Pathophysiological relevance of sputum MUC5AC and MUC5B levels in patients with mild asthma

[Background] Airway mucus hypersecretion is an important pathophysiological feature of asthma. MUC5AC and MUC5B are the major secreted polymeric mucins in airways, and their compositions affect mucus properties. Despite the increasing appreciation of MUC5AC and MUC5B compositions in asthmatic airways, their pathophysiological relevance remains to be fully understood in humans. [Methods] In this cross-sectional study, we prospectively enrolled newly referred steroid-untreated patients with mild asthma and healthy controls. We compared induced sputum MUC5AC and MUC5B levels between patients and controls. Subsequently, we assessed the correlation between MUC5AC and MUC5B levels and clinical indices in patients. Sputum MUC5AC and MUC5B levels were measured using enzyme-linked immunosorbent assays. [Results] Sputum MUC5AC and MUC5B levels were significantly higher in patients (n = 87) than in controls (n = 22) (p = 0.0002 and p = 0.006, respectively). The ratio of sputum MUC5AC to MUC5B tended to be higher in patients than in controls (p = 0.07). Sputum MUC5AC levels significantly and positively correlated with fractional exhaled nitric oxide at expiratory flow of 50 mL/s (Spearman's rho = 0.29, p = 0.006), sputum eosinophil proportion (rho = 0.34, p = 0.0013), and airway sensitivity (rho = 0.39, p = 0.0005). By contrast, sputum MUC5B levels significantly and positively correlated with airway sensitivity (rho = 0.35, p = 0.002) and negatively correlated with airway reactivity (rho = −0.33, p = 0.004). [Conclusions] Sputum MUC5AC is increased by protein levels and involved in airway type 2/eosinophilic inflammation and airway hyperresponsiveness in steroid-untreated patients with mild asthma

Sputum YKL-40 Levels and Pathophysiology of Asthma and Chronic Obstructive Pulmonary Disease.

Background: Recent evidence suggests that YKL-40, also called chitinase-3-like-1 protein, is involved in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Details of sputum YKL-40 in asthma and COPD, however, remain unknown. Objectives: To clarify associations of sputum YKL-40 levels with clinical indices in asthma and COPD. Methods: Thirty-nine patients with asthma, 14 age-matched never-smokers as controls, 45 patients with COPD, and 7 age-matched smokers as controls were recuited for this study. Sputum YKL-40 levels were measured and YKL-40 expression in sputum cells was evaluated by immunocytochemistry. Results: Sputum YKL-40 levels were higher in patients with COPD (346 ± 325 ng/ml) than in their smoker controls (125 ± 122 ng/ml; p < 0.05), but were not significantly different between patients with asthma (117 ± 170 ng/ml) and their controls (94 ± 44 ng/ml; p = 0.15). In patients with asthma only, sputum YKL-40 levels were positively correlated with disease severity (r = 0.34, p = 0.034) and negatively correlated with pre- and postbronchodilator %FEV(1) (r = -0.47 and -0.42, respectively; p < 0.01) and forced mid-expiratory flow (r = -0.48 and -0.46, respectively, p < 0.01). Sputum YKL-40 levels were positively correlated with sputum neutrophil counts in asthma (r = 0.55, p < 0.001) and with neutrophil and macrophage counts in COPD (r = 0.45 and 0.65, respectively, p < 0.01). YKL-40 was expressed in the cytoplasm of sputum neutrophils and macrophages in all groups. Conclusions: Elevated sputum YKL-40 reflects airflow obstruction in asthma whereas the roles of YKL-40 in the proximal airways in COPD remain to be elucidated

Association of Eosinophilic Inflammation with FKBP51 Expression in Sputum Cells in Asthma.

