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1.  Transfer factor for carbon monoxide in patients with COPD and diabetes: results from the German COSYCONET cohort 
Respiratory Research  2017;18:14.
An impairment of CO diffusing capacity has been shown in diabetic patients without lung disease. We analyzed how diffusing capacity in patients with COPD is affected by the concurrent diagnosis of diabetes.
Data from the initial visit of the German COPD cohort COSYCONET were used for analysis. 2575 patients with complete lung function data were included, among them 358 defined as diabetics with a reported physician diagnosis of diabetes and/or specific medication. Pairwise comparisons between groups and multivariate regression models were used to identify variables predicting the CO transfer factor (TLCO%pred) and the transfer coefficient (KCO%pred).
COPD patients with diabetes differed from those without diabetes regarding lung function, anthropometric, clinical and laboratory parameters. Moreover, gender was an important covariate. After correction for lung function, gender and body mass index (BMI), TLCO%pred did not significantly differ between patients with and without diabetes. The results for the transfer coefficient KCO were similar, demonstrating an important role of the confounding factors RV%pred, TLC%pred, ITGV%pred, FEV1%pred, FEV1/FVC, age, packyears, creatinine and BMI. There was not even a tendency towards lower values in diabetes.
The analysis of data from a COPD cohort showed no significant differences of CO transport parameters between COPD patients with and without diabetes, if BMI, gender and the reduction in lung volumes were taken into account. This result is in contrast to observations in lung-healthy subjects with diabetes and raises the question which factors, among them potential anti-inflammatory effects of anti-diabetes medication are responsible for this finding.
PMCID: PMC5237203  PMID: 28086884
COPD; Diabetes; Lung function; Diffusing capacity
2.  Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease 
Rationale: Chronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have been focused on genome-wide common variants without a specific focus on coding variants, but common and rare coding variants may also affect COPD susceptibility.
Objectives: To identify coding variants associated with COPD.
Methods: We tested nonsynonymous, splice, and stop variants derived from the Illumina HumanExome array for association with COPD in five study populations enriched for COPD. We evaluated single variants with a minor allele frequency greater than 0.5% using logistic regression. Results were combined using a fixed effects meta-analysis. We replicated novel single-variant associations in three additional COPD cohorts.
Measurements and Main Results: We included 6,004 control subjects and 6,161 COPD cases across five cohorts for analysis. Our top result was rs16969968 (P = 1.7 × 10−14) in CHRNA5, a locus previously associated with COPD susceptibility and nicotine dependence. Additional top results were found in AGER, MMP3, and SERPINA1. A nonsynonymous variant, rs181206, in IL27 (P = 4.7 × 10−6) was just below the level of exome-wide significance but attained exome-wide significance (P = 5.7 × 10−8) when combined with results from other cohorts. Gene expression datasets revealed an association of rs181206 and the surrounding locus with expression of multiple genes; several were differentially expressed in COPD lung tissue, including TUFM.
Conclusions: In an exome array analysis of COPD, we identified nonsynonymous variants at previously described loci and a novel exome-wide significant variant in IL27. This variant is at a locus previously described in genome-wide associations with diabetes, inflammatory bowel disease, and obesity and appears to affect genes potentially related to COPD pathogenesis.
PMCID: PMC4960630  PMID: 26771213
chronic obstructive pulmonary disease; genetics; exome; IL-27
3.  Muscle fibre type shifting in the vastus lateralis of patients with COPD is associated with disease severity: a systematic review and meta‐analysis 
Thorax  2007;62(11):944-949.
Skeletal muscle dysfunction is a common feature in chronic obstructive pulmonary disease (COPD) which is associated with intrinsic muscular abnormalities. One of the most consistently reported alterations is a shift from fibre type I to II in the vastus lateralis of these patients. Surprisingly, the relationship between this shift and the severity and phenotype of COPD remains unclear. A study was conducted to determine whether vastus lateralis muscle fibre type proportions are associated with COPD disease severity and to provide reference values for the proportions of fibre types in the vastus lateralis in COPD.
A systematic review and a meta‐analysis were conducted in which muscle fibre type data and markers of disease severity were collected from the literature.
The forced expiratory volume in 1 s (FEV1), the ratio of FEV1 to forced vital capacity (FVC) and body mass index were positively associated with the proportion of type I fibres in COPD. A proportion of 51% for vastus lateralis fibre type I and 13% for fibre type IIX were calculated from the combined data as normal values for patients with typical GOLD stage 3–4 COPD aged 60–70 years. Based on these reference values, a proportion of fibre type I <27% and of fibre type IIX >29% were defined as pathologically abnormal.
This review sheds new light on the relationship between skeletal muscle abnormalities and important hallmarks of the disease in severe COPD, and identifies absence of data in GOLD stages 1–2. This review also provides reference values on fibre type composition for diagnostic purposes in COPD.
