The role of clinical signs and spirometry in the diagnosis of obstructive airway diseases: a systematic analysis adapted to general practice settings.

BACKGROUND: In general practice (GP), the diagnosis of obstructive airway diseases much relies on diagnostic questions, in view of the limited availability of lung function. We systematically assessed the relative importance of such questions for diagnosing asthma and chronic obstructive pulmonary disease (COPD), either without or with information from spirometry. METHODS: We used data obtained in a pulmonary practice to ensure the validity of diagnoses and assessments. Subjects with a diagnosis of COPD (n=260), or asthma (n=433), or other respiratory diseases (n=230), and subjects without respiratory diseases (n=364, controls) were included. The diagnostic questions comprised eight items, covering smoking history, self-attributed allergic rhinitis, dyspnea, cough, phlegm and wheeze. Optionally standard parameters of the flow-volume-curve were included. Decision trees for the diagnosis of COPD and asthma were constructed, moreover a probabilistic diagnostic network based on the results of path analyses describing the relationship between variables. RESULTS: In the decision trees, age, sex, current smoking, wheezing, dyspnea upon mild exertion, self-attributed allergic rhinitis, phlegm, forced expiratory volume in one second (FEV1), and expiratory flow rates were relevant, depending on the diagnostic comparison, while cough, dyspnea upon strong exertion and ex-smoker status were not relevant. In contrast, the probabilistic network for the diagnosis of COPD and asthma versus controls incorporated all diagnostic questions, i.e., dyspnea upon mild or strong exertion, current smoking, ex-smoking, wheezing, cough and phlegm but from spirometry only FEV1. Depending on the individual pattern, the probability for COPD could raise from 25% to 81%, while the diagnostic gain for asthma was lower. CONCLUSIONS: The study developed simple diagnostic algorithms for asthma and COPD that take into account the relative importance of clinical signs and history, as well as spirometric data if available. The diagnostic accuracy was especially high for COPD. These algorithms may be helpful as a starting point in the standardisation of diagnostic strategies in GP practices. TRIAL REGISTRATION: The study is registered under DRKS00013935 at German Clinical Trials Register (DRKS, Date of registration 01/03/2018).

Prognosis and longitudinal changes of physical activity in idiopathic pulmonary fibrosis.

BACKGROUND: Physical activity (PA) is associated with disease severity in idiopathic pulmonary fibrosis (IPF), but longitudinal studies evaluating its prognostic value and changes over time are lacking. METHODS: We measured PA (steps per day, SPD) in a cohort of 46 IPF-patients (mean age, 67 years; mean FVC, 76.1%pred.) by accelerometry at baseline, recorded survival status during 3 years follow-up and repeated measurements in survivors. We compared the prognostic value of PA to established mortality predictors including lung function (FVC, DLCO) and 6-min walking-distance (6MWD). RESULTS: During follow-up (median 34 months) 20 patients (43%) died. SPD and FVC best identified non-survivors (AUROC-curve 0.79, p < 0.01). After adjustment for confounders (sex, age, therapy), a standardized increase (i.e. one SD) in SPD, FVC%pred. or DLCO%pred. was associated with a more than halved risk of death (HR < 0.50; p < 0.01). Compared to baseline, SPD, FVC, and 6MWD annually declined in survivors by 973 SPD, 130 ml and 9 m, resulting in relative declines of 48.3% (p < 0.001), 13.3% (p < 0.001) and 7.8% (p = 0.055), respectively. CONCLUSION: While PA predicts mortality of IPF patients similar to established functional measures, longitudinal decline of PA seems to be disproportionally large. Our data suggest that the clinical impact of disease progression could be underestimated by established functional measures.

Plasminogen activator inhibitor-1 is elevated in patients with COPD independent of metabolic and cardiovascular function.

