Airway Obstruction In Chronic Obstructive Pulmonary Disease Research Articles

Exosome-encapsulated lncRNA HOTAIRM1 contributes to PM2.5-aggravated COPD airway remodeling by enhancing myofibroblast differentiation.

Emphysema, myofibroblast accumulation and airway remodeling can occur in the lungs due to exposure to atmospheric pollution, especially fine particulate matter (PM2.5), leading to chronic obstructive pulmonary disease (COPD). Specifically, bronchial epithelium-fibroblast communication participates in airway remodeling, which results in COPD. An increasing number of studies are now being conducted on the role of exosome-mediated cell-cell communication in disease pathogenesis. Here, we investigated whether exosomes generated from bronchial epithelial cells could deliver information to normal stromal fibroblasts and provoke cellular responses, resulting in airway obstruction in COPD. We studied the mechanism of exosome-mediated intercellular communication between human bronchial epithelial (HBE) cells and primary lung fibroblasts (pLFs). We found that PM2.5-induced HBE-derived exosomes promoted myofibroblast differentiation in pLFs. Then, the exosomal lncRNA expression profiles derived from PM2.5-treated HBE cells and nontreated HBE cells were investigated using an Agilent Human LncRNA Array. Combining coculture assays and direct exosome treatment, we found that HBE cell-derived exosomal HOTAIRM1 facilitated the myofibroblast differentiation of pLFs. Surprisingly, we discovered that exosomal HOTAIRM1 enhanced pLF proliferation to secrete excessive collagen secretion, leading to airway obstruction by stimulating the TGF-β/SMAD3 signaling pathway. Significantly, PM2.5 reduced FEV1/FVC and FEV1 and increased the level of serum exosomal HOTAIRM1 in healthy people; moreover, serum exosomal HOTAIRM1 was associated with PM2.5-related reductions in FEV1/FVC and FVC. These findings show that PM2.5 triggers alterations in exosome components and clarify that one of the paracrine mediators of myofibroblast differentiation is bronchial epithelial cell-derived HOTAIRM1, which has the potential to be an effective prevention and therapeutic target for PM2.5-induced COPD.

The molecular and cellular mechanisms associated with the destruction of terminal bronchioles in COPD.

Peripheral airway obstruction is a key feature of chronic obstructive pulmonary disease (COPD), but the mechanisms of airway loss are unknown. This study aims to identify the molecular and cellular mechanisms associated with peripheral airway obstruction in COPD. Ten explanted lung specimens donated by patients with very severe COPD treated by lung transplantation and five unused donor control lungs were sampled using systematic uniform random sampling (SURS), resulting in 240 samples. These samples were further examined by micro-computed tomography (CT), quantitative histology and gene expression profiling. Micro-CT analysis showed that the loss of terminal bronchioles in COPD occurs in regions of microscopic emphysematous destruction with an average airspace size of ≥500 and <1000 µm, which we have termed a "hot spot". Based on microarray gene expression profiling, the hot spot was associated with an 11-gene signature, with upregulation of pro-inflammatory genes and downregulation of inhibitory immune checkpoint genes, indicating immune response activation. Results from both quantitative histology and the bioinformatics computational tool CIBERSORT, which predicts the percentage of immune cells in tissues from transcriptomic data, showed that the hot spot regions were associated with increased infiltration of CD4 and CD8 T-cell and B-cell lymphocytes. The reduction in terminal bronchioles observed in lungs from patients with COPD occurs in a hot spot of microscopic emphysema, where there is upregulation of IFNG signalling, co-stimulatory immune checkpoint genes and genes related to the inflammasome pathway, and increased infiltration of immune cells. These could be potential targets for therapeutic interventions in COPD.

Relationship of Serum Levels of IL-17, IL-18, TNF-α, and Lung Function Parameters in Patients with COPD, Asthma-COPD Overlap, and Bronchial Asthma.