PMCID: PMC2117111  PMID: 17526675
4.  Cellular protein breakdown and systemic inflammation are unaffected by pulmonary rehabilitation in COPD 
Thorax  2006;62(2):109-114.
Pulmonary rehabilitation can improve the functional capacity, but has a variable effect on the low fat‐free mass (FFM) in patients with chronic obstructive pulmonary disease.
Pulmonary rehabilitation would not affect catabolic drives such as systemic inflammation and also protein breakdown.
Patients (n = 40) were studied at the start of an 8‐week in‐patient pulmonary rehabilitation programme, at the end of the programme and 4 weeks later. FFM and functional capacity (quadriceps strength, handgrip strength and peak workload) were assessed. Pseudouridine (PSU) urinary excretion (cellular protein breakdown) and inflammatory status were determined. Healthy participants had a single baseline assessment (n = 18).
PSU, (IL)‐6 and soluble tumour necrosis factor (sTNF)α R75 were increased in patients compared with healthy participants, whereas FFM and functional capacity were reduced (all p<0.01). PSU was inversely related to both FFM and skeletal muscle function. FFM and functional parameters increased with rehabilitation, but PSU and inflammatory status were unaffected. The gain in FFM was lost 4 weeks after the completion of rehabilitation (p<0.01).
The anabolic effect of pulmonary rehabilitation improved FFM, but it did not reverse the increased protein breakdown or systemic inflammation. Thus, on cessation of pulmonary rehabilitation the FFM gains were lost owing to a loss of anabolic drive.
PMCID: PMC2111241  PMID: 16928709
5.  Preliminary study on the assessment of visceral adipose tissue using dual-energy x-ray absorptiometry in chronic obstructive pulmonary disease 
Visceral adipose tissue (VAT) was shown to be increased in patients with chronic obstructive pulmonary disease (COPD) compared to control subjects with comparable body mass index (BMI). Our aim was to determine the relation of VAT by dual-energy x-ray absorptiometry (DEXA) in patients with COPD by disease severity, BMI, other indices of body composition and static lung volumes.
294 COPD patients admitted for rehabilitation were studied. Lung function, static lung volumes and body composition (i.e. BMI, waist circumference, fat-free mass, fat mass and fat distribution between android and gynoid fat mass) were assessed before entering pulmonary rehabilitation. VAT was estimated within the android region by using DEXA. Patients were stratified for gender, BMI (cut-off of 25 kg/m2) and GOLD stage. To assess the impact of VAT on lung volumes, patients were also stratified for VAT less and above 50th percentile.
Both male and female patients with more severe airflow limitation had significantly lower VAT values, but these differences disappeared after stratification for BMI. VAT was significantly and strongly correlated with other body composition parameters (all p < 0.001). Patients with moderate to severe airflow limitation and lower VAT had increased static lung hyperinflation and lower diffusing capacity for carbon monoxide. Nevertheless, multivariate stepwise regression models including for BMI, age, gender and forced expiratory volume in 1 s (FEV1) as confounders did not confirm an independent role for VAT on static lung hyperinflation and diffusion capacity.
After stratification for BMI, VAT is comparable in moderate to very severe COPD patients. Furthermore, BMI and demographics, but not VAT, were independent predictors of static lung hyperinflation and diffusing capacity in COPD.
PMCID: PMC5048671  PMID: 27729977
Body composition; COPD; DEXA; Fat mass; Visceral adipose tissue
6.  Sleep quality disturbances and cognitive functioning in elderly patients with COPD 
ERJ Open Research  2016;2(3):00054-2016.
Information about the association between cognitive functions, such as copying function, and sleep disturbances in patients with chronic obstructive pulmonary disease (COPD) is lacking. This cross-sectional observational study aimed to investigate the association between copying function and self-reported sleep quality disturbances and disease severity in an elderly COPD population.
Cognitive function performances, assessed using the Mini-Mental State Examination, were compared in 562 ambulatory COPD patients with and without sleep disturbances; assessed using the Established Populations for Epidemiologic Studies of the Elderly questionnaire; and stratified by Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades.
Sleep disturbances overall were not correlated with cognitive functioning. A trend was revealed towards worse design copying in patients with sleep disturbances overall. GOLD I patients with difficulties falling asleep and nocturnal awakenings had worse copying ability compared to GOLD I patients without these sleep disturbances. Copying ability was worse for GOLD III than GOLD I, orientation was worse for GOLD II than GOLD I and language was worse for GOLD II and III than GOLD I.
To conclude, sleep disturbances seem to be a weak correlate of cognitive functioning, and are not a marker of disease severity.
Sleep disturbances are a weak correlate of cognitive functioning in COPD
PMCID: PMC5140015  PMID: 27957482
7.  Reproducibility and Validity of the 6-Minute Walk Test Using the Gait Real-Time Analysis Interactive Lab in Patients with COPD and Healthy Elderly 
PLoS ONE  2016;11(9):e0162444.