INTRODUCTION: Plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of fibrinolysis, is associated with thrombosis, obesity, insulin resistance, dyslipidemia, and premature aging, which all are coexisting conditions of chronic obstructive pulmonary disease (COPD). The role of PAI-1 in COPD with respect to metabolic and cardiovascular functions is unclear. METHODS: In this study, which was nested within a prospective cohort study, the serum levels of PAI-1 were cross-sectionally measured in 74 stable COPD patients (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stages I-IV) and 18 controls without lung disease. In addition, triglycerides, high-density lipoprotein cholesterol, fasting plasma glucose, waist circumference, blood pressure, smoking status, high-sensitive C-reactive protein (hs-CRP), adiponectin, ankle-brachial index, N-terminal pro-B-type natriuretic peptide, and history of comorbidities were also determined. RESULTS: The serum levels of PAI-1 were significantly higher in COPD patients than in controls, independent of a broad spectrum of possible confounders including metabolic and cardiovascular dysfunction. A multivariate regression analysis revealed triglyceride and hs-CRP levels to be the best predictors of PAI-1 within COPD. GOLD Stages II and III remained independently associated with higher PAI-1 levels in a final regression analysis. CONCLUSION: The data from the present study showed that the serum levels of PAI-1 are higher in patients with COPD and that moderate-to-severe airflow limitation, hypertriglyceridemia, and systemic inflammation are independent predictors of an elevated PAI-1 level. PAI-1 may be a potential biomarker candidate for COPD-specific and extra-pulmonary manifestations.

Clinical Correlates of Reduced Physical Activity in Idiopathic Pulmonary Fibrosis.

BACKGROUND: Little is known about the consequences of idiopathic pulmonary fibrosis (IPF) for physical activity (PA). OBJECTIVES: We aimed to investigate levels of PA in IPF and to study associations of PA with lung function, exercise capacity, symptoms, and quality of life. METHODS: In stable patients with IPF we measured PA (steps per day, SPD; physical activity level, PAL; minutes of moderate activity, MMA) by accelerometry (SenseWear Armband) for 1 week. We also assessed lung function (forced vital capacity, FVC; diffusing capacity for carbon monoxide, DLCO); exercise capacity (6-minute walking distance, 6MWD); dyspnea (modified Medical Research Council, mMRC); fatigue (Multidimensional Fatigue Inventory, MFI-20), and generic (12-Item Short Form Survey, SF-12) and health-related quality of life (St. George's Respiratory Questionnaire) as further clinical variables. RESULTS: We investigated 48 patients with IPF in two centers (mean age, 67 years; 75% male; 23% on long-term oxygen therapy; mean FVC 75%pred.; mean DLCO 43%pred.; mean 6MWD 355 ± 140 m; mean SPD 5,017 ± 3,360). On a bivariate level, all clinical variables were significantly associated with SPD (p < 0.05). The associations of mMRC, MFI-20, SF-12 (physical health), and 6MWD with SPD were independent of impaired lung function (p < 0.05). At multivariate analyses, either 6MWD (total explained variance of the model, total R2: 42%) or MFI-20 (total R2: 39%) were the strongest independent predictors of SPD. CONCLUSION: Fatigue and exercise capacity are strong and independent predictors of PA in patients with IPF, which suggests that both measures should be assessed when the consequences of IPF for PA in daily life are studied.

Reduced physical activity in lymphangioleiomyomatosis compared with COPD and healthy controls: disease-specific impact and clinical correlates.

