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Tomohiro Ichikawa,
Hisatoshi Sugiura,
Akira Koarai,
Takashi Kikuchi,
Masataka Hiramatsu,
Hiroki Kawabata,
Keiichiro Akamatsu,
Tsunahiko Hirano,
Masanori Nakanishi, Kazuto Matsunaga,
Yoshiaki Minakata,
Masakazu Ichinose
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ABSTRACT: Abnormal structural alterations termed remodeling, including fibrosis and alveolar wall destruction, are important features of the pathophysiology of chronic airway diseases such as chronic obstructive pulmonary disease (COPD) and asthma. 25-hydroxycholesterol (25-HC) is enzymatically produced by cholesterol 25-hydorxylase (CH25H) in macrophages and is reported to be involved in the formation of arteriosclerosis. We previously demonstrated that the expression of CH25H and production of 25HC were increased in the lungs of COPD. However, the role of 25-HC in lung tissue remodeling is unknown. In this study, we investigated the effect of 25-HC on fibroblast-mediated tissue remodeling using human fetal lung fibroblasts (HFL-1) in vitro. 25-HC significantly augmented α-smooth muscle actin (SMA) (P<0.001) and collagen I (P<0.001) expression in HFL-1. 25-HC also significantly enhanced the release and activation of matrix metallaoproteinase (MMP)-2 (P<0.001) and MMP-9 (P<0.001) without any significant effect on the production of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. 25-HC stimulated transforming growth factor (TGF)-β1 production (P<0.01) and a neutralizing anti-TGF-β antibody restored these 25-HC-augmented pro-fibrotic responses. 25-HC significantly promoted the translocation of nuclear factor (NF)-κB p65 into the nuclei (P<0.01), but not phospholylated-c-jun, a complex of activator protein-1. Pharmacological inhibition of NF-κB restored the 25-HC-augmented pro-fibrotic responses and TGF-β1 release. These results suggest that 25-HC could contribute to fibroblast-mediated lung tissue remodeling by promoting myofibroblast differentiation and the excessive release of extracellular matrix protein and MMPs via an NF-κB-TGF-β dependent pathway.
Experimental Cell Research 02/2013; · 3.58 Impact Factor
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ABSTRACT: BACKGROUND: The clinical features, physiology, and pathology of severe asthma are poorly understood. Recently, the forced vital capacity (FVC) has been shown to be reduced in severe asthma compared to mild asthma, possibly due to air trapping. However, the natural history and risk factors of obstructive change for such asthmatic patients have not been fully elucidated. METHODS: We examined the data of a retrospective analysis of lung function changes over a 10-year period in 54 severe asthma patients. RESULTS: The faster obstructive changes detected by FEV(1) (forced expiratory volume in one second) were accompanied by excessive loss of FVC (r = 0.85, p < 0.0001) and the reduction in FVC was 1.2 times larger than the FEV(1) change. Age, baseline FVC, exacerbation rate and oral corticosteroids use showed significantly negative correlations with the rate of annual change in FVC. CONCLUSIONS: These data indicate that the decline in FVC is more evident than FEV(1) in severe asthma, suggesting that small airway susceptibility may be the cause of rapid disease progression. Aging, exacerbations of asthma, and use of systemic corticosteroids are related to excess FVC decline, particularly if FVC is still normal.
Respiratory medicine 12/2012; · 2.33 Impact Factor
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ABSTRACT: Combinations of inhaled corticosteroids (ICS) and inhaled long-acting beta(2)-agonists (LABA) have become widely used for the initiation of maintenance treatment for asthma. However, it has not been fully elucidated whether ICS/LABA alters the time-course of different control outcome measures in steroid-naive patients with asthma compared to the treatment with ICS alone. We compared the time-response in Asthma Control Questionnaire (ACQ), forced expiratory volume in 1 s (FEV1), exhaled nitric oxide fraction (FENO), and airway responsiveness to methacholine (PD(200)) between budesonide (BUD) and budesonide/formoterol (BUD/FM). BUD/FM therapy significantly improved the ACQ score at week 2 and week 4 (p < 0.01 and p < 0.05), and increased FEV1 and the methacholine threshold at week 8 and week 24 (all p < 0.05) compared to BUD alone. A logistic function model showed that the BUD/FM combination significantly improved ACQ, FEV1, FENO and PD200 at a faster rate than BUD over 24 weeks (p < 0.001 for ACQ, FEV1, PD200, and p < 0.05 for FENO, z-test). A significant variance in the time-response was also found in the outcomes of the two treatment groups (FENO and ACQ > FEV1 and PD200, p < 0.001, z-test). The present study provides evidence that ICS/LABA combination therapy results in a more rapid improvement in asthma symptoms, lung function, and airway inflammation compared to ICS monotherapy in steroid-naive patients with asthma.
