes. It contributes to the beta-adrenoceptor's stimulation of ciliary motility. The airway epithelium releases NO. To study the complete role, real-time measurement of NO is made by specific amperometric sensor. The ciliary beat frequency in a rabbit cultured tracheal epithelium is measured in vitro through photoelectric method. Further studies are required to find the other possible pathways.

Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by functional impairment of cilia throughout the body. The involvement of copy number variation (CNV) in the development of PCD is largely unknown. Methods: We examined 93 Japanese patients with clinically suspected PCD from 84 unrelated families. CNV was examined either by exome sequencing of a PCD gene panel or by whole‐exome sequencing (WES). The identified alterations were validated by PCR and Sanger sequencing. Nasal ciliary ultrastructure was examined by electron microscopy. Results: Analysis of CNV by the panel or WES revealed a biallelic deletion in the dynein regulatory complex subunit 1 (DRC1) gene in 21 patients, which accounted for 49% of the PCD patients in whom a disease‐causing gene was found. Sanger sequencing of the PCR product revealed a 27,748‐bp biallelic deletion including exons 1–4 of DRC1 with identical breakpoints in all 21 patients. The ciliary ultrastructure of the patients with this CNV showed axonemal disorganization and the loss or gain of central microtubules. Conclusion: The deletion of DRC1 is the major cause of PCD in Japan and this alteration can cause various ciliary ultrastructural abnormalities. [ABSTRACT FROM AUTHOR]

A 65-year-old man was diagnosed with granulomatosis with polyangiitis (GPA) at the age of 47, when cytoplasmic anti-neutrophil cytoplasmic antibody (C-ANCA) serology was positive, and he had multiple nodular shadows in both lungs. He had been treated with prednisolone, cyclophosphamide (CPA) and plasma exchange. At the age of 64, a nodular shadow was newly detected in the right lower lung field and serum tumour marker increased. Subsequent positron emission tomography/computed tomography scan demonstrated accumulations of fluorodexyglucose (FDG) in the same area, mediastinum lymph nodes, thoracic wall, right iliac bone, and right retroperitoneum. The diagnosis of squamous cell lung cancer cT2bN2M1b Stage4 was made with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). There are no reports of cases that lung cancer has developed with GPA during the long-term treatment with CPA. We suggest that in such patients, the differential diagnosis should include not only the relapse of GPA, but also the rare possibility of development of carcinomas. [ABSTRACT FROM AUTHOR]

Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency in adults and children. We herein report a case of CVID, who was misdiagnosed with asthma due to wheezing episodes and relatively late onset. A 51-year-old woman had suffered from recurrent upper and lower airway infection for recent 2 years. She repeated wheezing attacks and was treated as asthma exacerbation triggered by infection. She was referred to our hospital for investigation and treatment. Lung function tests showed no reversibility of FEV 1 by β-adrenergic agonist, but the increase of V 50 /V 25 . Chest CT showed slight to moderate bronchial wall thickening and bronchiectasis. After that, she suffered from pneumonia with wheezing attacks twice a month, and immunodeficiency was strongly suspected. Her blood tests showed marked decreases of all classes of immunoglobulin and nearly lack of memory B cells, NKT cells and plasmacytoid dendritic cells. She was diagnosed with CVID, and was treated with replacement of gammaglobulin. Thereafter, her wheezing episodes with infection were remarkably improved. Because the delay of diagnosis with CVID likely causes poor mortality and morbidity, a possibility of CVID should be considered in patients with frequent asthma-like symptoms due to recurrent airway infection. [ABSTRACT FROM AUTHOR]

Objective: Cough variant asthma (CVA) is an important cause of chronic cough, and pathophysiological features of the disease appear to be similar to typical asthma. Because CVA is recognized as a precursor of asthma, early intervention with long-term antiinflammatory agents may be recommended. However, the role of combination therapy with inhaled corticosteroid and b2-agonist in the treatment of CVA has not been elucidated. To evaluate the effectiveness of the combination therapy, we investigated the clinical impact of regular treatment with salmeterol/fliticasone propionate combination (SFC) and inhaled salmeterol (SAL) alone in patients with CVA. Methods: The study was a randomized, controlled, parallel-group multi-center trial. Forty-three CVA patients were assigned to SFC (50/100 mg once daily) or SAL (50 mg twice daily) for 12 weeks. Then, these medications were stopped for the next 24 weeks. Main outcome measures were cough symptoms, pulmonary function and airway inflammation. Results: Treatment with each of SFC and SAL significantly decreased cough scores and increased FEV1 and PEF, where the efficacy was more pronounced with SFC than SAL. SFC also decreased sputum eosinophil counts and eosinophil cationic protein contents, whereas SAL had no effect. After discontinuation of the treatment, cough scores increased, pulmonary function and eosinophilic airway inflammation were aggravated and returned to the baseline levels. Conclusions: Maintenance therapy with SFC provides further improvements in cough symptoms, pulmonary function and airway inflammation, and discontinuation of the therapy causes worsening of the disease, indicating that stopping or interrupting anti-inflammatory therapy may not be advisable in patients with CVA. [ABSTRACT FROM AUTHOR]