RATIONALE: Sporadic lymphangioleiomyomatosis (LAM) is an orphan lung disease for which daily physical activity has not been studied so far and it is unclear whether a disease-specific impact beyond airflow limitation exists. Clinical correlates indicating reduced physical activity in addition to established parameters like airflow limitation and hypoxaemia are largely undetermined. METHOD: We measured physical activity (steps per day, SPD; physical activity level, PAL; minutes of moderate activity, MMA) in 34 women with LAM, 32 FEV1-matched female patients with COPD and 15 age-matched healthy women for 1 week using an accelerometer. In addition, we assessed lung function measurements, questionnaires for generic and respiratory health status (12-Item Short Form Survey, SF-12; St. George's Respiratory Questionnaire, SGRQ), dyspnoea (modified Medical Research Council dyspnoea scale, mMRC) and fatigue (Multidimensional Fatigue Inventory, MFI-20). RESULTS: Patients with LAM (mean age 52.7 years, mean FEV1 62.7% predicted) showed reduced SPD, PAL and MMA (p<0.01) compared with healthy controls and reduced MMA (p=0.032) compared with female patients with COPD (mean age 65.2 years, mean FEV1 62.6% predicted). In multivariate regression analyses, adjusting for FEV1 and long-term oxygen therapy, either generic health status (SF-12 physical health) or fatigue (MFI-20) were the strongest independent predictors for SPD in patients with LAM (p=0.006 and p=0.004, respectively). CONCLUSIONS: Physical activity in daily life is substatially reduced in LAM, when compared with healthy controls and COPD - indicating a disease specific impact. The regular assessment of fatigue and generic health status may improve disease management in LAM by taking daily physical activity of patients with LAM more adequately into account.

Neutrophil extracellular trap formation and extracellular DNA in sputum of stable COPD patients.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is characterized by neutrophilic airway inflammation. Neutrophil extracellular trap (NET) formation - a meshwork of neutrophil DNA components and neutrophil enzymes are involved in innate immunity and inflammation. Little is known about the presence of these structures in induced sputum from stable COPD patients. METHODS: Induced sputum samples of 23 COPD patients and 10 healthy controls were collected. Sputum cells were harvested, cultivated and stained for NET components. Extracellular DNA was quantified using a NanoDrop 2000 spectrophotometer. RESULTS: NET formation was markedly upregulated in COPD sputum compared with healthy controls, irrespective of sputum purulence or smoking status. NET formation was associated with significantly higher concentration of extracellular DNA in sputum supernatant (484 ng/µl in COPD versus 268 ng/µl in controls, p = 0.013). Log-transformed extracellular DNA correlated with log-transformed absolute neutrophil numbers in sputum (r = 0.60; p < 0.001) and airway obstruction (r = -0.43; p = 0.013). CONCLUSION: NET formation associated with higher concentrations of extracellular DNA may be a pathobiological feature of COPD-derived sputum neutrophils.

Reprogramming of COPD lung fibroblasts through formation of induced pluripotent stem cells.

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) eliminates many epigenetic modifications that characterize differentiated cells. In this study, we tested whether functional differences between chronic obstructive pulmonary disease (COPD) and non-COPD fibroblasts could be reduced utilizing this approach. Primary fibroblasts from non-COPD and COPD patients were reprogrammed to iPSCs. Reprogrammed iPSCs were positive for oct3/4, nanog, and sox2, formed embryoid bodies in vitro, and induced teratomas in nonobese diabetic/severe combined immunodeficient mice. Reprogrammed iPSCs were then differentiated into fibroblasts (non-COPD-i and COPD-i) and were assessed either functionally by chemotaxis and gel contraction or for gene expression by microarrays and compared with their corresponding primary fibroblasts. Primary COPD fibroblasts contracted three-dimensional collagen gels and migrated toward fibronectin less robustly than non-COPD fibroblasts. In contrast, redifferentiated fibroblasts from iPSCs derived from the non-COPD and COPD fibroblasts were similar in response in both functional assays. Microarray analysis identified 1,881 genes that were differentially expressed between primary COPD and non-COPD fibroblasts, with 605 genes differing by more than twofold. After redifferentiation, 112 genes were differentially expressed between COPD-i and non-COPD-i with only three genes by more than twofold. Similar findings were observed with microRNA (miRNA) expression: 56 miRNAs were differentially expressed between non-COPD and COPD primary cells; after redifferentiation, only 3 miRNAs were differentially expressed between non-COPD-i and COPD-i fibroblasts. Interestingly, of the 605 genes that were differentially expressed between COPD and non-COPD fibroblasts, 293 genes were changed toward control after redifferentiation. In conclusion, functional and epigenetic alterations of COPD fibroblasts can be reprogrammed through formation of iPSCs.