The 6-minute walk test (6MWT) in a regular hallway is commonly used to assess functional exercise capacity in patients with chronic obstructive pulmonary disease (COPD). However, treadmill walking might provide additional advantages over overground walking, especially if virtual reality and self-paced treadmill walking are combined. Therefore, this study aimed to assess the reproducibility and validity of the 6MWT using the Gait Real-time Analysis Interactive Lab (GRAIL) in patients with COPD and healthy elderly.
Sixty-one patients with COPD and 48 healthy elderly performed two 6MWTs on the GRAIL. Patients performed two overground 6MWTs and healthy elderly performed one overground test. Differences between consecutive 6MWTs and the test conditions (GRAIL vs. overground) were analysed. Patients walked further in the second overground test (24.8 m, 95% CI 15.2–34.4 m, p<0.001) and in the second GRAIL test (26.8 m, 95% CI 13.9–39.6 m). Healthy elderly improved their second GRAIL test (49.6 m, 95% CI 37.0–62.3 m). The GRAIL 6MWT was reproducible (intra-class coefficients = 0.65–0.80). The best GRAIL 6-minute walk distance (6MWD) in patients was shorter than the best overground 6MWD (-27.3 ± 49.1 m, p<0.001). Healthy elderly walked further on the GRAIL than in the overground condition (23.6 ± 41.4 m, p<0.001). Validity of the GRAIL 6MWT was assessed and intra-class coefficient values ranging from 0.74–0.77 were found.
The GRAIL is a promising system to assess the 6MWD in patients with COPD and healthy elderly. The GRAIL 6MWD seems to be more comparable to the 6MWDs assessed overground than previous studies on treadmills have reported. Furthermore, good construct validity and reproducibility were established in assessing the 6MWD using the GRAIL in patients with COPD and healthy elderly.
PMCID: PMC5015964  PMID: 27607426
8.  Hyperleptinemia is associated with impaired pulmonary host defense 
JCI insight  2016;1(8):e82101.
We have previously reported that obesity attenuates pulmonary inflammation in both patients with acute respiratory distress syndrome (ARDS) and in mouse models of the disease. We hypothesized that obesity-associated hyperleptinemia, and not body mass per se, drives attenuation of the pulmonary inflammatory response and that this e_ect could also impair the host response to pneumonia. We examined the correlation between circulating leptin levels and risk, severity, and outcome of pneumonia in 2 patient cohorts (NHANES III and ARDSNet-ALVEOLI) and in mouse models of diet-induced obesity and lean hyperleptinemia. Plasma leptin levels in ambulatory subjects (NHANES) correlated positively with annual risk of respiratory infection independent of BMI. In patients with severe pneumonia resulting in ARDS (ARDSNet-ALVEOLI), plasma leptin levels were found to correlate positively with subsequent mortality. In obese mice with pneumonia, plasma leptin levels were associated with pneumonia severity, and in obese mice with sterile lung injury, leptin levels were inversely related to bronchoalveolar lavage neutrophilia, as well as to plasma IL-6 and G-CSF levels. These results were recapitulated in lean mice with experimentally induced hyperleptinemia. Our findings suggest that the association between obesity and elevated risk of pulmonary infection may be driven by hyperleptinemia.
PMCID: PMC4916854  PMID: 27347561
9.  Hyperleptinemia is associated with impaired pulmonary host defense 
JCI Insight  null;1(8):e82101.
We have previously reported that obesity attenuates pulmonary inflammation in both patients with acute respiratory distress syndrome (ARDS) and in mouse models of the disease. We hypothesized that obesity-associated hyperleptinemia, and not body mass per se, drives attenuation of the pulmonary inflammatory response and that this effect could also impair the host response to pneumonia. We examined the correlation between circulating leptin levels and risk, severity, and outcome of pneumonia in 2 patient cohorts (NHANES III and ARDSNet-ALVEOLI) and in mouse models of diet-induced obesity and lean hyperleptinemia. Plasma leptin levels in ambulatory subjects (NHANES) correlated positively with annual risk of respiratory infection independent of BMI. In patients with severe pneumonia resulting in ARDS (ARDSNet-ALVEOLI), plasma leptin levels were found to correlate positively with subsequent mortality. In obese mice with pneumonia, plasma leptin levels were associated with pneumonia severity, and in obese mice with sterile lung injury, leptin levels were inversely related to bronchoalveolar lavage neutrophilia, as well as to plasma IL-6 and G-CSF levels. These results were recapitulated in lean mice with experimentally induced hyperleptinemia. Our findings suggest that the association between obesity and elevated risk of pulmonary infection may be driven by hyperleptinemia.
Circulating leptin levels correlate with the risk of respiratory infection independent of BMI in patients and mice.
PMCID: PMC4916854  PMID: 27347561
10.  COPD and exercise: does it make a difference? 
Breathe  2016;12(2):e38-e49.