Determination of markers of systemic inflammation is one of the important directions in the study of pathogenesis and improvement of diagnosis of chronic obstructive pulmonary disease (COPD), asthma-COPD overlap (ACO), and bronchial asthma (BA). The aim of our work was a comparative study of the features of changes in serum levels of IL-17, IL-18, and TNF-α in patients with COPD, ACO, and BA with various severity of the disease, as well as evaluation of the relationship between the level of these cytokines and lung ventilation function. A total of 147 patients with COPD (n = 58), ACO (n = 57), and BA (n = 32) during a stable period have been examined in this study. The control group included 21 healthy nonsmokers with similar sex-age indicators. Serum levels of IL-17, IL-18, and TNF-α were determined by ELISA. The concentrations of these cytokines in the circulation in the studied patients with COPD, ACO, and BA were higher than those in healthy nonsmokers (p ≤ 0.001). IL-17 and IL-18 levels in the blood serum were comparable in all examined patients. The mean TNF-α concentrations in the circulation in COPD and ACO were significantly higher than those in BA (p < 0.001). In patients with COPD, the levels of IL-17 and TNF-α increased progressively against the background of a decrease in numerous spirometric indicators, which allows us to consider these cytokines as systemic biomarkers of disease severity. In BA, the inverse correlations between the level of IL-17 and FEV1/FVC (%) and FEV1 have been found. In patients with ACO, the increase in IL-18 levels was associated with a decrease in FEV1 and TNF-α with FEV1/FVC (%). These findings indicate that IL-17, IL-18, and TNF-α can participate in the mechanisms of systemic inflammation and the genesis of disorders of airway obstruction in COPD, AСO, and BA. An increase in the levels of IL-17 and TNF-α may be associated with impaired bronchial patency in COPD and BA. The established associations of the IL-18 concentration in the blood serum and FEV1 only in patients with ACO allow using the level of IL-18 as a potential marker of the degree of impaired airway obstruction in this disease.

A combination of handheld spirometer device and questionnaire- A potential screening tool for early diagnosis of chronic obstructive pulmonary disease

Background: Many cases of chronic obstructive pulmonary disease (COPD) continue to be undiagnosed or misdiagnosed. Screening of these patients with spirometry may help in detecting airflow obstruction before the subject develops clinical symptoms. But it is neither feasible nor cost effective and cannot be applied to huge population in India. Therefore, a need for a simple and cost effective method to identify persons who might have the early stages of COPD is warranted. The present study was done:- To identify the utility of COPD population screener (COPD-PS) questionnaire + COPD-6 Hand-held spirometer device (HSD) as a screening tool for early diagnosis of COPD. To identify the sensitivity and specificity of COPD-PS and COPD-6 device, individually and when used in combination, in the diagnosis of COPD. Methodology: This is a cross sectional observational study done using a questionnaire (COPD-PS) and Hand-held spirometer device (COPD-6) during the three months period from May to July 2018 in the department of Pulmonary Medicine in Nizams Institute of Medical Sciences (NIMS). This study was approved by our institution’s ethics committee. Results: Out of the 89 patients screened, 69 had COPD-PS score >/=5 and 52 had a COPD-6 (FEV1/FVC6) Conclusions: The combination of COPD-PS and COPD-6 is highly effective in early detection of undiagnosed airway obstruction in COPD and can guide effectively in subjecting the high risk patients to spirometry for confirming the diagnosis of COPD. Keywords: Chronic obstructive pulmonary disease (COPD); Spirometry; Questionnaire; Screening tool.

The relationship of bronchiectasis to airway obstruction and inflammation in patients with chronic obstructive pulmonary disease