Pulmonary Pharmacology & Therapeutics 10/2012; · 2.80 Impact Factor
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Nihon Naika Gakkai Zasshi 08/2012; 101(8):2219-25.
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Journal of the American Geriatrics Society 08/2012; 60(8):1587-8. · 3.74 Impact Factor
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Akira Koarai,
Satoru Yanagisawa,
Hisatoshi Sugiura,
Tomohiro Ichikawa,
Takashi Kikuchi,
Kanako Furukawa,
Keiichiro Akamatsu,
Tsunahiko Hirano,
Masanori Nakanishi, Kazuto Matsunaga,
Yoshiaki Minakata,
Masakazu Ichinose
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ABSTRACT: 25-hydroxycholesterol (25-HC) is one of the oxysterols, which are oxidized derivatives of cholesterol, and has been reported to be involved in the pathogenesis of atherosclerosis and Alzheimer's disease. In lung, the possible involvement of 25-HC in airway diseases has been revealed. In the present study, we examined whether 25-HC affects the release of cytokines and also modulates the responses of toll-like receptor 3 (TLR3) in airway epithelial cells.
The effect of 25-HC on the release of cytokines from primary human bronchial epithelial cells after stimulation with or without polyinosine-polycytidylic acid [poly(I:C)], a ligand for TLR3, and the signal transduction were examined.
25-HC significantly potentiated the release of interleukin-8 (IL-8) and IL-6 from the cells. This effect was more potent compared with that of other oxysterols, 22-HC and 27-HC. GW3965 and TO901317, synthetic agonists of liver X receptors that are receptors for oxysterols, did not augment the IL-8 release. 25-HC enhanced the nuclear factor-kappa B (NF-κB) DNA binding activity and translocation of phosphorylated c-Jun into the nucleus. The release of IL-8 was inhibited by the NF-κB inhibitor, caffeic acid phenethyl ester (CAPE), an inhibitor of nuclear factor kappa-B alpha (IκBα) inhibitor, BAY 11-7085, and an inhibitor of nuclear factor kappa-B kinase-2 (IKK-2) inhibitor, SC-514, but not by a c-Jun N-terminal kinase (JNK) inhibitory peptide, L-JNKi1. 25-HC significantly potentiated IL-8 release in poly(I:C)-treated cells and the augmentation was inhibited by CAPE, BAY 11-7085, and SC-514. Furthermore, 25-HC potentiated the translocation of interferon regulatory factor 3 into the nucleus and the release of interferon-beta (IFN-β) in poly(I:C)-treated cells.
These data demonstrated that 25-HC augments the release of IL-8 and IL-6 via NF-κB signalling pathway and enhances the release of IL-8 and IFN-β after stimulation of TLR3 in airway epithelial cells. 25-HC may be involved in the neutrophilic airway inflammation through the stimulant effect of IL-8 and IL-6 release and also potentiate the TLR3-mediated innate immunity in airway diseases.
Respiratory research 07/2012; 13:63. · 3.36 Impact Factor
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ABSTRACT: Cigarette smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD). Recently, toll-like receptor 3 (TLR3) was shown to recognize pathogen-associated molecular patterns, especially viral-derived double-stranded RNA, and to be involved in immune responses. However, the effects of cigarette smoke on TLR3 remain unclear. In this study, it was examined whether cigarette smoke affects the expression and responses of TLR3 in human macrophages.