Key points
Physiological changes are observed following a structured exercise training programme in patients with COPD, without changes in resting lung function.
Exercise training is the cornerstone of a comprehensive pulmonary rehabilitation programme in patients with COPD.
Most comorbidities in patients referred for pulmonary rehabilitation remain undiagnosed and untreated.
After careful screening, it is safe for COPD patients with comorbidities to obtain significant and clinically relevant improvements in functional exercise capacity and health status after an exercise-based pulmonary rehabilitation programme.
Educational aims
To inform readers of the positive effects of exercise-based pulmonary rehabilitation in patients with COPD, even with comorbid conditions.
To inform readers of the importance of physical activity in patients with COPD.
Exercise training is widely regarded as the cornerstone of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD). Indeed, exercise training has been identified as the best available means of improving muscle function and exercise tolerance in patients with COPD. So, exercise training truly makes a difference in the life of patients with COPD. In this review, an overview is provided on the history of exercise training (as standalone intervention or as part of a comprehensive pulmonary rehabilitation programme), exercise training in comorbid patients with COPD, and the impact of physical activity counselling in a clean air environment.
Exercise training in COPD, as part of a comprehensive pulmonary rehabilitation programme, makes a profound difference
PMCID: PMC4933612  PMID: 27408645
11.  Indications for distinct pathogenic mechanisms of asbestos and silica through gene expression profiling of the response of lung epithelial cells 
Human Molecular Genetics  2014;24(5):1374-1389.
Occupational and environmental exposures to airborne asbestos and silica are associated with the development of lung fibrosis in the forms of asbestosis and silicosis, respectively. However, both diseases display distinct pathologic presentations, likely associated with differences in gene expression induced by different mineral structures, composition and bio-persistent properties. We hypothesized that effects of mineral exposure in the airway epithelium may dictate deviating molecular events that may explain the different pathologies of asbestosis versus silicosis. Using robust gene expression-profiling in conjunction with in-depth pathway analysis, we assessed early (24 h) alterations in gene expression associated with crocidolite asbestos or cristobalite silica exposures in primary human bronchial epithelial cells (NHBEs). Observations were confirmed in an immortalized line (BEAS-2B) by QRT-PCR and protein assays. Utilization of overall gene expression, unsupervised hierarchical cluster analysis and integrated pathway analysis revealed gene alterations that were common to both minerals or unique to either mineral. Our findings reveal that both minerals had potent effects on genes governing cell adhesion/migration, inflammation, and cellular stress, key features of fibrosis. Asbestos exposure was most specifically associated with aberrant cell proliferation and carcinogenesis, whereas silica exposure was highly associated with additional inflammatory responses, as well as pattern recognition, and fibrogenesis. These findings illustrate the use of gene-profiling as a means to determine early molecular events that may dictate pathological processes induced by exogenous cellular insults. In addition, it is a useful approach for predicting the pathogenicity of potentially harmful materials.
PMCID: PMC4402341  PMID: 25351596
12.  Common Genetic Variants Associated with Resting Oxygenation in Chronic Obstructive Pulmonary Disease 
Hypoxemia is a major complication of chronic obstructive pulmonary disease (COPD) that correlates with disease prognosis. Identifying genetic variants associated with oxygenation may provide clues for deciphering the heterogeneity in prognosis among patients with COPD. However, previous genetic studies have been restricted to investigating COPD candidate genes for association with hypoxemia. To report results from the first genome-wide association study (GWAS) of resting oxygen saturation (as measured by pulse oximetry [Spo2]) in subjects with COPD, we performed a GWAS of Spo2 in two large, well characterized COPD populations: COPDGene, including both the non-Hispanic white (NHW) and African American (AA) groups, and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We identified several suggestive loci (P < 1 × 10−5) associated with Spo2 in COPDGene in the NHW (n = 2810) and ECLIPSE (n = 1758) groups, and two loci on chromosomes 14 and 15 in the AA group (n = 820) from COPDGene achieving a level of genome-wide significance (P < 5 × 10−8). The chromosome 14 single-nucleotide polymorphism, rs6576132, located in an intergenic region, was nominally replicated (P < 0.05) in the NHW group from COPDGene. The chromosome 15 single-nucleotide polymorphisms were rare in subjects of European ancestry, so the results could not be replicated. The chromosome 15 region contains several genes, including TICRR and KIF7, and is proximal to RHCG (Rh family C glyocoprotein gene). We have identified two loci associated with resting oxygen saturation in AA subjects with COPD, and several suggestive regions in subjects of European descent with COPD. Our study highlights the importance of investigating the genetics of complex traits in different racial groups.
PMCID: PMC4224086  PMID: 24825563
chronic obstructive pulmonary disease; hypoxemia; pulse oximetry; genome-wide association study; oxygen saturation
13.  Chest CT measures of muscle and adipose tissue in COPD: gender-based differences in content and in relationships with blood biomarkers 
Academic radiology  2014;21(10):1255-1261.