Background: Chronic obstructive pulmonary disease (COPD) and bronchiectasis are diseases of respiratory tract with significant mortality and morbidity. These two diseases can be seen together occasionally and are thought to change each other's course by adversely affecting the prognosis. The aim of our study was to identify the signs of bronchiectasis in COPD patients, to investigate its possible effects on disease prognosis, and to evaluate these signs for diagnostic convenience. Materials and Methods: This prospective study included a total of s[table 60] moderate/severe COPD patients who were admitted to Yedikule Chest Diseases and Chest Surgery Training and Research Hospital between January 2015 and February 2016. The patients were divided into two groups according to the presence of bronchiectasis as confirmed radiologically: 35 patients in the bronchiectasis group and 25 patients in the control group. Demographic data of the patients were questioned and systemic inflammation parameters, spirometric measurements, blood gas analysis, and clinical evaluation findings were recorded. Results: Bronchiectasis was detected in 58.3% of COPD patients. Patients in two groups are similar in sociodemographical, spirometrical and clinical parameters (P > 0.05). Laboratory tests showed similar result in between two groups but carbon dioxide(CO2) values in the blood gas analysis were found to be higher in the bronchiectasis group (P Conclusion: Bronchiectasis is common in COPD patients. In two divided groups, blood gas carbon dioxide values, which affect mortality, were shown to be higher in the bronchiectasis group. This is a new addition to literature that bronchiectatic COPD patients are experiencing different respiratory failure patterns affecting mortality. Diffuse type bronchiectasis has more effect in spirometric results of COPD patients. Also, airway obstruction in COPD is well correlated with elevated sputum PMNL values which represent airway inflammation and if this is combined with high clinical suspicion it guides to a cost effective way for guiding radiological investigations for bronchiectasis.

The chronic obstructive pulmonary disease comorbidity spectrum in Japan differs from that in western countries.

Patients with Chronic Obstructive Pulmonary Disease (COPD) frequently suffer from various comorbidities, such as cardiovascular disease, osteoporosis, depression, malnutrition, metabolic syndrome, diabetes, and lung cancer. These comorbidities have a significant impact on disease severity and survival. In fact, guidelines from both the Global Initiative for Chronic Obstructive Lung Disease and the Japanese Respiratory Society recommend that physicians take comorbidities into account when they evaluate COPD severity. These guidelines also emphasize the importance of managing comorbidities alongside airway obstruction in COPD. The mechanisms by which the many COPD-related comorbidities develop are still unclear. Aging and smoking are well-established as major factors. However, systemic inflammation may also contribute to the disease process. Having developed from the classical theory to differentiate COPD patients into "pink puffers" and "blue bloaters", COPD is now generally considered as a heterogeneous condition. On this point, we have noticed that the characteristics of Japanese COPD patients tend to differ from those of Westerners. Specifically, Japanese patients tend to be older, to have lower body mass index, to suffer from emphysema-dominant lung disease, and to experience exacerbations less frequently. The comorbidity spectrum of Japanese COPD patients also seems to differ from that of Westerners. For instance, in Japanese patients, cardiovascular disease and metabolic syndrome are less prevalent, whereas osteoporosis and malnutrition are more frequent. In order to treat Japanese COPD patients optimally, we must pay particular attention to their unique demographics and comorbidity spectrum, which contrast with those of Western COPD patients.

Relationship between expression of matrix metalloproteinase-9 and adenylyl cyclase-associated protein 1 in chronic obstructive pulmonary disease.

To investigate the relationship between expression of matrix metalloproteinase (MMP)-9 and expression of adenylyl cyclase-associated protein (CAP)-1 in chronic obstructive pulmonary disease (COPD). Patients with possible respiratory disease were recruited into the study and divided into a COPD group and a non-COPD group on diagnosis. Pulmonary function tests were performed and serum concentrations of MMP-9 were measured using an enzyme-linked immunosorbent assay. MMP-9 and CAP1 expression were analysed in lung tissue and bronchoalveolar lavage fluid in all available samples using immunohistochemistry and Western blot, respectively. In addition, expression of MMP-9 and CAP1 in vitro was investigated using immunofluorescence. Expression of CAP1 in response to MMP-9 was measured in the human alveolar epithelial cell line HP-AEpiC, using Western blot. A total of 90 patients were included in the study: 52 were in the COPD group and 38 in the non-COPD group. Serum MMP-9 concentrations were significantly higher in the COPD than in the non-COPD group. MMP-9 serum concentrations were negatively correlated with forced expiratory volume in 1 s (FEV1), FEV1 as a percentage of the normal predicted value and the ratio of FEV1 to forced vital capacity, and were positively correlated with residual volume (RV), total lung capacity (TLC) and RV/TLC values. In lung tissue and bronchoalveolar lavage fluid samples, MMP-9 and CAP1 expression were inversely related. This relationship was confirmed in HP-AEpiC cells. High expression of MMP-9 and low expression of CAP1 was demonstrated in the COPD group compared with the non-COPD group. This study demonstrated an inverse relationship between CAP1 and MMP-9 expression, and high expression of MMP-9 and low expression of CAP1 in those with COPD compared with the non-COPD group. Overexpression of MMP-9 in lung tissue and its interaction with CAP1 is likely to play a major role in airway obstruction in COPD.

