Improvement of Airflow Limitation by Fluticasone Propionate/Salmeterol in Chronic Obstructive Pulmonary Disease: What is the Specific Marker?

Backgrounds: Inhaled corticosteroids (ICS)/inhaled long-acting beta2-agonists (LABA) combination drugs are widely used for the long-term management of chronic obstructive pulmonary disease (COPD). However, COPD is a heterogeneous condition and treatment with ICS is associated with a higher risk of pneumonia. The identification of a specific marker for predicting the efficacy of ICS/LABA on pulmonary function would be useful in the treatment of COPD. Methods: Fourteen COPD patients receiving tiotropium therapy participated consecutively. The relationship between the baseline exhaled nitric oxide (FENO) levels as well as serum markers and changes in pulmonary function by fluticasone propionate (FP)/salmeterol (SAL) were analyzed. Results: FP/SAL therapy significantly improved forced vital capacity, forced expiratory volume in 1 s (FEV1), and the third phase slope of the single nitrogen washout curve (ΔN2) as well as the FENO level. The baseline FENO levels and positive specific IgE (atopy+) were significantly associated with airway obstructive changes assessed by FEV1 and ΔN2. A baseline FENO level >35 ppb yielded 80.0% sensitivity and 66.7% specificity for identifying the subjects with significant improvement in FEV1 (greater than 200 mL). An atopy+ yielded 60.0% sensitivity and 88.9% specificity for an improvement in FEV1. When combined with FENO > 35 ppb and atopy+, it showed 40% sensitivity and 100.0% specificity for FEV1 improvement. Alternatively, COPD subjects with FENO ≤ 35 ppb and atopy− did not show significant improvement in FEV1. Conclusion: Combining FENO and specific IgE may be a useful marker for predicting the response to ICS/LABA on airflow limitation in COPD

Increase of nitrosative stress in patients with eosinophilic pneumonia

<p>Abstract</p> <p>Background</p> <p>Exhaled nitric oxide (NO) production is increased in asthma and reflects the degree of airway inflammation. The alveolar NO concentration (Calv) in interstitial pneumonia is reported to be increased. However, it remains unknown whether NO production is increased and nitrosative stress occurs in eosinophilic pneumonia (EP). We hypothesized that nitrosative stress markers including Calv, inducible type of NO synthase (iNOS), and 3-nitrotyrosine (3-NT), are upregulated in EP.</p> <p>Methods</p> <p>Exhaled NO including fractional exhaled NO (FE_NO) and Calv was measured in ten healthy subjects, 13 patients with idiopathic pulmonary fibrosis (IPF), and 13 patients with EP. iNOS expression and 3-NT formation were assessed by immunocytochemistory in BALf cells. The exhaled NO, lung function, and systemic inflammatory markers of the EP patients were investigated after corticosteroid treatment for 4 weeks.</p> <p>Results</p> <p>The Calv levels in the EP group (14.4 ± 2.0 ppb) were significantly higher than those in the healthy subjects (5.1 ± 0.6 ppb, p < 0.01) and the IPF groups (6.3 ± 0.6 ppb, p < 0.01) as well as the FE_NOand the corrected Calv levels (all p < 0.01). More iNOS and 3-NT positive cells were observed in the EP group compared to the healthy subject and IPF patient. The Calv levels had significant positive correlations with both iNOS (r = 0.858, p < 0.05) and 3-NT positive cells (r = 0.924, p < 0.01). Corticosteroid treatment significantly reduced both the FE_NO(p < 0.05) and the Calv levels (p < 0.01). The magnitude of reduction in the Calv levels had a significant positive correlation with the peripheral blood eosinophil counts (r = 0.802, p < 0.05).</p> <p>Conclusions</p> <p>These results suggested that excessive nitrosative stress occurred in EP and that Calv could be a marker of the disease activity.</p

Late Mesozoic bivalve faunas of the Tetori Group, Japan

東京学芸大学博士（学術

Exhaled Nitric Oxide Cutoff Values for Asthma Diagnosis According to Rhinitis and Smoking Status in Japanese Subjects