Rationale and Objective
Computed tomography (CT) of the chest can be used to assess pectoralis muscle area (PMA) and subcutaneous adipose tissue area (SAT). Adipose tissue content is associated with inflammatory mediators in chronic obstructive pulmonary disease (COPD) subjects. Based on gender differences in body composition, we aimed to assess the hypothesis that in subjects with COPD the relationships between PMA, SAT, and blood biomarkers of inflammation differ by gender.
Materials and Methods
We compared chest CT measures of PMA and SAT on a single slice at aortic arch and supraesternal notch levels from 73 subjects (28 women) with COPD between genders. The relationships of PMA and SAT to biomarkers were assessed using within-gender regression models.
Women had a lower PMA and higher SAT than men (difference range for PMA, 13.3–22.8 cm2; for SAT, 11.8–12.4 cm2; P<0.05 for all comparisons) at both anatomic levels. These differences in PMA and SAT remained significant after adjustment for age and body mass index. Within-gender regression models adjusted for age showed that SAT was directly associated with C-reactive protein (for aortic arch level, P=0.04) and fibrinogen (for both anatomic locations, P=0.003) only in women, whereas PMA was not associated with any biomarkers in either gender.
It appears that in subjects with COPD there are gender-based differences in the relationships between subcutaneous adipose tissue and inflammatory biomarkers.
PMCID: PMC4389286  PMID: 25088837
14.  Impact of cardiovascular comorbidities on COPD Assessment Test (CAT) and its responsiveness to pulmonary rehabilitation in patients with moderate to very severe COPD: protocol of the Chance study 
BMJ Open  2015;5(7):e007536.
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. Patients with COPD are characterised by a reduced health status, which can be easily assessed by the COPD Assessment Test (CAT). Previous studies show that health status can be worsened by the presence of comorbidities. However, the impact of cardiovascular comorbidities on health status as assessed with CAT is not sufficiently investigated. Therefore, the current study has the following objectives: (1) to study the clinical, (patho)physiological and psychosocial determinants of the CAT, and impact of previously established and/or newly diagnosed cardiovascular comorbidities on health status in tertiary care patients with COPD; (2) to assess the effects of pulmonary rehabilitation on CAT scores in patients with COPD; (3) to develop reference values for the CAT in Dutch elderly patients without COPD; and (4) to validate the CAT in a broad sample of Dutch patients with COPD.
Methods and analysis
The COPD, Health status and Comorbidities (Chance) study is a monocentre study consisting of an observational cross-sectional part and a longitudinal part. Demographic and clinical characteristics will be assessed in primary care, secondary care and tertiary care patients with COPD, and in patients without COPD. To assess health status, the CAT, Clinical COPD Questionnaire (CCQ) and St George's Respiratory Questionnaire (SGRQ) will be used. The longitudinal part consists of a comprehensive pulmonary rehabilitation programme in 500 tertiary care patients. For the cross-sectional part of the study, 150 patients without COPD, 100 primary care patients and 100 secondary care patients will be assessed during a single home visit.
Ethics and dissemination
The Medical Ethical Committee of the Maastricht University Medical Centre+ (MUMC+), Maastricht, the Netherlands (METC 11-3-070), has approved this study. The study has been registered at the Dutch Trial Register (NTR 3416).
PMCID: PMC4513521  PMID: 26198426
Chronic Obstructive Pulmonary Disease; COPD assessment test; Health status; Cardiovascular comorbidities
15.  An observational, longitudinal study on the home environment of people with chronic obstructive pulmonary disease: the research protocol of the Home Sweet Home study 
BMJ Open  2014;4(11):e006098.
Chronic obstructive pulmonary disease (COPD) represents an important public health challenge. Patients are confronted with limitations during activities of daily living (ADLs). Resident loved ones of patients with COPD may be uniquely positioned to witness these limitations. COPD may have an impact on not only the patients’ life, but also on the lives of the resident loved ones. Furthermore, COPD exacerbation-related hospital admissions often occur in patients with COPD. However, whether and to what extent these admissions influence resident loved ones’ burden and health status remains currently unknown. Therefore, the primary objectives of this study are to investigate the differences between patients with COPD and resident loved ones’ perceptions of patients’ health status and problematic ADLs and to study prospectively the effects of a COPD exacerbation on resident loved ones’ perceptions of patients’ health status and problematic ADLs.
Methods and analysis
An observational, longitudinal study will be performed in 192 patients with COPD and their 192 resident loved ones. Primary outcomes are daily functioning, ADL, disease-specific health status, generic health status and dyspnoea. These will be assessed during home visits at baseline and after 12 months. Additional home visits will be performed when a COPD exacerbation-related hospital admission occurs during the 12-month follow-up period.