Anti-inflammatory effects of budesonide in human lung fibroblast are independent of histone deacetylase 2.

OBJECTIVE AND DESIGN: Reduced expression of histone deacetylase 2 (HDAC2) in alveolar macrophages and epithelial cells may account for reduced response of chronic obstructive pulmonary disease (COPD) patients to glucocorticoids. HDAC2 expression and its role in mediating glucocorticoid effects on fibroblast functions, however, has not been fully studied. This study was designed to investigate whether HDAC2 mediates glucocorticoid effects on release of inflammatory cytokines and matrix metalloproteinases (MMPs) from human lung fibroblasts. METHODS: Human lung fibroblasts (HFL-1 cells) were stimulated with interleukin (IL)-1 ß plus tumor necrosis factor (TNF)-α in the presence or absence of the glucocorticoid budesonide. Cytokines (IL-6 and IL-8) were quantified by enzyme linked immunosorbent assay (ELISA) and MMPs (MMP-1 and MMP-3) by immunoblotting in culture medium. The role of HDAC2 was investigated using a pharmacologic inhibitor as well as a small interfering ribonucleic acid (siRNA) targeting HDAC2. RESULTS: We have demonstrated that budesonide concentration-dependently (10(-10)-10(-7) M) inhibited IL-6, IL-8, MMP-1, and MMP-3 release by HFL-1 cells in response to IL-1ß plus TNF-α. While an HDAC inhibitor significantly blocked the inhibitory effect of budesonide on human bronchial epithelial cells (HBECs) and monocytes (THP-1 cells), it did not block the inhibitory effect of budesonide on release of cytokines and MMPs from HFL-1 cells. Similarly, an HDAC2-siRNA blocked budesonide inhibition of cytokine release in HBECs, but it did not block the inhibitory effect of budesonide on HFL-1 cytokine and MMP release. Furthermore, budesonide significantly blocked release of cytokines and MMPs to a similar degree in normal and COPD lung fibroblasts as well as in HFL-1 cells exposed or not exposed to cigarette smoke extract. CONCLUSION: These findings suggest that, in contrast to airway epithelial cells and monocytes/macrophages, HDAC2 is not required for budesonide to inhibit MMP and cytokine release by lung fibroblasts and this inhibitory pathway appears to be intact in cultured fibroblasts from COPD patients. These results also suggest that budesonide has the potential to modulate fibroblast-mediated tissue remodeling following airway inflammation in COPD, which is mediated via an HDAC2 independent pathway.

HOPE-preservation of paraffin-embedded sputum samples--a new way of bioprofiling in COPD.

Induced sputum is a non-invasive sampling technique for the analysis of airway inflammation in various lung diseases and comprises valuable potential for the identification of biomarkers and therapeutic targets by molecular methods. In the context of biobanking with preservation of induced sputum samples for subsequent analyses we applied the HEPES-glutamic acid buffer-mediated organic solvent protection effect (HOPE)-technique for preparation of induced sputum samples. Induced sputum samples of 20 patients with moderate to severe chronic obstructive pulmonary disease (COPD) and 12 healthy controls were collected. Cell pellets of induced sputum samples were preserved with HOPE and subsequently embedded in paraffin. Immunostaining of paraffin-block sections for interleukin-8, interleukin-17, myeloperoxidase, matrixmetalloproteinase-9, CD68, and CD8 revealed distinct signals without antigen retrieval. Moreover, RNA was extracted and successfully used for transcription microarray analysis. Sputum samples preserved by the HOPE-technique display a tool to address scientific approaches in pulmonary research, which can enable the identification of new biomarkers and therapeutic targets in respiratory diseases.