Peripheral blood leukocyte counts as a marker of severity of functional lung impairment in OAD patients attending a tertiary care hospital in Manipur, India

Background: Systemic inflammation is associated with impaired lung function and inflammation is a part of Obstructive Airway Disease (OAD). Chronic obstructive pulmonary disease (COPD) and bronchial asthma are the two most common OAD. In view of this, the present study was done with the objective of determining the relationship between the various grades of severity of airway obstruction in COPD and asthma with blood leukocyte counts. Methods: A cross-sectional study enrolling 40 COPD & 25 asthmatic patients of both sexes. Lung function was studied by computerized spirometer (Helios 402) and blood leukocyte counts (absolute neutrophil count, absolute eosinophil count, absolute basophil count, absolute lymphocyte count and absolute monocyte count) were determined by using suitable diluting fluids. Results: Grading of COPD and asthma severity was done according to GOLD and GINA guidelines respectively based on FEV1% predicted. With the increase in severity of airway obstruction, FEV1 was found to decline in both the groups. Out of 40 COPD patients, 12.5 % of patients had mild, 20% had moderate, 40% had severe and 27.5% had very severe COPD. Out of 25 asthma patients, 48% had mild, 32% had moderate and 20% had severe asthma. There was a significant increase in neutrophil count with the increase in COPD severity and with the increase in asthma severity, eosinophil count increases significantly. . Monocyte count was also increased with the decline in lung function in both the groups. Conclusion:Peripheral blood leukocyte counts are useful and can be used as an indirect & inexpensive marker of severity of functional lung impairment in OAD patients.

Impulse oscillometry in the diagnosis of airway resistance in chronic obstructive pulmonary disease.

Spirometry is a standard lung function test for diagnosis and staging of chronic obstructive pulmonary disease (COPD). Impulse oscillometry (IOS) can be complementary to spirometry, especially in patients at advanced age and with physical or mental disorders who cannot be diagnosed through spirometry. The aim of this study was to compare IOS and spirometry in the assessment of airway obstruction in COPD. The study was conducted in 112 stable COPD patients, including 29 females and 83 males of the mean age of 69±11 years. The oscillometric evaluation included total (R5), peripheral (R5-R20), and negative reactance (X5), which were compared with the predicted forced expiratory volume in 1 s (FEV1%pred). The findings show a significantly negative correlation between FEV1%pred and the R5, R5-R20, and X5. COPD patients had increased R5, R5-R20, and X5. The severity of bronchial obstruction found by impulse oscillometry correlated well the spirometric assessment. IOS is a simple to perform test that may be helpful for functional examination of COPD patients.

Prevalence and correlates of osteoporosis in chronic obstructive pulmonary disease patients in India.