Ethics and dissemination
This protocol was approved by the Medical Ethics Committee of the Catharina Hospital Eindhoven, the Netherlands (NL42721.060.12/M12-1280) and is registered in the Dutch Trial Register (NTR3941).
PMCID: PMC4244479  PMID: 25384686
Chronic Obstructive Pulmonary Disease; Home environment; Resident loved one; Family caregiver; Activities of Daily Living; Quality of Life
16.  Cigarette Smoke Extract Induces a Phenotypic Shift in Epithelial Cells; Involvement of HIF1α in Mesenchymal Transition 
PLoS ONE  2014;9(10):e107757.
In COPD, matrix remodeling contributes to airflow limitation. Recent evidence suggests that next to fibroblasts, the process of epithelial-mesenchymal transition can contribute to matrix remodeling. CSE has been shown to induce EMT in lung epithelial cells, but the signaling mechanisms involved are largely unknown and subject of this study. EMT was assessed in A549 and BEAS2B cells stimulated with CSE by qPCR, Western blotting and immunofluorescence for epithelial and mesenchymal markers, as were collagen production, cell adhesion and barrier integrity as functional endpoints. Involvement of TGF-β and HIF1α signaling pathways were investigated. In addition, mouse models were used to examine the effects of CS on hypoxia signaling and of hypoxia per se on mesenchymal expression. CSE induced EMT characteristics in A549 and BEAS2B cells, evidenced by decreased expression of epithelial markers and a concomitant increase in mesenchymal marker expression after CSE exposure. Furthermore cells that underwent EMT showed increased production of collagen, decreased adhesion and disrupted barrier integrity. The induction of EMT was found to be independent of TGF-β signaling. On the contrary, CS was able to induce hypoxic signaling in A549 and BEAS2B cells as well as in mice lung tissue. Importantly, HIF1α knock-down prevented induction of mesenchymal markers, increased collagen production and decreased adhesion after CSE exposure, data that are in line with the observed induction of mesenchymal marker expression by hypoxia in vitro and in vivo. Together these data provide evidence that both bronchial and alveolar epithelial cells undergo a functional phenotypic shift in response to CSE exposure which can contribute to increased collagen deposition in COPD lungs. Moreover, HIF1α signaling appears to play an important role in this process.
PMCID: PMC4199572  PMID: 25329389
17.  Leptin as regulator of pulmonary immune responses: Involvement in respiratory diseases 
Leptin is an adipocyte-derived hormone, recognized as a critical mediator of the balance between food intake and energy expenditure by signalling through its functional receptor (Ob-Rb) in the hypothalamus. Structurally, leptin belongs to the long-chain helical cytokine family, and is now known to have pleiotropic functions in both innate and adaptive immunity. The presence of the functional leptin receptor in the lung together with evidence of increased airspace leptin levels arising during pulmonary inflammation, suggests an important role for leptin in lung development, respiratory immune responses and eventually pathogenesis of inflammatory respiratory diseases. The purpose of this article is to review our current understanding of leptin and its functional role on the different resident cell types of the lung in health as well as in the context of three major respiratory conditions being chronic obstructive pulmonary disease (COPD), asthma, and pneumonia.
PMCID: PMC4122282  PMID: 23542720
Leptin; Asthma; COPD; Pneumonia; Pulmonary immunity
18.  Prevalence of Metabolic Syndrome in COPD Patients and Its Consequences 
PLoS ONE  2014;9(6):e98013.
The prevalence of metabolic syndrome in COPD patients and its impact on patient related outcomes has been little studied. We evaluated the prevalence of metabolic syndrome and clinical and functional characteristics in patients with COPD and healthy subjects.
228 COPD patients and 156 healthy subjects were included. Metabolic syndrome was defined using criteria of the IDF. In all patients spirometry, body composition, functional exercise performance, and mood and health status were assessed. Groups were stratified for BMI and gender.
Metabolic syndrome was present in 57% of the COPD patients and 40% of the healthy subjects. After stratification for BMI, presence of metabolic syndrome in patients with a BMI ≥25 kg/m2 was higher than in healthy peers. Patients with metabolic syndrome and a BMI <25 kg/m2 had higher BMI, fat free mass index and bone mineral density, and a lower 6MWD than the BMI matched patients without metabolic syndrome. Spirometry, maximal ergometry, mood and health status, and blood gases were not different between those groups. In COPD patients with metabolic syndrome self-reported co-morbidities and medication use were higher than in those without.
Metabolic syndrome is more prevalent in overweight or obese COPD patients than in BMI matched healthy subjects. Metabolic syndrome did not additionally impact patients' functional outcomes, but did impact the prevalence of co-morbidities.
PMCID: PMC4064974  PMID: 24950070
19.  Early body weight loss during concurrent chemo-radiotherapy for non-small cell lung cancer 
Background and purpose
Radiation-esophagitis and weight loss are frequently observed toxicities in patients treated with concurrent chemo-radiotherapy (CT-RT) for non-small cell lung cancer (NSCLC) and might be related. The purpose was to investigate whether weight loss already starts early after initiation of CT-RT and precedes radiation-esophagitis.