Episodic breathlessness in patients with advanced disease: a systematic review.

CONTEXT: Although episodic breathlessness (EB) is reported to be highly prevalent in advanced disease, our understanding about it is limited. OBJECTIVES: The aim of this study was to systematically review and synthesize the evidence on EB regarding definition, characteristics, and patients' experiences. METHODS: Systematic review using searches in six databases, hand search, and personal contacts with authors in the field. Search terms included the combination of "episodic" and "breathlessness" (and synonyms) with five different diseases. Selection criteria included patients with advanced disease and information about EB based on original research. All retrieved studies were reviewed by two independent investigators. RESULTS: Twenty-seven studies (of 7584) were included in this review. Only eight studies explored EB as a primary outcome. EB is poorly defined. It is characterized by high prevalence (81%-85%), high frequency (daily), short duration (often less than 10 minutes), and severe peak intensity. EB either develops without any known trigger or is triggered by physical exertion, emotions, or environmental influences. CONCLUSION: EB is a common symptom in patients with advanced disease, but information about characteristics and experiences is limited. As there is no common terminology, an agreed definition is needed to foster research to develop effective treatments for EB.

Attenuation of inhibitory prostaglandin E2 signaling in human lung fibroblasts is mediated by phosphodiesterase 4.

The etiology of chronic obstructive pulmonary disease (COPD) is complex and involves an aberrant inflammatory response. Prostaglandin (PG)E2 is elevated in COPD, is a key modulator of lung fibroblast functions, and may influence COPD progression. Most studies evaluating the effects of PGE2 on lung fibroblasts have used acute exposures. The current study evaluated whether longer-term exposure would induce attenuation of PGE2 signaling as part of an autoregulatory pathway. Human fetal lung fibroblasts were pretreated with PGE2 for 24 hours, and migration and cAMP accumulation in response to acute stimulation with PGE2 were assessed. Fibroblasts from adults with and without COPD were pretreated, and migration was assessed. PGE2 pretreatment attenuated subsequent PGE2-mediated inhibition of chemotaxis and cAMP stimulation. This attenuation was predominantly due to an increase in phosphodiesterase (PDE)4-mediated degradation of cAMP rather than to decreased activation of PGE2 receptors (receptor desensitization). Albuterol- and iloprost-mediated signaling were also attenuated after PGE2 pretreatment, suggesting that activation of PDE4 was able to broadly modulate multiple cAMP-coupled pathways. Lung fibroblasts from adult control subjects pretreated with PGE2 also developed attenuation of PGE2-mediated inhibition of chemotaxis. In contrast, fibroblasts obtained from patients with COPD maintained inhibitory PGE2 signaling after PGE2 pretreatment. These data identify a PDE4-mediated attenuation of PGE2 inhibitory signaling in normal fibroblasts that appears to be altered in COPD fibroblasts. These alterations may contribute to COPD pathogenesis and could provide novel therapeutic targets.

Effect of combination treatment on lung volumes and exercise endurance time in COPD.

BACKGROUND: Data comparing two bronchodilators vs. one bronchodilator plus inhaled corticosteroid (ICS) on hyperinflation and exercise endurance in chronic obstructive pulmonary disease (COPD) are scarce, though these therapeutic strategies are widely used in clinical practice. METHODS: We performed a randomized, crossover clinical trial of two × 8 weeks comparing tiotropium (18 µg once daily) + salmeterol (50 µg twice daily) (T + S) to salmeterol + fluticasone (50/500 µg twice daily) (S + F) in COPD (forced expiratory volume in 1 s (FEV(1)) ≤65% predicted, and thoracic gas volume (TGV) ≥120% predicted). Coprimary endpoints were postbronchodilator TGV and exercise endurance time (EET). RESULTS: In 309 patients, at baseline, prebronchodilator FEV(1) was 1.36 L (46% predicted), TGV was 5.42 L (165% predicted), and EET = 458 s. Relative to S + F, T + S lowered postdose TGV by 182 ± 44 ml after 4 weeks (p < 0.0001) and 87 ± 44 ml after 8 weeks (p < 0.05). EET was nonsignificantly increased following T + S treatment (20 ± 15 s at 4 weeks, 15 ± 13 s at 8 weeks) vs. S + F. BORG dyspnea score at exercise isotime was reduced in favor of T + S. CONCLUSION: The two bronchodilators decreased hyperinflation significantly more than one bronchodilator and ICS. This difference was not reflected in EET. (ClinicalTrials.gov number, NCT00530842).