Background: Measurement of the exhaled nitric oxide fraction (FEno) has been proposed as a useful diagnostic test for asthma. However, most of the data concerning the fEno cutoff values for the diagnosis of asthma have not yet examined using standard procedures. Furthermore, there is no detailed study that investigated the cutoff values that takes into account patient factors that influence the FEno levels. Methods: FEno was measured in 142 steroid-naive asthmatics and 224 control subjects using an online electrochemical nitric oxide analyzer in accordance with the current guidelines. Subjects without respiratory symptoms and normal spirometric parameters were included in the control group. Asthma was diagnosed on the basis of the presence of significant airway reversibility and/or airway hyperresponsiveness during clinical follow up 6 months after FEno measurements. Results: FEno was significantly higher in asthmatic patients compared with control subjects (p < 0.01). Based on all study subjects, the receiver operating characteristic curves indicated that the cutoff value of FEno 22 parts per billion (ppb) was associated with the highest combination of sensitivity (90.8%) and specificity (83.9%). Multivariate analysis showed allergic rhinitis, current smoking, and asthma were significant factors influencing the FEno levels. The cutoff values of FEno to discriminate asthma from non-asthma ranged from 18 to 28 ppb depending on rhinitis and smoking status. Conclusions: The cutoff values presented may be useful for the interpretation of FEno values in the clinical practice

Molecular Mechanism of the Additive Effects of Leukotriene Modifier in Asthmatic Patients Receiving Steroid Therapy

Background: The addition of leukotriene modifier (LM) may be a useful approach for uncontrollable asthma despite treatment with inhaled corticosteroid (ICS), especially in asthmatics comorbid with allergic rhinitis (AR), although little is known about its molecular mechanism. We evaluated the additive effects of LM with ICS on pulmonary function and airway inflammation in asthmatics with or without AR. Methods: Eighteen uncontrolled steroid-treated asthmatics, nine with and nine without AR, were enrolled. Spirometry, peak expiratory flow (PEF) measurements, and exhaled breath condensate sampling were performed before and 8 weeks after LM administration. The lowest PEF over the course of one week, expressed as a percentage of the highest PEF (Min%Max PEF), was used as an index of fluctuation of the airway caliber. Airway cytokine expression was analyzed with a protein array. Results: A significant improvement in forced expiratory volume in one second as a percentage of the predicted value (%FEV1) and Min%Max PEF was seen in the subgroup of asthma with AR. Although there was no significant difference in the baseline cytokine values between the groups, the exhaled RANTES level was significantly reduced by LM in the asthma with AR group. The changes in the RANTES level were significantly related to the changes in the %FEV1 and Min%Max PEF values. Conclusions: LM caused a greater improvement in pulmonary function and airway inflammation in asthmatics with AR. The RANTES-mediated pathway may be involved in the improvement of the airflow limitation and airway lability by LM additive therapy in asthmatics receiving steroid therapy

Oxidative Stress Enhances Toll-Like Receptor 3 Response to Double-Stranded RNA in Airway Epithelial Cells

Virus infections are a major cause of chronic obstructive pulmonary disease (COPD) exacerbations. Recently, Toll-like receptor 3 (TLR3) has been demonstrated to react to double-stranded RNA (dsRNA) and to be involved in the immune responses after viral infections. In the present study, we examined whether oxidative stress, which is involved in the pathogenesis of COPD, enhances the responses of TLR3 in airway epithelial cells. The effect of hydrogen peroxide (H2O2) on the release of IL-8 from BEAS-2B cells and primary human bronchial epithelial cells after stimulation with polyinosine-polycytidylic acid [poly(I:C)], a synthetic analog of viral dsRNA and a ligand for TLR3, and the signal transduction were examined. One hundred to 150 μM H2O2 significantly potentiated the release of IL-8 from the epithelial cells after stimulation with 10 μg/ml poly(I:C). The H2O2-augmented IL-8 release was inhibited by treatment with N-acetylcysteine. One hundred micromoles of H2O2 enhanced the translocation of nuclear factor (NF)-κB p65, but not that of interferon regulatory factor-3 (IRF-3), into the nucleus and the NF-κB DNA binding activity after poly(I:C) stimulation, which effect was inhibited not by the silencing of IRF-3 but by MG132, a proteasome inhibitor, or dexamethasone. One hundred micromoles of H2O2 potentiated the TLR3 expression on the airway epithelial cells treated with poly(I:C). These data suggest that oxidative stress augments the response of TLR3 in airway epithelial cells via NF-κB and that this effect might be partly mediated by the enhancement of TLR3 expression. Modulation of this pathway may be a therapeutic target for viral-induced exacerbations of COPD