The expression of TLR3 in alveolar macrophages from human lung tissues was analysed by immunohistochemistry, and the correlation of TLR3 expression with smoking history and lung function was evaluated. In addition, the effect of cigarette smoke on the expression and responses of TLR3 in macrophage lineage cells was investigated.
TLR3-positive alveolar macrophage numbers were significantly increased in smokers and COPD patients compared with non-smoking control subjects, but there was no difference between smokers and COPD patients. TLR3-positive macrophage numbers were positively correlated with smoking history and inversely correlated with corrected carbon monoxide diffusing capacity, but were not correlated with % predicted forced expiratory volume in 1 s. Furthermore, cigarette smoke extract potentiated the expression of TLR3 in monocyte-derived macrophages and significantly augmented the release of interleukin-8, as well as total matrix metalloproteinase-9 activity, in cells treated with TLR3 ligand.
These data suggest that cigarette smoke augments the expression and responses of TLR3 in human macrophages, and this may contribute to neutrophilic airway inflammation and parenchymal destruction in the lungs of smokers and patients with COPD.
Respirology 05/2012; 17(6):1018-25. · 2.42 Impact Factor
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Hisatoshi Sugiura,
Akira Koarai,
Tomohiro Ichikawa,
Yoshiaki Minakata, Kazuto Matsunaga,
Tsunahiko Hirano,
Keiichiro Akamatsu,
Satoru Yanagisawa,
Makoto Furusawa,
Yumiko Uno,
Masashi Yamasaki,
Yoshinori Satomi,
Masakazu Ichinose
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ABSTRACT: 25-Hydroxycholesterol (25-HC) is produced from cholesterol by the enzyme cholesterol 25-hydroxylase and is associated with atherosclerosis of vessels. Recently, 25-HC was reported to cause inflammation in various types of tissues. The aim of this study was to assess the production of 25-HC in the airways and to elucidate the role of 25-HC in neutrophil infiltration in the airways of patients with chronic obstructive pulmonary disease (COPD).
Eleven control never-smokers, six control ex-smokers without COPD and 13 COPD patients participated in the lung tissue study. The expression of cholesterol 25-hydroxylase in the lung was investigated. Twelve control subjects and 17 patients with COPD also participated in the sputum study. The concentrations of 25-HC in sputum were quantified by liquid chromatography/mass spectrometry/mass spectrometry analysis. To elucidate the role of 25-HC in neutrophilic inflammation of the airways, the correlation between 25-HC levels and neutrophil counts in sputum was investigated.
The expression of cholesterol 25-hydroxylase was significantly enhanced in lung tissue from COPD patients compared with that from control subjects. Cholesterol 25-hydroxylase was localized in alveolar macrophages and pneumocytes of COPD patients. The concentration of 25-HC in sputum was significantly increased in COPD patients and was inversely correlated with percent of predicted forced vital capacity, forced expiratory volume in 1 s and diffusing capacity of carbon monoxide. The concentrations of 25-HC in sputum were significantly correlated with sputum interleukin-8 levels and neutrophil counts.
25-HC production was enhanced in the airways of COPD patients and may play a role in neutrophilic inflammation.