A 56-year-old man complained progressive dyspnea, fatigue and fever for one month. His chest CT exhibited faint ground-glass opacities, and the levels of serum LDH and soluble interleukin 2 receptor were markedly elevated. Positron emission tomography (PET) showed high uptake of 18-fluoro deoxy glucose (18FDG) only on both lungs. We performed transbronchial lung biopsies (TBLB) for the diagnosis. After bronchoscopy, he had prolonged hypoxemia. Because defects of 99m-Technetium macroaggregated albumin (99mTc-MAA) in pulmonary blood flow scintigraphy were consistent with the distribution of 18FDG uptake in PET, we speculated that the presence of intravascular lymphoma (IVL) cells in the capillaries might have behaved like tumor embolism. We started rescue by prednisolone based on treatment of lymphoma. As a result, his hypoxemia was gradually improved. Histological findings in TBLB specimen showed that CD20+CD79+Bcl-2+c-myc+ lymphoma cells were localized to small vessel lumina in alveoli and bronchioles, and he was definitely diagnosed with lung intravascular large B cell lymphoma (IVLBCL). He was treated with complete cyclophosphamide, doxorubicin, vincristine, and prednisolone with rituximab (R–CHOP) in combination with intrathecal methotrexate injection. After eight cycles of R–CHOP and three times of intrathecal methotrexate, 18FDG uptake of PET on both lungs completely disappeared, achieving complete metabolic remission. We experienced a rare case of lung IVLBCL developed with respiratory failure successfully rescued by prednisolone prior to definite diagnosis. [ABSTRACT FROM AUTHOR]

Diffuse panbronchiolitis ( DPB) and asthma are obstructive airway diseases, the former being characterized by Th1-type and the latter by Th2-type airway inflammation. Differential diagnosis is often a problem, but coexistence has rarely been reported. A 76-year-old man with asthma was admitted to our hospital because of one-month history of dyspnoea on exertion with bilateral diffuse granular shadows. He also had a history of chronic sinusitis. Auscultation of the lungs showed coarse crackles and wheezes. Laboratory data revealed an elevated total serum immunoglobulin E and a high titre of cold agglutinin. Bronchoscopic evaluations of the shadows revealed compatible pathological findings in both DPB and asthma. Low-dose macrolide caused a prompt reduction of symptoms, along with improvements in radiographic findings and pulmonary functions, whereas the eosinophilic airway inflammation transiently worsened. When DPB and asthma coexist, the balance of Th1/Th2 immune response may be reciprocally altered by therapeutic intervention. [ABSTRACT FROM AUTHOR]

Although the budesonide and formoterol in a single inhaler for maintenance and reliever therapy has been evaluated in recent studies, the effects on eosinophilic airway inflammation remain uncertain. The purpose of this study was to compare the efficacy, including anti-inflammatory effects, of as-needed budesonide/formoterol with salbutamol in Japanese patients with moderate-to-severe asthma. Patients with asthma using an inhaled corticosteroid plus a long-acting beta2-agonist as a controller and at least one asthma exacerbation in the previous 12 months were randomized to budesonide/formoterol maintenance therapy (160/4.5 micrograms, 2 inhalations twice daily) plus either as-needed budesonide/formoterol (160/4.5 micrograms; n = 32) or salbutamol (100 micrograms; n = 31) up to 4 inhalation daily for 48 weeks. The time to first asthma exacerbation was significantly prolonged with as-needed budesonide/formoterol compared with salbutamol (log-rank test; p = 0.0342). There was a 66% reduction in the hazard ratio for a first exacerbation with as-needed budesonide/formoterol (p = 0.0334). The frequencies of both mild and severe exacerbations and reliever use were consistently less with budesonide/formoterol than salbutamol. As-needed budesonide/formoterol significantly improved in lung function and symptom scores compared with salbutamol. In addition, the contents of eosinophil cationic protein and B12 tryptase, as well as number of eosinophils and mast cells in induced sputum, decreased to a greater extent with budesonide/formoterol compared with salbutamol. In conclusion, the budesonide and formoterol for maintenance and reliever therapy seems more effective in controlling persistent asthma with a significant reduction of airway inflammation. Clinical trial 121104, www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