Background:Chronic obstructive pulmonary disease (COPD) is a syndrome of progressive airflow limitation caused by the abnormal inflammatory reaction of the airway and lung parenchyma. Osteoporosis is one of the major extrapulmonary manifestations of COPD. The, prevalence of osteoporosis in COPD patients in Indian population is unknown.Objectives:To study the prevalence of osteoporosis in COPD and to define various risk factors associated with reduced bone mineral density (BMD) in COPD.Materials and Methods:The study was done in the department of Pulmonary Medicine of a tertiary care hospital. All the diagnosed cases of COPD according to the Global Initiative for Obstructive Lung Disease (GOLD) guidelines were included in this study. The present study was a prospective study in for a period of 1 year. A brief history of the patients was taken, especially regarding duration of illness, number of exacerbations in the past 3 years, smoking in pack years, and history of steroid use (both systemic and inhaled steroids) after which cumulative dose of steroids was calculated. Spirometry was done in all these patients to stage the severity of COPD according to GOLD criteria. DEXA scan of the lumbar spine was done using bone densitometer to determine osteoporosis. A world Health Organization (WHO) criterion for definition of osteoporosis was applied and patients with T-score of > –2.5 standard deviation (SD) were diagnosed to have osteoporosis, –1 SD to –2.5 SD were diagnosed to have osteopenia and < –1 SD as normal. Statistical analysis for association of COPD with osteoporosis was done using chi-square test. Risk factors for osteoporosis were identified by univariate and multivariate logistic regression analysis.Results:A total of 102 COPD patients were included in the study. Among these, 68 patients (66.6%) had osteoporosis and 20 patients (19.6%) had osteopenia. Majority (64.7%) of the patients who had osteoporosis had stage III and stage IV COPD disease. It was observed that as the severity grade of COPD increased, the risk of osteoporosis also increased. The bone mineral density (BMD) showed a significant difference among different stages of COPD. As the severity of the stage of COPD increased, BMD decreased. It was also observed that patients with lower body mass index (BMI) had higher prevalence of osteoporosis (37.3%) as compared to overweight patients. On univariate analysis, it was observed that risk factors for osteoporosis were female sex, higher number of exacerbations, BMI, and severity of COPD. After using multivariate logistic regression analysis, stage IV COPD (odds ratio (OR): 34.48, 95% confidence interval (CI): 1.59–1,000, P < 0.02), number of acute exacerbations >3 (OR: 30.3, 95% CI: 4.74–200, P < 0.01), and steroid cumulative dose >1,000 mg (OR: 7.35, 95% CI: 0.92–58.5, P < 0.04) were observed to be significant risk factors for osteoporosis in COPD patients.Conclusions:In the present study, the prevalence of osteoporosis was 66.6% and another 19.6% had osteopenia. As the severity of COPD increased, the risk of osteoporosis increased. GOLD stage III and stage IV patient had significantly lower BMD as compared to stage I and stage II of COPD disease. Stage IV COPD disease, use of oral or parenteral glucocorticoids, and repeated number of exacerbations were found to be independent risk factors for osteoporosis in COPD patients. Thus, high clinical suspicion and early diagnosis and treatment is required in the evaluation of osteoporosis in COPD patients so that the quality of life can be improved in these patients.

Morphological measurements in computed tomography correlate with airflow obstruction in chronic obstructive pulmonary disease: systematic review and meta-analysis

ObjectivesTo determine the correlation between CT measurements of emphysema or peripheral airways and airflow obstruction in chronic obstructive pulmonary disease (COPD).MethodsPubMed, Embase and Web of Knowledge were searched from 1976 to 2011. Two reviewers independently screened 1,763 citations to identify articles that correlated CT measurements to airflow obstruction parameters of the pulmonary function test in COPD patients, rated study quality and extracted information. Three CT measurements were accessed: lung attenuation area percentage < -950 Hounsfield units, mean lung density and airway wall area percentage. Two airflow obstruction parameters were accessed: forced expiratory volume in the first second as percentage from predicted (FEV1 %pred) and FEV1 divided by the forced volume vital capacity.ResultsSeventy-nine articles (9,559 participants) were included in the systematic review, demonstrating different methodologies, measurements and CT airflow obstruction correlations. There were 15 high-quality articles (2,095 participants) in the meta-analysis. The absolute pooled correlation coefficients ranged from 0.48 (95 % CI, 0.40 to 0.54) to 0.65 (0.58 to 0.71) for inspiratory CT and 0.64 (0.53 to 0.72) to 0.73 (0.63 to 0.80) for expiratory CT.ConclusionsCT measurements of emphysema or peripheral airways are significantly related to airflow obstruction in COPD patients. CT provides a morphological method to investigate airway obstruction in COPD.Key Points • Computed tomography is widely performed in patients with chronic obstructive pulmonary disease (COPD) • CT provides quantitative morphological methods to investigate airflow obstruction in COPD • CT measurements correlate significantly with the degree of airflow obstruction in COPD • Expiratory CT measurements correlate more strongly with airflow obstruction than inspiratory CT • Low-dose CT decreases the radiation dose for diagnosis and quantitative emphysema evaluation Electronic supplementary materialThe online version of this article (doi:10.1007/s00330-012-2480-8) contains supplementary material, which is available to authorized users.

