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Background: Vilanterol (GW642444M) (VI) is a novel, inhaled, long-acting β(2) agonist with inherent 24-h activity under development as a once-daily combination therapy with an inhaled corticosteroid for COPD and asthma. This study assessed the dose response, efficacy, and safety of VI at doses of 3 to 50 μg in patients with moderate to severe COPD.Methods: Six hundred two patients (intent-to-treat) were randomized (double-blind) to VI 3, 6.25, 12.5, 25, or 50 μg or placebo once daily for 28 days. The primary end point was change from baseline in trough FEV1 at the end of the 28-day treatment period. Secondary end points included 0- to 24-h weighted mean FEV(1) on days 1 and 28 and time to increases of ≥ 100 mL or ≥ 12% from baseline FEV(1) on day 1. Safety assessments included adverse events, vital signs, ECG assessment, and clinical laboratory tests.Results: VI once daily for 28 days significantly improved trough FEV(1) in a dose-dependent manner vs placebo. Clinically relevant treatment differences of ≥ 130 mL in trough and 0- to 24-h weighted mean FEV(1) were observed with VI 25- and 50-μg doses vs placebo. All doses of VI were associated with a low incidence of treatment-related adverse events/serious adverse events, with no suggestion of effects on BP, pulse rate, QT intervals corrected for heart rate calculated by Fridericia formula, or blood glucose and potassium levels.Conclusions: VI 25 and 50 μg once daily provided both statistically and clinically relevant 24-h improvements in lung function in patients with COPD compared with placebo. All doses of VI had a safety and tolerability profile similar to placebo. [ABSTRACT FROM AUTHOR]

Rationale: Although cigarette smoking is the most important risk factor for COPD, COPD develops in only a minority of smokers, suggesting a significant genetic role. To solve the underlying pathophysiologic mechanism, it is critical to understand genes and their final product, ie, proteins. We investigated the exclusive proteins from the lung tissues obtained from COPD patients using proteomics., Methods: Nontumorous lung tissue specimens were obtained from patients who underwent surgery for lung cancer. We included 22 subjects: nonsmokers (n = 8), smokers without COPD (healthy smokers, n = 7), and smokers with COPD (n = 7). Proteins were separated from their spots with two-dimensional polyacrylamide gel electrophoresis and examined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). To validate the proteins from the above procedures, Western blotting and immunohistochemistry were conducted., Results: Twelve protein spots from COPD group significantly increased or decreased compared with the other two groups were chosen for MALDI-TOF-MS analysis. Eight proteins were up-regulated in the COPD group as compared with the nonsmokers. Meanwhile, five proteins from the COPD group were up-regulated and five were down-regulated when compared with healthy smokers. Of these, matrix metalloproteinase (MMP)-13 and thioredoxin-like 2 were significantly increased in the COPD patients by Western blot and immunohistochemistry. MMP-13 was mainly expressed in the alveolar macrophages and type II pneumocytes; however, thioredoxin-like 2 was primarily seen in the bronchial epithelium., Conclusions: MMP-13 and thioredoxin-like 2 in lungs increased in patients with COPD. MMP-13 was mainly expressed in the alveolar macrophages and type II pneumocytes. In contrast, thioredoxin-like 2 was primarily seen in the bronchial epithelium.

Background: Asthma is chronic airway inflammation that occurs together with reversible airway obstruction. T-lymphocytes play an important role in the pathogenesis of asthma. Proteomic technology has rapidly developed in the postgenomic era, and it is now widely accepted as a complementary technology to genetic profiling. We investigated the changes of proteins in T-lymphocytes of asthma patients by using standard proteome technology: two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), and a database search., Methods: The proteins of CD3+ T-lymphocytes were isolated from whole blood of six steroid-naive asthmatic patients and of six healthy volunteers. 2D-PAGE was performed and the silver-stained protein spots were comparatively analyzed between the asthma and control groups using an image analyzer. Some differentially expressed spots were identified by MALDI-TOF-MS and database search. The messenger RNA expressions of some identified proteins were examined by real-time polymerase chain reaction (RT-PCR)., Results: Thirteen protein spots in the T-lymphocytes of the asthmatic patients were increased and 12 spots were decreased compared to those of the normal subjects. Among the identified proteins, the increased expression of the messenger RNA of phosphodiesterase 4C and thioredoxin-2 and the decreased expression of the messenger RNA of glutathione S-transferase M3 were confirmed by RT-PCR in the asthmatic patients., Conclusions: Proteomic examination of the peripheral T-lymphocytes revealed some differentially expressed proteins in the asthmatic patients. The possibility of using the differentially expressed proteins as important biomarkers and therapeutic targets in asthma patients warrants further studies.