[Background]: Airway eosinophilia is a predictor of steroid responsiveness in steroid-naı¨ve asthma. However, the relationship between airway eosinophilia and the expression of FK506-binding protein 51 (FKBP51), a glucocorticoid receptor cochaperone that plays a role in steroid insensitivity in asthma, remains unknown. [Objective]: To evaluate the relationship between eosinophilic inflammation and FKBP51 expression in sputum cells in asthma. [Methods]: The FKBP51 mRNA levels in sputum cells from steroid-naı¨ve patients with asthma (n = 31) and stable asthmatic patients on inhaled corticosteroid (ICS) (n = 28) were cross-sectionally examined using real-time PCR. Associations between FKBP51 levels and clinical indices were analyzed. [Results]: In steroid-naı¨ve patients, the FKBP51 levels were negatively correlated with eosinophil proportions in blood (r =20.52) and sputum (r =20.57), and exhaled nitric oxide levels (r =20.42) (all p,0.05). No such associations were observed in patients on ICS. In steroid-naı¨ve patients, improvement in forced expiratory volume in one second after ICS initiation was correlated with baseline eosinophil proportions in blood (r = 0.74) and sputum (r = 0.76) and negatively correlated with FKBP51 levels (r =20.73) (all p,0.0001) (n = 20). Lastly, the FKBP51 levels were the lowest in steroid-naı¨ve asthmatic patients, followed by mild to moderate persistent asthmatic patients on ICS, and the highest in severe persistent asthmatic patients on ICS (p,0.0001). [Conclusions]: Lower FKBP51 expression in sputum cells may reflect eosinophilic inflammation and glucocorticoid responsiveness in steroid-naı¨ve asthmatic patients

Effects of 24-week add-on treatment with ciclesonide and montelukast on small airways inflammation in asthma.

[Background]Eosinophilic inflammation of the small airways is a key process in asthma that often smolders in treated patients. The long-term effects of add-on therapy on the persistent inflammation in the small airways remain unknown.Objective To examine the effects of add-on therapy with either ciclesonide, an inhaled corticosteroid with extrafine particles, or montelukast on small airway inflammation. [Methods]Sixty patients with stable asthma receiving inhaled corticosteroid treatment were enrolled in a randomized, open-label, parallel comparison study of 24-week add-on treatment with ciclesonide or montelukast. Patients were randomly assigned to 3 groups: ciclesonide (n = 19), montelukast (n = 22), or no add-on as controls (n = 19). At baseline and at weeks 4, 12, and 24, extended nitric oxide analysis; pulmonary function tests, including impulse oscillometry; blood eosinophil counts; and asthma control tests (ACTs) were performed. [Results]A total of 18 patients in the ciclesonide group, 19 in the montelukast group, and 15 in the control group completed the study and were analyzed. With repeated-measures analysis of variance, ciclesonide produced a significant decrease in alveolar nitric oxide and a significant improvement in ACT scores over time. Montelukast produced significant decreases in alveolar nitric oxide concentrations and blood eosinophil counts over time and slightly improved ACT scores, whereas no such changes were observed in the control group. Alveolar nitric oxide concentrations with ciclesonide and reactance area at low frequencies with montelukast produced greater improvements over time compared with control. [Conclusion]Ciclesonide add-on therapy and montelukast add-on therapy may act differently, but both separately can improve small airway abnormalities and provide better asthma control

Accuracy Assessment of Photochemical Reflectance Index (PRI) and Chlorophyll Carotenoid Index (CCI) Derived from GCOM-C/SGLI with In Situ Data

The photochemical reflectance index (PRI) and the chlorophyll carotenoid index (CCI) are carotenoid-sensitive vegetation indices, which can monitor vegetation&rsquo;s photosynthetic activities. One unique satellite named &ldquo;Global Change Observation Mission-Climate (GCOM-C)&rdquo; is equipped with a sensor, &ldquo;Second Generation Global Imager (SGLI)&rdquo;, which has the potential to frequently and simultaneously observe PRI and CCI over a wide swath. However, the observation accuracy of PRI and CCI derived from GCOM-C/SGLI remains unclear in forests. Thus, we demonstrated their accuracy assessment by comparing them with in situ data. We collected in situ spectral irradiance data at four forest sites in Japan for three years. We statistically compared satellite PRI with in situ PRI, and satellite CCI with in situ CCI. From the obtained results, the satellite PRI showed poor agreement (the best: r=0.294 (p&lt;0.05)) and the satellite CCI showed good agreement (the best: r=0.911 (p&lt;0.001)). The greater agreement of satellite CCI is possibly because satellite CCI contained fewer outliers and satellite CCI was more resistant to small noise, compared to satellite PRI. Our results suggest that the satellite CCI is more suitable for practical use than the satellite PRI with the latest version (version 3) of GCOM-C/SGLI&rsquo;s products