Respirology 02/2012; 17(3):533-40. · 2.42 Impact Factor
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Hisatoshi Sugiura,
Hiroki Kawabata,
Tomohiro Ichikawa,
Akira Koarai,
Satoru Yanagisawa,
Takashi Kikuchi,
Yoshiaki Minakata, Kazuto Matsunaga,
Masanori Nakanishi,
Tsunahiko Hirano,
Keiichiro Akamatsu,
Kanako Furukawa,
Masakazu Ichinose
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ABSTRACT: The anti-inflammatory effects of theophylline have been reported to include inhibition of the release of proinflammatory mediators from macrophages and neutrophils. Overproduction of reactive nitrogen species (RNS) has been reported in the airways of patients with chronic obstructive pulmonary disease (COPD), and this causes tissue inflammation and injury. We investigated whether peroxynitrite stimulated the release of matrix metalloproteinases 2 and 9 (MMP-2 and -9; gelatinases) from human fetal lung fibroblasts (HFL-1 cell line) and whether theophylline inhibited the peroxynitrite-augmented release of MMPs. HFL-1 cells and primary lung fibroblasts were treated with peroxynitrite (an RNS), and gelatinases levels were evaluated by gelatin zymography. The inhibitory effect of theophylline on the peroxynitrite-augmented release of MMP-2 and MMP-9 was also investigated. To explore the cell signaling pathways involved in the peroxynitrite-induced gelatinases release and the inhibitory effect of theophylline, transforming growth factor-β(1) (TGF-β(1)), nuclear factor-κB (NF-κB), and histone deacetylase (HDAC) were measured. Peroxynitrite significantly augmented the release of MMP-2 and MMP-9 by fibroblasts (P < 0.01), as well as TGF-β(1) release (P < 0.01), NF-κB activation (P < 0.01), and HDAC2 inactivation (P < 0.01). An NF-κB inhibitor diminished the RNS-augmented release of MMPs and TGF-β(1) (P < 0.01), and a neutralizing TGF-β antibody also diminished MMP release (P < 0.01). Theophylline significantly inhibited the peroxynitrite-augmented release of MMP-2 and MMP-9 in HFL-1 cells and normal adult lung fibroblasts, and it also inhibited the peroxynitrite-mediated HDAC2 inactivation, NF-κB activation, and TGF-β(1) release in HFL-1 cells (all P < 0.01). These results suggest that peroxynitrite can influence tissue remodeling by promoting gelatinases release, while theophylline suppresses peroxynitrite-induced tissue remodeling via pathways involving NF-κB/TGF-β(1) and/or HDAC in the HFL-1 cell line.
AJP Lung Cellular and Molecular Physiology 01/2012; 302(8):L764-74. · 3.66 Impact Factor
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Takashi Kikuchi,
Hisatoshi Sugiura,
Akira Koarai,
Tomohiro Ichikawa,
Yoshiaki Minakata, Kazuto Matsunaga,
Masanori Nakanishi,
Tsunahiko Hirano,
Keiichirou Akamatsu,
Satoru Yanagisawa,
Kanako Furukawa,
Hiroki Kawabata,
Masakazu Ichinose
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ABSTRACT: 27-Hydroxycholesterol (27-OHC) is produced from cholesterol by sterol 27-hydroxylase as an intermediate in the biosynthesis pathway of bile acid. Recently, 27-OHC was reported to cause inflammation and apoptosis in various types of cells. The aim of this study was to assess the production of 27-OHC in the airways of patients with COPD and to elucidate the possible role of 27-OHC in the tissue fibrosis of COPD.
Lung tissues were obtained from six control subjects and six patients with COPD, and sputum samples were obtained from 11 healthy subjects and 15 patients with COPD. The expression of sterol 27-hydroxylase in the lung was investigated by immunohistochemistry. The amounts of 27-OHC in the sputum were quantified by the liquid chromatography-tandem mass spectrometry method. Because peribronchial fibrosis in peripheral airways is involved in the airflow limitation of COPD, we investigated the profibrotic effects of 27-OHC in vitro.
The expression of sterol 27-hydroxylase was significantly enhanced in the lung tissues of patients with COPD compared with control subjects. The amounts of 27-OHC in the sputum were significantly increased in the patients with COPD (P < .01), and the degree of 27-OHC production was negatively correlated with lung function (P < .01). 27-OHC augmented the differentiation of lung fibroblasts into myofibroblasts and the production of extracellular matrix protein through activation of nuclear factor-κB and subsequent transforming growth factor-β(1) upregulation.
27-OHC production is enhanced in the airways of patients with COPD and might be involved in the pathogenesis of COPD.
Chest 01/2012; 142(2):329-37. · 5.25 Impact Factor
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ABSTRACT: The quantification of physical activity is useful for the management of chronic obstructive pulmonary disease (COPD) but has not been fully established yet. The DynaPort Activity Monitor(®) (DAM), a triaxial accelerometer is the only well validated accelerometer in Caucasians but it has not been validated in Japanese COPD patients. We initially evaluated the reproducibility of the DAM in Japanese healthy subjects. Next, the within-subject repeatability and the determinants of physical activity were investigated in Japanese COPD patients.