Systemic biomarkers of neutrophilic inflammation, tissue injury and repair in COPD patients with differing levels of disease severity.

The identification and validation of biomarkers to support the assessment of novel therapeutics for COPD continues to be an important area of research. The aim of the current study was to identify systemic protein biomarkers correlated with measures of COPD severity, as well as specific protein signatures associated with comorbidities such as metabolic syndrome. 142 protein analytes were measured in serum of 140 patients with stable COPD, 15 smokers without COPD and 30 non-smoking controls. Seven analytes (sRAGE, EN-RAGE, NGAL, Fibrinogen, MPO, TGF-α and HB-EGF) showed significant differences between severe/very severe COPD, mild/moderate COPD, smoking and non-smoking control groups. Within the COPD subjects, univariate and multivariate analyses identified analytes significantly associated with FEV(1), FEV(1)/FVC and DLCO. Most notably, a set of 5 analytes (HB-EGF, Fibrinogen, MCP-4, sRAGE and Sortilin) predicted 21% of the variability in DLCO values. To determine common functions/pathways, analytes were clustered in a correlation network by similarity of expression profile. While analytes related to neutrophil function (EN-RAGE, NGAL, MPO) grouped together to form a cluster associated with FEV(1) related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-α) formed another cluster associated with both DLCO and FEV(1) related parameters. Associations of Fibrinogen with DLCO and MPO with FEV(1)/FVC were stronger in patients without metabolic syndrome (r  =  -0.52, p  =  0.005 and r  =  -0.61, p =  0.023, respectively) compared to patients with coexisting metabolic syndrome (r  =  -0.25, p  =  0.47 and r  =  -0.15, p  =  0.96, respectively), and may be driving overall associations in the general cohort. In summary, our study has identified known and novel serum protein biomarkers and has demonstrated specific associations with COPD disease severity, FEV(1), FEV(1)/FVC and DLCO. These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD.

Effect of fissure integrity on lung volume reduction using a polymer sealant in advanced emphysema.

RATIONALE: Interlobar fissure integrity has previously correlated with responsiveness to endobronchial lung volume reduction therapy in patients with advanced emphysema. OBJECTIVE: This report summarises the effect of interlobar fissure integrity on responses to treatment with a novel endoscopic tissue sealant (AeriSeal emphysematous lung sealant (ELS)) that collapses hyperinflated lung. METHODS: Fissure status, lung volumes, tissue density and disease heterogeneity were assessed radiographically in 28 patients (age 63.4±6.1 years, 20 men) with advanced upper lobe predominant emphysema (density=888.0±18.2 HU; upper lobe tissue density < -950 = 2.62±1.74). Post-treatment changes in lobar volume, pulmonary function, exercise capacity, symptoms and quality of life were compared in patients with complete fissures (CFs) and incomplete fissures (ICFs). RESULTS: ELS therapy reduced lung volumes independent of interlobar fissure integrity. In patients with upper lobe emphysema and CFs, lobar volume reduction was 214±127 ml/treatment compared with 256±175 ml/treatment in those with ICFs (p=0.453). Reductions in gas trapping and improvements in spirometry, functional capacity and quality of life were similar in patients with CFs and ICFs. Stepwise multiple regression modelling confirmed that fissure integrity did not contribute to post-treatment changes in forced expiratory volume in 1 s, residual volume/total lung capacity ratio or lobar volume measured by CT analysis. CONCLUSIONS: Interlobar fissure integrity, an important determinant of responsiveness to endobronchial lung volume reduction therapy in prior studies, had minimal impact on physiological and functional responses to ELS therapy in patients with severe upper lobe predominant emphysema. CLINICAL TRIAL REGISTRATION NUMBER: Registration numbers for trials contributing to datasets in this report: NCT00884962, NCT01051258 and NCT01181466.