Accuracy Assessment of Photochemical Reflectance Index (PRI) and Chlorophyll Carotenoid Index (CCI) Derived from GCOM-C/SGLI with In Situ Data

The photochemical reflectance index (PRI) and the chlorophyll carotenoid index (CCI) are carotenoid-sensitive vegetation indices, which can monitor vegetation’s photosynthetic activities. One unique satellite named “Global Change Observation Mission-Climate (GCOM-C)” is equipped with a sensor, “Second Generation Global Imager (SGLI)”, which has the potential to frequently and simultaneously observe PRI and CCI over a wide swath. However, the observation accuracy of PRI and CCI derived from GCOM-C/SGLI remains unclear in forests. Thus, we demonstrated their accuracy assessment by comparing them with in situ data. We collected in situ spectral irradiance data at four forest sites in Japan for three years. We statistically compared satellite PRI with in situ PRI, and satellite CCI with in situ CCI. From the obtained results, the satellite PRI showed poor agreement (the best: r=0.294 (p0.05)) and the satellite CCI showed good agreement (the best: r=0.911 (p0.001)). The greater agreement of satellite CCI is possibly because satellite CCI contained fewer outliers and satellite CCI was more resistant to small noise, compared to satellite PRI. Our results suggest that the satellite CCI is more suitable for practical use than the satellite PRI with the latest version (version 3) of GCOM-C/SGLI’s products

Sputum YKL-40 Levels and Pathophysiology of Asthma and Chronic Obstructive Pulmonary Disease.

Background: Recent evidence suggests that YKL-40, also called chitinase-3-like-1 protein, is involved in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Details of sputum YKL-40 in asthma and COPD, however, remain unknown. Objectives: To clarify associations of sputum YKL-40 levels with clinical indices in asthma and COPD. Methods: Thirty-nine patients with asthma, 14 age-matched never-smokers as controls, 45 patients with COPD, and 7 age-matched smokers as controls were recuited for this study. Sputum YKL-40 levels were measured and YKL-40 expression in sputum cells was evaluated by immunocytochemistry. Results: Sputum YKL-40 levels were higher in patients with COPD (346 ± 325 ng/ml) than in their smoker controls (125 ± 122 ng/ml; p < 0.05), but were not significantly different between patients with asthma (117 ± 170 ng/ml) and their controls (94 ± 44 ng/ml; p = 0.15). In patients with asthma only, sputum YKL-40 levels were positively correlated with disease severity (r = 0.34, p = 0.034) and negatively correlated with pre- and postbronchodilator %FEV(1) (r = -0.47 and -0.42, respectively; p < 0.01) and forced mid-expiratory flow (r = -0.48 and -0.46, respectively, p < 0.01). Sputum YKL-40 levels were positively correlated with sputum neutrophil counts in asthma (r = 0.55, p < 0.001) and with neutrophil and macrophage counts in COPD (r = 0.45 and 0.65, respectively, p < 0.01). YKL-40 was expressed in the cytoplasm of sputum neutrophils and macrophages in all groups. Conclusions: Elevated sputum YKL-40 reflects airflow obstruction in asthma whereas the roles of YKL-40 in the proximal airways in COPD remain to be elucidated

Wide-scope targeted analysis of bioactive lipids in human plasma by LC/MS/MS

Quantitative information on blood metabolites can be used in developing advanced medical strategies such as early detection and prevention of disease. Monitoring bioactive lipids such as steroids, bile acids, and PUFA metabolites could be a valuable indicator of health status. However, a method for simultaneously measuring these bioactive lipids has not yet been developed. Here, we report a LC/MS/MS method that can simultaneously measure 144 bioactive lipids, including steroids, bile acids, and PUFA metabolites, from human plasma, and a sample preparation method for these targets. Protein removal by methanol precipitation and purification of bioactive lipids by solid-phase extraction improved the recovery of the targeted compounds in human plasma samples, demonstrating the importance of sample preparation methods for a wide range of bioactive lipid analyses. Using the developed method, we studied the plasma from healthy human volunteers and confirmed the presence of bioactive lipid molecules associated with sex differences and circadian rhythms. The developed method of bioactive lipid analysis can be applied to health monitoring and disease biomarker discovery in precision medicine