The durations of locomotion, standing, and sitting measured by the DAM were compared to those of the self-records (Study 1). COPD patients wore the DAM for 3 days and the durations of each activity of 2 selected days were compared to assess the repeatability (Study 2). The relationship between the duration of locomotion and the physiological properties were examined (Study 3).
The activities measured by the DAM were significantly associated with those of the self-records (p<0.001). The values of the intra-class correlation coefficient (ICC) for the reproducibility were over 0.99, and the agreement with the self-records was observed for the DAM. Similarly, the values of ICC for repeatability were over 0.84 in all activities, and there was no systematic bias in the COPD patients. The duration of locomotion was negatively correlated with the total lung capacity (TLC) and closing capacity/TLC, but not with other pulmonary functions, exercise capacity, muscle force, dyspnea, or modified BODE index.
The triaxial accelerometer is reliable for evaluating the physical activity of Japanese COPD patients.
Internal Medicine 01/2012; 51(4):369-75. · 0.94 Impact Factor
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ABSTRACT: The DynaPort Activity Monitor (DAM) has been reported to be useful to evaluate the activity in healthy subjects and patients with chronic obstructive pulmonary disease (COPD). However, it is difficult to estimate the activity of COPD patients using DAM, because its battery works only for several hours and sensors should be worn at two parts of the body. A newly developed compact, single-position triaxial accelerometer (Actimarker) can measure the activity for >1 month, but has not been validated for COPD patients. Objectives: The validity of the Actimarker was evaluated in COPD patients.
In study 1, the validity of the device was tested in 14 stable COPD patients by comparing it with DAM. In study 2, the influence of the weather on activity was examined. In study 3, the number of measurement days required to ensure repeatability was determined.
The durations of activity measured by the Actimarker and DAM were significantly correlated at intensity values ≥2.0, ≥2.5 and ≥3.0 METs. The duration of activity on rainy days was significantly shorter than that on non-rainy days. The values of intraclass correlation coefficients were >0.8 in 3-, 4- or 5-day measurements, and there was no systematic bias at any number of days or intensities with Bland-Altman plots.
The validity of the Actimarker was confirmed, and repeatability was obtained when the data from at least 3 non-rainy weekdays were analyzed. Actimarker appears to be useful as a simplified method to evaluate the physical activity of COPD patients.
Respiration 09/2011; 83(4):300-7. · 2.26 Impact Factor
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Kanako Furukawa,
Hisatoshi Sugiura, Kazuto Matsunaga,
Tomohiro Ichikawa,
Akira Koarai,
Tsunahiko Hirano,
Satoru Yanagisawa,
Yoshiaki Minakata,
Keiichiro Akamatsu,
Masae Kanda,
Manabu Nishigai,
Masakazu Ichinose
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ABSTRACT: 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.
Exhaled NO including fractional exhaled NO (FENO) 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.
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 FENO and 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 FENO (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).
These results suggested that excessive nitrosative stress occurred in EP and that Calv could be a marker of the disease activity.
Respiratory research 06/2011; 12:81. · 3.36 Impact Factor
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ABSTRACT: Measurement of the exhaled nitric oxide fraction (FE(NO)) has been proposed as a useful diagnostic test for asthma. However, most of the data concerning the FE(NO) 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 FE(NO) levels.
FE(NO) 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 FE(NO) measurements.
FE(NO) 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 FE(NO) 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 FE(NO) levels. The cutoff values of FE(NO) to discriminate asthma from non-asthma ranged from 18 to 28 ppb depending on rhinitis and smoking status.
The cutoff values presented may be useful for the interpretation of FE(NO) values in the clinical practice.
Allergology International 04/2011; 60(3):331-7.