Prostaglandin E2 stimulates the production of vascular endothelial growth factor through the E-prostanoid-2 receptor in cultured human lung fibroblasts.

Fibroblasts are the major mesenchymal cells present within the interstitium of the lung and are a major source of vascular endothelial growth factor (VEGF), which modulates the maintenance of pulmonary microvasculature. Prostaglandin E(2) (PGE(2)) acts on a set of E-prostanoid (EP) receptors that activate multiple signal transduction pathways leading to downstream responses. We investigated the modulation by PGE(2) of VEGF release by human lung fibroblasts. Human lung fibroblasts were cultured until reaching 90% confluence in tissue culture plates, after which the culture media were changed to serum-free Dulbecco's modified Eagle's medium, with or without PGE(2), and with specific agonists or antagonists for each EP receptor. After 2 days, culture media were assayed for VEGF by ELISA. The results demonstrated that PGE(2) and the EP2 agonist ONO-AE1-259-01 significantly stimulated the release of VEGF in a concentration-dependent manner. Agonists for other EP receptors did not stimulate the release of VEGF. The stimulatory effect of PGE(2) was blocked by the EP2 antagonist AH6809, but was not blocked by antagonists for other EP receptors. The protein kinase-A (PKA) inhibitor KT-5720 also blocked the stimulatory effect of PGE(2). The increased release of VEGF induced by PGE(2) was accompanied by a transient increase in the concentration of VEGF mRNA. These findings demonstrate that PGE(2) can modulate the release of VEGF by human lung fibroblasts through its actions in the EP2 receptor/PKA pathway. This activity may contribute to the maintenance of pulmonary microvasculature in the alveolar wall.

The impact of anxiety and depression on outcomes of pulmonary rehabilitation in patients with COPD.

BACKGROUND: Anxiety and depression are prevalent comorbidities in COPD and are related to a worse course of disease. The present study examined the impact of anxiety and depression on functional performance, dyspnea, and quality of life (QoL) in patients with COPD at the start and end of an outpatient pulmonary rehabilitation (PR) program. METHODS: Before and after PR, 238 patients with COPD (mean FEV(1) % predicted = 54, mean age = 62 years) underwent a 6-min walking test (6MWT). In addition, anxiety, depression, QoL, and dyspnea at rest, after the 6MWT, and during activities were measured. RESULTS: Except for dyspnea at rest, improvements were observed in all outcome measures after PR. Multiple regression analyses showed that before and after PR, anxiety and depression were significantly associated with greater dyspnea after the 6MWT and during activities and with reduced QoL, even after controlling for the effects of age, sex, lung function, and smoking status. Moreover, before and after PR, anxiety was related to greater dyspnea at rest, whereas depression was significantly associated with reduced functional performance in the 6MWT. CONCLUSIONS: This study demonstrates that anxiety and depression are significantly associated with increased dyspnea and reduced functional performance and QoL in patients with COPD. These negative associations remain stable over the course of PR, even when improvements in these outcomes are achieved during PR. The results underline the clinical importance of detecting and treating anxiety and depression in patients with COPD.

Physical activity is the strongest predictor of all-cause mortality in patients with COPD: a prospective cohort study.