The future of combining inhaled drugs for COPD

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality globally, and its prevalence is projected to continue to increase owing to trends in smoking. Treatment of COPD has evolved from the initial adaptations of drugs and treatment strategies successfully used in asthma into more specific pharmacological strategies following global guidelines. Bronchodilating anticholinergic and beta-2-stimulating agents and anti-inflammatory corticosteroid drugs delivered by inhalators are the mainstay of COPD treatment. Despite significant progress, current pharmacotherapies neither fully alleviate the airway obstruction in COPD, nor reverse the progressive nature of the disease. This review discusses inhalation therapies which have recently become clinically available or are being developed, with focus on combination therapies. There is accumulating evidence that the combination of two or all three drug classes, triple therapy, is superior to single drug therapy. Several fixed combinations of both currently available and novel molecules will be launched for clinical use within the next few years. Also, improved understanding of subgroups within the clinical spectrum of COPD, is likely to offer new potentials to improve COPD care.

A brief review of chronic obstructive pulmonary disease.

A recent study, based on a combination of multidetector computed tomography scanning of an intact specimen with microcomputed tomography and histological analysis of lung tissue samples, reported that the number of terminal bronchioles were reduced from approximately 44,500/lung pair in control (donor) lungs to approximately 4800/lung pair in lungs donated by individuals with very severe (Global initiative for chronic Obstructive Lung Disease stage 4) chronic obstructive pulmonary disease (COPD) treated by lung transplantation. The present short review discusses the hypothesis that a rapid rate of terminal bronchiolar destruction causes the rapid decline in lung function leading to advanced COPD. With respect to why the terminal bronchioles are targeted for destruction, the postulated mechanisms of this destruction and the possibility that new treatments are able to either prevent or reverse the underlying cause of airway obstruction in COPD are addressed.

Dynamic change in respiratory resistance during inspiratory and expiratory phases of tidal breathing in patients with chronic obstructive pulmonary disease

Background and objectiveChronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation consisting of airway obstruction and parenchymal emphysema, with loss of elastic recoil. The forced oscillation technique can detect impairment of lung function by measuring lung impedance during normal tidal breathing. Respiratory resistance (Rrs) in COPD has been well-studied, but the differences in Rrs in the inspiratory and expiratory phases between mild and moderate COPD remain poorly understood. Since airway obstruction in COPD is known to change dynamically during tidal breathing and might affect Rrs, the differences in Rrs during tidal breathing between mild and moderate COPD were evaluated.MethodsMild (n = 13) and moderate (n = 13) COPD patients were recruited at Tokyo University Hospital (Tokyo, Japan). Rrs was measured using MostGraph-01 (Chest MI, Inc, Tokyo, Japan), which depicted Rrs in a frequency-and respiratory cycle-dependent manner in three-dimensional graphics. Rrs was evaluated at 4–35 Hz during tidal breathing.ResultsRrs changed dynamically during tidal breathing in COPD. The mean Rrs values were significantly greater in the moderate COPD group than in the mild group. The maximal and minimal Rrs values at higher frequencies in the respiratory cycle were significantly greater in moderate COPD. In inspiratory–expiratory breath analysis, the maximal and minimal Rrs values at 20 Hz and 35 Hz were significantly greater in the moderate group, whereas at 4 Hz they did not differ significantly between the groups.ConclusionRrs changed dynamically during tidal breathing in patients with COPD. The Rrs values at higher frequencies were greater in moderate COPD than in mild COPD. Rrs at higher frequencies might reflect the degree of airway obstruction in tidal breathing in patients with COPD and might be a useful marker for evaluation of airway obstruction at an early stage of COPD.

Combination of roflumilast with a beta-2 adrenergic receptor agonist inhibits proinflammatory and profibrotic mediator release from human lung fibroblasts