A 51-year-old woman had been receiving medical treatment for asthma since she was 21 years old. However, her asthma was poorly controlled despite treatment involving combination inhalation of high-dose corticosteroid and long-acting β2-aderenergic agonist (LABA) and regularly taking oral steroids. Hearing loss and otorrhea appeared at the age of 44, and she was given a diagnosis of eosinophilic otitis media (EOM) and received medical treatment. In 2007, symptoms of asthma and otitis media deteriorated. In December 2009, omalizumab therapy was started for refractory asthma. After 2 months of omalizumab treatment, not only asthma, but also hearing loss improved. It is suggested that early initiation of omalizumab therapy may inhibit the progression of progressive EOM. [ABSTRACT FROM AUTHOR]

Cough variant asthma (CVA) is a common cause of chronic persistent cough, in which allergic airway inflammation may play a role. Although current guidelines recommend bronchodilators and anti-inflammatory drugs for the treatment, comparison of the efficacy of these medications has not been investigated. This study was designed to evaluate the effectiveness of pranlukast, a leukotriene receptor antagonist, and salmeterol, a long-acting beta2-adrenergic agonist, in the treatment of CVA. The study was a randomized, controlled, parallel-group, multicenter trial. After a 4-week run-in period, 49 patients with newly diagnosed CVA were assigned to receive oral pranlukast (225 mg, b.i.d.) or inhaled salmeterol (100 μg, b.i.d.) for 4 weeks. Primary outcome measure was cough symptom and secondary outcome measures were pulmonary function and eosinophilic airway inflammation. Treatment with pranlukast and salmeterol each decreased cough symptom scores, where the changes from baseline values were significantly greater in the pranlukast group than in the salmeterol group. Forced expiratory volume in 1 second and peak expiratory flow (PEF) increased in the two treatment groups with the same magnitudes, but significant decreases in diurnal variation of PEF and eosinophil counts and eosinophil cationic protein contents in the peripheral blood and induced sputum were observed only in the pranlukast group. In view of antitussive and anti-inflammatory actions, the leukotriene receptor antagonist pranlukast seems to be more effective than the long-acting beta2-adrenergic agonist salmeterol in the treatment of CVA. [ABSTRACT FROM AUTHOR]

Changes in ionic composition of airway surface fluid may modulate airway epithelial functions. We tested the hypothesis that fluctuations of ambient ionic composition could affect airway epithelial Ca2+ dynamics and Ca2+-dependent cellular functions, including NO release and PGE2 production in vitro. The responses of intracellular Ca2+ concentration ([Ca2+]i) to changes in extracellular Cl− and Na+ concentrations ([Cl−]e, [Na+]e) in the human bronchial epithelial cell line, 16HBE cells, were measured by the fura-2 method. The NO release to the medium after lowering [Cl−]e was measured by an amperometric NO sensor. PGE2 production was measured by radioimmunoassay. Changing to isotonic low [Cl−]e solution by substitution with gluconate caused a sustained increase in [Ca2+]i in a concentration-dependent manner, with the maximal [Ca2+]i increase from the baseline level being 243 ± 110 nM with Cl-free solution. The effect was not altered by thapsigargin but abolished by EGTA and by Cl channel blockers, including diphenylamine-2-carboxylate, disodium 4,4′-diisothiocyanatostilbene-2,2′-disulfonate, and disodium cromoglycate. In contrast, the effect of reduction of [Na+]e by substitution with N-methyl-D-glucamine+ on [Ca2+]i was less than that of reduction of [Cl−]e. The reduction of [Cl−]e caused a concentration-dependent rise in NO contents in the medium and PGE2 production. This release of NO was inhibited by EGTA but not by dexamethasone pretreatment. These results suggest that the decrease in ambient [Cl−] induces Ca2+ mobilization probably through Ca2+ influx, followed by the release of NO and PGE2, thereby modulating various cellular functions. [ABSTRACT FROM AUTHOR]

An air-liquid interface culture system accelerates cell differentiation and growth in airway epithelial cells. In this study, the authors investigated whether glutathione (GSH) affects cell growth in an air-liquid interface culture. Various components of the cellular GSH system were measured and the number of cells was counted after conversion from an immersed feeding to an air-liquid interface. The effect of medium supplementation with cystine, a precursor of GSH, on cell growth was also examined. After conversion to an air-liquid interface, the cellular GSH level increased by 4 to 5-fold. The increase in GSH preceded the rise in cell number. The glutathione disulfide (GSSG)/total GSH ratio (an indicator of oxidative stress) increased initially and reached a plateau (time 0: 0.379%±0.054%; day 2: 0.824%±0.063%; day 6: 0.806%±0.093%). The level of glutathione reductase activity in the cells increased in a time-dependent manner, whereas the glutathione peroxidase activity level declined. When the amount of cystine in the medium was varied after conversion, the cellular GSH level was closely correlated with the rate of cell growth. In conclusion, air exposure causes oxidative stress in cultured cells and produces a change in the cellular glutathione system, resulting in the promotion of cell growth. [ABSTRACT FROM AUTHOR]