Study Object: Diffuse panbronchiolitis (DPB) is a hypersecretory airway disease, and the mechanism of mucus hypersecretion in DPB is poorly understood. Moreover, mucin synthesis in the airways has been reported to be regulated by neutrophilic inflammation-induced epidermal growth factor receptor (EGFR) expression, and the degranulation of goblet cells is known to be mediated by neutrophilic elastase. In this study, we examined the relationship between EGFR expression in the bronchiolar epithelium with neutrophilic inflammation and mucus hypersecretion in the tissues of DPB patients., Design: The tissue specimens of 13 DPB patients and 6 healthy control subjects were examined by alcian blue/periodic acid-Schiff (AB/PAS) staining for mucous glycoconjugates, and by immunohistochemical staining for MUC5AC, EGFR, tumor necrosis factor-alpha, and CD16 on neutrophils., Results: Neutrophilic inflammation was significantly higher in the tissue of DPB patients than in that of control subjects (p = 0.002). In the bronchiolar epithelium, goblet cell metaplasia, by AB/PAS staining and mucin MUC5AC expression, was significantly higher than that in control subjects (p = 0.001 and p = 0.002, respectively). In addition, the morphometric quantification of intraluminal mucus secretion showed that the areas of the bronchiolar lumen occupied by mucus secretion were significantly increased in the tissue of DPB patients (p = 0.001), suggesting goblet cell degranulation. EGFR expression was observed in the bronchiolar epithelium of DPB patients, but not in that of control subjects., Conclusions: In DPB, we suggest that mucus hypersecretion due to goblet cell metaplasia is closely associated with neutrophilic inflammation and the expression of EGFR. The study also shows that intraluminal secretion due to the degranulation of goblet cells degranulation is related to neutrophilic inflammation.

Background: Virtually all the information available on the prevalence of obstructive airway disease is from Western countries. There are no data from Korea, and reports from other regions of Asia are poorly documented., Objectives: To evaluate the prevalence and correlates of airway obstruction in a community-based setting in Korea., Design: A cross-sectional, population-based study., Setting: Ansan City, near Seoul, South Korea., Participants: A sample of 1,160 community-dwelling men and women aged >or= 18 years (73.1% of the men and 4.1% of the women were either current or former smokers)., Measurements: Subjects underwent physical examinations following a standardized protocol. Data on demographic and health-related factors also were collected. Pulmonary function testing was administered according to American Thoracic Society (ATS) recommendations., Results: The prevalence of airway obstruction was 10.3% (men, 17%; women, 5.6%) by ATS criteria. Ninety percent of the cases of airway obstruction were mild in degree. Twenty percent of male current smokers had airway obstruction. After adjusting for age, gender, and alcohol consumption, the odds of disease was 3.2 times greater in subjects who had smoked for >or= 20 pack-years vs never smokers (95% confidence interval [CI], 1.7 to 6.2). The adjusted odds of disease were 4.3-fold higher in subjects >or= 45 years of age vs those who were younger (95% CI, 2.6 to 7.0)., Conclusions: Since airway obstruction is strongly related to age and smoking, the prevalence of obstructive airway disease in countries like Korea, where the population is rapidly aging and cigarette smoking is on the rise among younger individuals (particularly among women), can be expected to increase. Further efforts to diagnose early obstructive airway disease and to prevent or delay its onset should be emphasized as a major public health concern.