BackgroundSmall airway narrowing is an important pathology which impacts lung function in chronic obstructive pulmonary disease (COPD). The accumulation of fibroblasts and myofibroblasts contribute to inflammation, remodeling and fibrosis by production and release of mediators such as cytokines, profibrotic factors and extracellular matrix proteins. This study investigated the effects of the phosphodiesterase 4 inhibitor roflumilast, combined with the long acting β2 adrenergic agonist indacaterol, both approved therapeutics for COPD, on fibroblast functions that contribute to inflammation and airway fibrosis.MethodsThe effects of roflumilast and indacaterol treatment were characterized on transforming growth factor β1 (TGFβ1)-treated normal human lung fibroblasts (NHLF). NHLF were evaluated for expression of the profibrotic mediators endothelin-1 (ET-1) and connective tissue growth factor (CTGF), expression of the myofibroblast marker alpha smooth muscle actin, and fibronectin (FN) secretion. Tumor necrosis factor-α (TNF-α) was used to induce secretion of chemokine C-X-C motif ligand 10 (CXCL10), chemokine C-C motif ligand 5 (CCL5) and granulocyte macrophage colony-stimulating factor (GM-CSF) from NHLF and drug inhibition was assessed.ResultsEvaluation of roflumilast (1-10 μM) showed no significant inhibition alone on TGFβ1-induced ET-1 and CTGF mRNA transcripts, ET-1 and FN protein production, alpha smooth muscle expression, or TNF-α-induced secretion of CXCL10, CCL5 and GM-CSF. A concentration-dependent inhibition of ET-1 and CTGF was shown with indacaterol treatment, and a submaximal concentration was chosen for combination studies. When indacaterol (0.1 nM) was added to roflumilast, significant inhibition was seen on all inflammatory and fibrotic mediators evaluated, which was superior to the inhibition seen with either drug alone. Roflumilast plus indacaterol combination treatment resulted in significantly elevated phosphorylation of the transcription factor cAMP response element-binding protein (CREB), an effect that was protein kinase A-dependent. Inhibition of protein kinase A was also found to reverse the inhibition of indacaterol and roflumilast on CTGF.ConclusionsThese results demonstrate that addition of roflumilast to a LABA inhibits primary fibroblast/myofibroblast function and therapeutically this may impact lung fibroblast proinflammatory and profibrotic mediator release which contributes to small airway remodeling and airway obstruction in COPD.

Innovations to Achieve Excellence in COPD Diagnosis and Treatment in Primary Care

Recognition of chronic obstructive pulmonary disease (COPD) is often missed or delayed in primary care. Once recognized, COPD is often undertreated or episodically treated, focusing on acute exacerbations without establishing maintenance treatment to control ongoing disease. Diagnostic and therapeutic pessimism result in missed opportunities to reduce exacerbations, maintain physical functioning, and reduce emergent health care requirements. Proactive diagnosis and evidence-based management can alleviate the impact of COPD on patients' lives. Smoking cessation has been proven to slow the rate of lung function decline. Maintenance pharmacotherapy and immunizations reduce exacerbations. Pulmonary rehabilitation improves respiratory symptoms and physical functioning and reduces rehospitalizations after exacerbations. Self-management education improves health-related quality of life and reduces inpatient and emergency care usage. Maintenance treatment with long-acting inhaled bronchodilators is appropriate beginning in moderate COPD to maintain airway patency and reduce exacerbations. Tiotropium is US Food and Drug Administration (FDA) approved to treat bronchospasm and reduce exacerbations in patients with COPD; salmeterol/fluticasone is FDA approved to treat airflow obstruction in COPD and reduce exacerbations in patients with a history of exacerbations. Other maintenance long-acting bronchodilators—salmeterol, formoterol, and budesonide/formoterol—are FDA approved to treat airway obstruction in COPD but lack an approved indication against exacerbations. FDA warnings on the use of long-acting beta-adrenergic agents (LABAs) in asthma specifically exempt COPD and do not apply to LABA/inhaled corticosteroid combinations used in COPD. The actual effectiveness achieved in practice with any COPD therapies depends on patients' inhaler technique, adherence, and persistence. Medication usage rates and inhaler proficiency may be improved by concordance, in which the health care provider and patient collaborate to make treatment plans sustainable in the patient's daily life. Practice redesign for whole-patient primary care provides additional tools for comprehensive COPD management. Innovations such as group visits and the patient-centered medical home provide newer ways to interact with COPD patients and their families. Patient-focused and evidence-based options enable primary care practices to manage COPD longitudinally and improve patient outcomes through the course of the disease.