Materials and methods
In a retrospective cohort, weight and esophagitis grade ≥2 were assessed during the first weeks of (CT-)RT in patients treated with concurrent (n = 102) or sequential (n = 92) therapy. In a prospective validation study, data on body weight, esophagitis grade ≥2, nutritional intake and muscle strength were obtained before, during and following CT-RT.
In the retrospective cohort, early weight loss was observed in concurrently treated patients (p = 0.002), independent of esophagitis ≥ grade 2. Early weight loss was also observed in the prospective cohort (p = 0.003) and was not accompanied by decreases in nutritional intake. In addition lower limb muscle strength rapidly declined (p = 0.042). In the later weeks of treatment, further body weight loss occurred (p < 0.001) despite increased nutritional supplementation and body weight was only partly recovered after 4 weeks post CT-RT (p = 0.003).
Weight loss during concurrent CT-RT for NSCLC starts early and prior to onset of esophagitis, requiring timely and intense nutritional rehabilitation.
Electronic supplementary material
The online version of this article (doi:10.1007/s13539-013-0127-5) contains supplementary material.
PMCID: PMC4053563  PMID: 24452446
Weight loss; Chemotherapy; Concurrent; Esophagitis; Non-small cell lung cancer; Radiotherapy
20.  Characteristics and determinants of endurance cycle ergometry and six-minute walk distance in patients with COPD 
Exercise tolerance can be assessed by the cycle endurance test (CET) and six-minute walk test (6MWT) in patients with Chronic Obstructive Pulmonary Disease (COPD). We sought to investigate the characteristics of functional exercise performance and determinants of the CET and 6MWT in a large clinical cohort of COPD patients.
A dataset of 2053 COPD patients (43% female, age: 66.9 ± 9.5 years, FEV1% predicted: 48.2 ± 23.2) was analyzed retrospectively. Patients underwent, amongst others, respiratory function evaluation; medical tests and questionnaires, one maximal incremental cycle test where peak work rate was determined and two functional exercise tests: a CET at 75% of peak work rate and 6MWT. A stepwise multiple linear regression was used to assess determinants.
On average, patients had impaired exercise tolerance (peak work rate: 56 ± 27% predicted, 6MWT: 69 ± 17% predicted). A total of 2002 patients had CET time of duration (CET-Tend) less than 20 min while only 51 (2.5%) of the patients achieved 20 min of CET-Tend . In former patients, the percent of predicted peak work rate achieved differed significantly between men (48 ± 21% predicted) and women (67 ± 31% predicted). In contrast, CET-Tend was longer in men (286 ± 174 s vs 250 ± 153 s, p < 0.001). Also, six minute walking distance (6MWD) was higher in men compared to women, both in absolute terms as in percent of predicted (443 m, 67%predicted vs 431 m, 72%predicted, p < 0.05). Gender was associated with the CET-Tend but BMI, FEV1 and FRC were related to the 6MWD highlighting the different determinants of exercise performance between CET and 6MWT.
CET-Tend is a valuable outcome of CET as it is related to multiple clinical aspects of disease severity in COPD. Gender difference should temper the interpretation of CET.
PMCID: PMC4229855  PMID: 24885117
Exercise; 6MWT; CET; CPET; COPD
21.  COgnitive-Pulmonary Disease 
BioMed Research International  2014;2014:697825.
Over the past few decades, chronic obstructive lung disease (COPD) has been considered a disease of the lungs, often caused by smoking. Nowadays, COPD is regarded as a systemic disease. Both physical effects and effects on brains, including impaired psychological and cognitive functioning, have been demonstrated. Patients with COPD may have cognitive impairment, either globally or in single cognitive domains, such as information processing, attention and concentration, memory, executive functioning, and self-control. Possible causes are hypoxemia, hypercapnia, exacerbations, and decreased physical activity. Cognitive impairment in these patients may be related to structural brain abnormalities, such as gray-matter pathologic changes and the loss of white matter integrity which can be induced by smoking. Cognitive impairment can have a negative impact on health and daily life and may be associated with widespread consequences for disease management programs. It is important to assess cognitive functioning in patients with COPD in order to optimize patient-oriented treatment and to reduce personal discomfort, hospital admissions, and mortality. This paper will summarize the current knowledge about cognitive impairment as extrapulmonary feature of COPD. Hereby, the impact of smoking on cognitive functioning and the impact of cognitive impairment on smoking behaviour will be examined.
PMCID: PMC3971492  PMID: 24738069
22.  The COgnitive-Pulmonary Disease (COgnitive-PD) study: protocol of a longitudinal observational comparative study on neuropsychological functioning of patients with COPD 
BMJ Open  2014;4(3):e004495.