Objectives: Cytotoxic T-lymphocyte antigen (CTLA)-4 is a homolog of CD28, which is expressed only on activated T cells. It binds to accessory molecule B7 and mediates T-cell-dependent immune response. Signaling through CTLA-4 may down-regulate type 1 T-helper cell proliferation; moreover, some studies suggest that CTLA-4 might also deliver a positive signal to type 2 T-helper cell activation. Disruption of this delicate balance of immune regulation may lead to autoimmune diseases or atopic diseases. To evaluate the possible role of CTLA-4 polymorphisms in bronchial asthma, we investigated the association between polymorphisms (exon 1 +49 A/G, promoter -318 C/T) and atopy, asthma severity, and bronchial hyperresponsiveness in bronchial asthma patients and a group of healthy control subjects., Patients: Eighty-eight asthmatic patients and 88 healthy control subjects were studied., Measurements and Results: Asthma severity assessment, methacholine challenge, allergy skinprick test, and serum total IgE measurements were performed. The genotypes of the CTLA-4 promoter (-318 C/T) and exon 1 (+49 A/G) in all subjects were determined using the polymerase chain reaction and restriction fragment length polymorphism. The CTLA-4 promoter (-318 C/T) polymorphism was shown to be associated with asthma severity, but not with asthma, atopy, or bronchial hyperresponsiveness. A significant association was found between severe asthma and the T allele (p = 0.037). The CTLA-4 exon 1 (+49 A/G) polymorphism was shown to be associated with bronchial hyperresponsiveness, but not with asthma, atopy, or asthma severity. Asthmatic patients of the GG genotype had more hyperresponsive airways than those with the AG or AA genotype (p = 0.019)., Conclusions: The CTLA-4 promoter (-318 C/T) T allele may serve as a clinically useful marker of severe asthma. The CTLA-4 exon 1 (+49 A/G) polymorphism may have a disease-modifying effect in asthmatic airways.

Objectives: The possibility that a bronchial inflammatory process could be involved with a chronic nonproductive cough without other potential causes such as postnasal drip syndrome, bronchial asthma, gastroesophageal reflux, chronic bronchitis, bronchiectasis, or the use of angiotensin-converting enzyme inhibitors has not been clearly described. We investigated the possibility that a chronic nonproductive cough without other potential causes is associated with airway inflammation, and if this is so, what the relationship might be between this inflammation and the possible etiology of the cough., Subjects: Twenty-five adults with chronic nonproductive cough as an isolated symptom over a 3-week period, and 5 healthy control subjects were studied., Measurements and Results: Clinical assessments, cough scores, methacholine challenges, allergy skin prick tests, and bronchoscopies for bronchial biopsies were performed. In the bronchial biopsies, the patients were divided into the following two subgroups: 21 patients who were infiltrated with eosinophils vs the healthy control group (median, 12.0 vs. 0.0 cells/mm(2), respectively; p < 0.01); and 4 patients who were infiltrated with lymphocytes vs the healthy control group (median, 84.5 vs. 22.0 cells/mm(2), respectively; p < 0.01). With the methacholine challenge test, 5 of the 21 eosinophil-infiltrated patients received diagnoses of cough-variant asthma, and the other 16 patients received diagnoses of eosinophilic bronchitis. In the lymphocyte-infiltrated group, all four patients received diagnoses of lymphocytic bronchitis., Conclusions: These results suggest that a chronic nonproductive cough as an isolated symptom is associated with airway inflammation due to eosinophil and lymphocyte infiltration. The causes of the chronic nonproductive cough were eosinophilic bronchitis, cough-variant asthma, and lymphocytic bronchitis.

Background: Differential diagnosis of solitary pulmonary nodules (SPNs) can be difficult in areas, such as Korea, where tuberculosis is endemic. Nested polymerase chain reaction (PCR) is a widely used method to test a very small amount of pathogen and to detect Mycobacterium tuberculosis from fine needle aspirates., Objectives: The usefulness of nested PCR for the detection of M tuberculosis from tuberculous SPN and for the differential diagnosis of SPN was evaluated., Methods: Thirty-three patients in whom a diagnosis of SPN was made based on a CT scan of the chest were enrolled in this study. Included were 17 malignant and 16 benign SPNs. Nested PCR was carried out for the detection of M tuberculosis by using TB-1, TB-2, TB-28, and TB-29C on fine needle aspirates from the nodule in all 33 cases., Results: Aspirates from malignant neoplasms, pneumonia, and sequestration were all negative on nested PCR for tuberculosis. One of the three radiologically suspected tuberculous nodules without response to anti-tuberculosis drugs (uncertain) yielded positive results on nested PCR for the detection of M tuberculosis. In contrast, 7 out of 8 (87.5%) aspirates from proven tuberculous nodules showed positive results on nested PCR. Nested PCR could be used to detect M tuberculosis in fine needle aspirates from tuberculous SPNs with good sensitivity (87.5%) and specificity (96.0%)., Conclusion: Nested PCR for the detection of M tuberculosis in fine needle aspirates may be useful in the differential diagnosis of SPNs.