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ABSTRACT: Backgrounds: Inhaled corticosteroids (ICS)/inhaled long-acting beta(2)-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 (FE(NO)) 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 (FEV(1)), and the third phase slope of the single nitrogen washout curve (ΔN(2)) as well as the FE(NO) level. The baseline FE(NO) levels and positive specific IgE (atopy+) were significantly associated with airway obstructive changes assessed by FEV(1) and ΔN(2). A baseline FE(NO) level >35 ppb yielded 80.0% sensitivity and 66.7% specificity for identifying the subjects with significant improvement in FEV(1) (greater than 200 mL). An atopy+ yielded 60.0% sensitivity and 88.9% specificity for an improvement in FEV(1). When combined with FE(NO) > 35 ppb and atopy+, it showed 40% sensitivity and 100.0% specificity for FEV(1) improvement. Alternatively, COPD subjects with FE(NO) ≤ 35 ppb and atopy- did not show significant improvement in FEV(1). Conclusion: Combining FE(NO) and specific IgE may be a useful marker for predicting the response to ICS/LABA on airflow limitation in COPD.
Frontiers in pharmacology. 01/2011; 2:36.
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ABSTRACT: The measurement of the exhaled nitric oxide fraction (FE(NO)) is proposed as a useful marker of airway inflammation. In healthy adults, there have been a few studies of the reference ranges for FE(NO) in Caucasians. A community study in other regions may reveal any possible ethnic differences in the FE(NO) levels.
A total of 240 healthy adults aged between 18 to 74 years were recruited from four medical centers in Japan. Current smokers and subjects having a history of atopic disease were not included. FE(NO) was measured using an online electrochemical nitric oxide analyzer according to the current guidelines. The reference ranges for FE(NO) were estimated using two different statistical methods recommended by International Federation of Clinical Chemistry and Laboratory Medicine.
The mean FE(NO) was 16.9 ppb (parts per billion) with a 95% prediction interval (2.5 to 97.5 percentiles) of 6.5 to 35.0 ppb in healthy Japanese adults. Normality assumptions were met for the logarithm-transformed FE(NO). The geometric mean FE(NO) was 15.4 ppb with a mean ± two standard deviations of 6.5 to 36.8 ppb. Age, gender, height, and past smoking history were not associated with the FE(NO) levels.
The reference ranges for FE(NO) in healthy Japanese adults were similar to those of Caucasians. It seems reasonable that the upper limit of FE(NO) for healthy adults should be set at approximately 36.0 ppb irrespective of ethnic differences.
Allergology International 12/2010; 59(4):363-7.
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Yoshiaki Minakata,
Hiroki Ueda,
Keiichiro Akamatsu,
Masae Kanda,
Satoru Yanagisawa,
Tomohiro Ichikawa,
Akira Koarai,
Tsunahiko Hirano,
Hisatoshi Sugiura, Kazuto Matsunaga,
Masakazu Ichinose
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ABSTRACT: Comorbidities of chronic obstructive pulmonary disease (COPD) have been recognized as an important issue in COPD management. We have reported that patients with liver diseases show a higher prevalence of COPD, but the number of patients with liver diseases was small and the details of liver diseases were not clearly investigated. In this study, we investigated the prevalence of COPD in patients with liver diseases by recruiting a large number of patients, and also investigated was the effect of hepatitis virus infection on COPD prevalence.
Six hundred sixty-six patients were recruited from 9 primary care clinics and three hospitals. All of these patients were aged 40 years or older with chronic diseases and had not been diagnosed as having respiratory diseases. A spirometry was performed without administration of an inhaled bronchodilator. Airflow limitation was defined as FEV1/FVC<70%. Underlying diseases were diagnosed by doctors of the clinics or the hospitals.
Two hundred fifty-six patients had liver diseases, and 410 did not. Of 410 patients without liver diseases, 37 patients (9.0%) were diagnosed as COPD, and of 256 patients with liver diseases, 35 patients (13.8%) were COPD. When the prevalence was analyzed according to smoking, age and gender, liver diseases showed a significantly high odds ratio (2.10, 95%CI 1.23-3.57, p=0.006), but hepatitis virus infection showed a non-significant tendency toward a high odds ratio.
The patients with liver diseases had a significantly high prevalence of COPD. The presence of liver disease might become a useful predictor for the early detection of COPD.
