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

Physical inactivity is associated with decreased growth differentiation factor 11 in chronic obstructive pulmonary disease

Rie Tanaka,1 Hisatoshi Sugiura,1 Mitsuhiro Yamada,1 Tomohiro Ichikawa,1 Akira Koarai,1 Naoya Fujino,1 Satoru Yanagisawa,1 Katsuhiro Onodera,1 Tadahisa Numakura,1 Kei Sato,1 Yorihiko Kyogoku,1 Hirohito Sano,1 Shun Yamanaka,1 Tatsuma Okazaki,1 Tsutomu Tamada,1 Motohiko Miura,2 Tsuneyuki Takahashi,3 Masakazu Ichinose1 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan; 2Department of Respiratory Medicine, Tohoku Rosai Hospital, Aoba-ku, Sendai, Japan; 3Department of Internal Medicine, Tohoku Medical and Pharmaceutical University Wakabayashi Hospital, Wakabayashi-ku, Sendai, Japan Background: Growth differentiation factor 11 (GDF11) is reported to possess anti-aging and rejuvenating effects, including muscle regeneration and to be highly expressed in skeletal muscle. Recently, we demonstrated that the levels of plasma GDF11 were decreased in COPD. However, the effect of decreased circulating GDF11 in the pathophysiology of COPD remains unknown. The aim of this study is to investigate the association between the plasma GDF11 levels and various clinical parameters in patients with COPD. Patients and methods: Eighteen ex-smokers as control subjects and 70 COPD patients participated in the current study. We measured the levels of plasma GDF11 using immunoblotting, lung function, physical activity using a triaxial accelerometer, quadriceps strength, exercise capacity, and systemic inflammatory markers. We investigated the association between the levels of plasma GDF11 and these clinical parameters. Results: The levels of plasma GDF11 in the COPD patients had significant positive correlations with the data of lung function. Furthermore, the levels of plasma GDF11 were significantly correlated with the physical activity, quadriceps strength, and exercise capacity. Moreover, the levels of plasma GDF11 were significantly correlated with the data of inflammatory markers. Although various factors were related to GDF11, the multiple regression analysis showed that physical activity was significantly associated with the levels of plasma GDF11. Conclusion: Physical inactivity was significantly related to the decreased GDF11 levels in COPD, which might be useful for understanding the pathogenesis of COPD. Clarifying the relationships between the physical inactivity and GDF11 may reveal a potentially attractive therapeutic approach in COPD via increasing the plasma levels of GDF11. Keywords: physical activity, muscle strength, rejuvenating factor, COP

Possible involvement of acetylcholine-mediated inflammation in airway diseases

Inhaled bronchodilator treatment with a long acting muscarinic antagonist (LAMA) reduces symptoms and the risk of exacerbations in COPD and asthma. However, increasing evidence from cell culture and animal studies suggests that anti-muscarinic drugs could also possess anti-inflammatory effects. Recent studies have revealed that acetylcholine (ACh) can be synthesized and released from both neuronal and non-neuronal cells, and the released ACh can potentiate airway inflammation and remodeling in airway diseases. However, these anti-inflammatory effects of anti-muscarinic drugs have not yet been confirmed in COPD and asthma patients. This review will focus on recent findings about the possible involvement of ACh in airway inflammation and remodeling, and the anti-inflammatory effect of anti-muscarinic drugs in airway diseases. Clarifying the acetylcholine-mediated inflammation could provide insights into the mechanisms of airway diseases, which could lead to future therapeutic strategies for inhibiting the disease progression and exacerbations. Keywords: Airway inflammation, Airway remodeling, Anti-muscarinic drug, Cholinergic regulation, Non-neuronal AC