Chronic Obstructive Pulmonary Disease: Reactive Past, Preventive Future

Chronic Obstructive Pulmonary Disease: Reactive Past, Preventive Future

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

Squamous metaplasia (SM) is common in smokers and is associated with airway obstruction in chronic obstructive pulmonary disease (COPD). A major mechanism of airway obstruction in COPD is thickening of the small airway walls. We asked whether SM actively contributes to airway wall thickening through alteration of epithelial-mesenchymal interactions in COPD. Using immunohistochemical staining, airway morphometry, and fibroblast culture of lung samples from COPD patients; genome-wide analysis of an in vitro model of SM; and in vitro modeling of human airway epithelial-mesenchymal interactions, we provide evidence that SM, through the increased secretion of IL-1beta, induces a fibrotic response in adjacent airway fibroblasts. We identify a pivotal role for integrin-mediated TGF-beta activation in amplifying SM and driving IL-1beta-dependent profibrotic mesenchymal responses. Finally, we show that SM correlates with increased severity of COPD and that fibroblast expression of the integrin alpha(v)beta(8), which is the major mediator of airway fibroblast TGF-beta activation, correlated with disease severity and small airway wall thickening in COPD. Our findings have identified TGF-beta as a potential therapeutic target for COPD.

Quantitative Assessment of Peripheral Airway Obstruction on Paired Expiratory/Inspiratory Thin-section Computed Tomography in Chronic Obstructive Pulmonary Disease With Emphysema

We examined the hypothesis that paired inspiratory/expiratory computed tomography (CT) scans in a limited-lung area that excludes emphysema may provide a more accurate evaluation of peripheral airway obstruction in patients with chronic obstructive pulmonary disease (COPD) with emphysema. This study included 32 patients with COPD. The cross-sectional area between -500 and -1024 HU was segmented as whole-lung. The relative areas (RA) less than -950 HU for the whole-lung (RA<-950) were segmented as emphysema, and pixels less than -900 HU for the whole-lung (RA<-900) were segmented to evaluate air trapping. Next, the cross-sectional area between -500 and -950 HU that excludes emphysema was segmented as limited-lung, and pixels between -900 and -950 HU for the limited-lung (RA900-950) were segmented. The changes in RA<-900 (RA<-900-change) and RA900-950 (RA900-950-change) between inspiration and expiration were calculated. Correlations between CT measurements and the results of pulmonary function tests (PFT) were evaluated. There was no significant difference between the mean inspiratory RA<-950 and expiratory RA<-950 (P = 0.245), but the mean expiratory RA900-950 decreased significantly compared with the mean inspiratory RA900-950 (P < 0.001). The correlation coefficients between PFT parameters and the RA900-900-change in the limited-lung without emphysema were higher than that of the RA<-900-change in the whole-lung. The paired inspiratory/expiratory CT measurements in the limited-lung without emphysema correlated more closely with the PFTs. Our observations suggest that paired inspiratory/expiratory CT scans in the limited-lung excluding emphysema are sensitive for the evaluation of airway obstruction in COPD with emphysema.

Nasal symptoms, airway obstruction and disease severity in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by inflammation of the lung in association with airflow obstruction. There is increasing evidence of upper airway involvement in COPD and we have reported that this nasal inflammation is proportional to that in the lung. Given recognized relationships between lower airway inflammation and spirometric indices such as the Forced Expiratory Volume in one second (FEV(1)), we hypothesized that there may be a relationship between nasal obstruction and FEV(1) in COPD. We also sought to investigate relationships between nasal symptoms and nasal patency in COPD. We assessed the nasal and pulmonary airways, using acoustic rhinometry and spirometry respectively, in 51 patients with COPD. The presence of chronic nasal symptoms in COPD was associated with reduced nasal patency (6.04 cm(2) symptoms vs. 9.55 cm(2) no symptoms, at the second minimum cross-sectional area, P = 0.049). Nasal patency in COPD was inversely proportional to pulmonary airflow obstruction, and therefore to COPD disease severity (e.g. FEV(1)% predicted vs. second minimum cross-sectional area, r = 0.36, P = 0.009). The degree of nasal airway obstruction in COPD reflects the impairment to pulmonary airflow, and is greater in the presence of chronic nasal symptoms. This study provides further evidence of pan-airway involvement in COPD.