Internal Medicine 01/2010; 49(24):2687-91. · 0.94 Impact Factor
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ABSTRACT: Background: Exhaled breath condensate (EBC) measurements have recently been reported to be useful for the detection of inflammatory molecules in the airways. However, the clinical relevance of EBC analysis in asthma therapy has not been determined yet. Objectives: To investigate whether EBC analysis has any potential for predicting the steroid response in asthmatics. Methods: Eighteen steroid-naive asthmatics were enrolled. EBC collection, spirometry and a methacholine challenge test were performed before and 12 weeks after inhaled steroid therapy. Exhaled IL-4, IL-17, RANTES, macrophage inflammatory protein (MIP)-1α, MIP-1β, IL-8, IFN-γ-inducible protein (IP)-10, TNF-α and TGF-β were simultaneously analyzed by a protein array, and the relationship between baseline molecule expression and steroid-mediated changes in forced expiratory volume in 1 s (FEV(1)) and airway responsiveness was investigated. Results: Steroid therapy improved FEV(1) values and the methacholine threshold. Among the molecules examined, increased IL-4 and RANTES levels as well as decreased IP-10 levels at baseline were significantly correlated with an improvement in FEV(1). By contrast, molecule levels were not related to changes in the responsiveness to methacholine. In addition, changes in FEV(1) values were significantly associated with reductions in IL-4 and RANTES levels. Conclusions: EBC measurements of IL-4, RANTES and IP-10 might be useful for predicting the steroid-mediated FEV(1) improvement in asthma.
Respiration 09/2009; 78(4):393-398. · 2.26 Impact Factor
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ABSTRACT: 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 (H(2)O(2)) 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 muM H(2)O(2) significantly potentiated the release of IL-8 from the epithelial cells after stimulation with 10 microg/ml poly(I:C). The H(2)O(2)-augmented IL-8 release was inhibited by treatment with N-acetylcysteine. One hundred micromoles of H(2)O(2) enhanced the translocation of nuclear factor (NF)-kappaB p65, but not that of interferon regulatory factor-3 (IRF-3), into the nucleus and the NF-kappaB 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 H(2)O(2) 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-kappaB 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.
American Journal of Respiratory Cell and Molecular Biology 08/2009; 42(6):651-60. · 5.13 Impact Factor
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Satoru Yanagisawa,
Akira Koarai,
Hisatoshi Sugiura,
Tomohiro Ichikawa,
Masae Kanda,
Rie Tanaka,
Keiichiro Akamatsu,
Tsunahiko Hirano, Kazuto Matsunaga,
Yoshiaki Minakata,
Masakazu Ichinose
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ABSTRACT: Excessive oxidative stress has been reported to be generated in inflamed tissues and contribute to the pathogenesis of inflammatory lung diseases, exacerbations of which induced by viral infections are associated with toll-like receptor (TLR) activation. Among these receptors, TLR8 has been reported as a key receptor that recognizes single-strand RNA virus. However, it remains unknown whether TLR8 signaling is potentiated by oxidative stress. The aim of this study is to examine whether oxidative stress modulates TLR8 signaling in vitro.
Human peripheral blood neutrophils were obtained from healthy non-smokers and stimulated with TLR 7/8 agonist imidazoquinoline resiquimod (R848) in the presence or absence of hydrogen peroxide (H2O2). Neutrophilic responses including cytokine release, superoxide production and chemotaxis were examined, and the signal transduction was also analyzed.
Activation of TLR8, but not TLR7, augmented IL-8 release. The R848-augmented IL-8 release was significantly potentiated by pretreatment with H2O2 (p < 0.01), and N-acetyl-L-cysteine reversed this potentiation. The combination of H2O2 and R848 significantly potentiated NF-kB phosphorylation and IkBalpha degradation. The H2O2-potentiated IL-8 release was suppressed by MG-132, a proteosome inhibitor, and by dexamethasone. The expressions of TLR8, myeloid differentiation primary response gene 88 (MyD88), and tumor necrosis factor receptor-associated factor 6 (TRAF6) were not affected by H2O2.
TLR8-mediated neutrophilic responses were markedly potentiated by oxidative stress, and the potentiation was mediated by enhanced NF-kB activation. These results suggest that oxidative stress might potentiate the neutrophilic inflammation during viral infection.
Respiratory research 07/2009; 10:50. · 3.36 Impact Factor