BACKGROUND: Systemic effects of COPD are incompletely reflected by established prognostic assessments. We determined the prognostic value of objectively measured physical activity in comparison with established predictors of mortality and evaluated the prognostic value of noninvasive assessments of cardiovascular status, biomarkers of systemic inflammation, and adipokines. METHODS: In a prospective cohort study of 170 outpatients with stable COPD (mean FEV(1), 56% predicted), we assessed lung function by spirometry and body plethysmography; physical activity level (PAL) by a multisensory armband; exercise capacity by 6-min walk distance test; cardiovascular status by echocardiography, vascular Doppler sonography (ankle-brachial index [ABI]), and N-terminal pro-B-type natriuretic peptide level; nutritional and muscular status by BMI and fat-free mass index; biomarkers by levels of high-sensitivity C-reactive protein, IL-6, fibrinogen, adiponectin, and leptin; and health status, dyspnea, and depressive symptoms by questionnaire. Established prognostic indices were calculated. The median follow-up was 48 months (range, 10-53 months). RESULTS: All-cause mortality was 15.4%. After adjustments, each 0.14 increase in PAL was associated with a lower risk of death (hazard ratio [HR], 0.46; 95% CI, 0.33-0.64; P < .001). Compared with established predictors, PAL showed the best discriminative properties for 4-year survival (C statistic, 0.81) and was associated with the highest relative risk of death per standardized decrease. Novel predictors of mortality were adiponectin level (HR, 1.34; 95% CI, 1.06-1.71; P = .017), leptin level (HR, 0.81; 95% CI, 0.65-0.99; P = .042), right ventricular function (Tei-index) (HR, 1.26; 95% CI, 1.04-1.54; P = .020), and ABI < 1.00 (HR, 3.87; 95% CI, 1.44-10.40; P = .007). A stepwise Cox regression revealed that the best model of independent predictors was PAL, adiponectin level, and ABI. The composite of these factors further improved the discriminative properties (C statistic, 0.85). CONCLUSIONS: We found that objectively measured physical activity is the strongest predictor of all-cause mortality in patients with COPD. In addition, adiponectin level and vascular status provide independent prognostic information in our cohort.

Reduced miR-146a increases prostaglandin E2in chronic obstructive pulmonary disease fibroblasts.

RATIONALE: Persistent inflammation plays a major role in chronic obstructive pulmonary disease (COPD) pathogenesis, but its mechanisms are incompletely defined. Overproduction of the inflammatory mediator prostaglandin (PG) E2 by COPD fibroblasts contributes to reduced repair function. OBJECTIVES: The present study determined if fibroblasts from subjects with COPD overproduce PGE2 after stimulation with the inflammatory cytokines IL-1ß and tumor necrosis factor-α, and further defined the mechanism for overproduction. METHODS: Fibroblasts were isolated from parenchymal tissue obtained from smokers with and without COPD undergoing lung surgery. PGE2, cyclooxygenases (COX), and miR-146a in these cells were evaluated by in vitro studies. MEASUREMENTS AND MAIN RESULTS: After stimulation with inflammatory cytokines, COPD fibroblasts produced 2.7-fold more PGE2 compared with controls with similar smoking history. The increase in PGE2 depended on induction of COX-2, which increased to a greater degree in fibroblasts from subjects with COPD. Cytokines also induced microRNA miR-146a expression in both fibroblasts, but significantly less in COPD fibroblasts. miR-146a caused degradation of COX-2 mRNA; reduced expression prolonged COX-2 mRNA half-life in fibroblasts from subjects with COPD. Cytokine-stimulated PGE2 production and miR-146a expression in cultured fibroblasts correlated with clinical severity assessed by expiratory airflow and diffusion capacity. CONCLUSIONS: miR-146a seems to play a pathogenetic role in the abnormal inflammatory response in COPD. Increased half-life of inflammatory mRNAs is a mechanism of abnormal inflammation in this disease.