Intact cognitive functioning is necessary for patients with chronic obstructive pulmonary disease (COPD) to understand the value of healthy lifestyle guidelines, to make informed decisions and subsequently act on it. Nevertheless, brain abnormalities and cognitive impairment have been found in patients with COPD. To date, it remains unknown which cognitive domains are affected and what the possible consequences are of cognitive impairment. Therefore, objectives of the study described are to determine neuropsychological functioning in patients with COPD, and its influence on health status, daily functioning and pulmonary rehabilitation outcome. Furthermore, structural and functional brain abnormalities and the relationship with cognitive and daily functioning will be explored.
Methods and analysis
A longitudinal observational comparative study will be performed in 183 patients with COPD referred for pulmonary rehabilitation and in 90 healthy control participants. Demographic and clinical characteristics, activities of daily living and knowledge about COPD will be assessed. Baseline cognitive functioning will be compared between patients and controls using a detailed neuropsychological testing battery. An MRI substudy will be performed to compare brain abnormalities between 35 patients with COPD with cognitive impairment and 35 patients with COPD without cognitive impairment. Patients will be recruited between November 2013 and November 2015.
Ethics and dissemination
The study has been approved by the Medical Ethics Committee of the University Hospital Maastricht and Maastricht University (NL45127.068.13/METC 13-3-035) and is registered in the Dutch trial register. All participants will provide written informed consent and can withdraw from the study at any point in time. Assessment and home visit data material will be managed anonymously. The results obtained can be used to optimise patient-oriented treatment for cognitively impaired patients with COPD. The findings will be disseminated in international peer-reviewed journals and through research conferences.
PMCID: PMC3948451  PMID: 24589828
Respiratory Medicine (see Thoracic Medicine); Neuropathology
23.  Association of plasma sRAGE, but not esRAGE with lung function impairment in COPD 
Respiratory Research  2014;15(1):24.
Plasma soluble Receptor for Advanced Glycation End Product (sRAGE) is considered as a biomarker in COPD. The contribution of endogenous sRAGE (esRAGE) to the pool of plasma sRAGE and the implication of both markers in COPD pathogenesis is however not clear yet. The aim of the current study was therefore to measure plasma levels of esRAGE comparative to total sRAGE in patients with COPD and a control group. Further, we established the relations of esRAGE and total sRAGE with disease specific characteristics such as lung function and DLCO, and with different circulating AGEs.
Plasma levels of esRAGE and sRAGE were measured in an 88 patients with COPD and in 55 healthy controls. FEV1 (%predicted) and FEV1/VC (%) were measured in both groups; DLCO (%predicted) was measured in patients only. In this study population we previously reported that the AGE Nϵ-(carboxymethyl) lysine (CML) was decreased, Nϵ-(carboxyethyl) lysine (CEL) increased and pentosidine was not different in plasma of COPD patients compared to controls.
Plasma esRAGE (COPD: 533.9 ± 412.4, Controls: 848.7 ± 690.3 pg/ml; p = 0.000) was decreased in COPD compared to controls. No significant correlations were observed between plasma esRAGE levels and lung function parameters or plasma AGEs. A positive correlation was present between esRAGE and total sRAGE levels in the circulation. Confirming previous findings, total sRAGE (COPD: 512.6 ± 403.8, Controls: 1834 ± 804.2 pg/ml; p < 0.001) was lower in patients compared to controls and was positively correlated FEV1 (r = 0.235, p = 0.032), FEV1/VC (r = 0.218, p = 0.047), and DLCO (r = 0.308, p = 0.006). sRAGE furthermore did show a significant positive association with CML (r = 0.321, p = 0.003).
Although plasma esRAGE is decreased in COPD patients compared to controls, only total sRAGE showed a significant and independent association with FEV1, FEV1/VC and DLCO, indicating that total sRAGE but not esRAGE may serve as marker of COPD disease state and severity.
PMCID: PMC3944004  PMID: 24564838
25.  A randomised controlled trial on the efficacy of advance care planning on the quality of end-of-life care and communication in patients with COPD: the research protocol 
BMJ Open  2014;4(1):e004465.
Recent research shows that advance care planning (ACP) for patients with chronic obstructive pulmonary disease (COPD) is uncommon and poorly carried out. The aim of the present study was to explore whether and to what extent structured ACP by a trained nurse, in collaboration with the chest physician, can improve outcomes in Dutch patients with COPD and their family.
Methods and analysis
A multicentre cluster randomised controlled trial in patients with COPD who are recently discharged after an exacerbation has been designed. Patients will be recruited from three Dutch hospitals and will be assigned to an intervention or control group, depending on the randomisation of their chest physician. Patients will be assessed at baseline and after 6 and 12 months. The intervention group will receive a structured ACP session by a trained nurse. The primary outcomes are quality of communication about end-of-life care, symptoms of anxiety and depression, quality of end-of-life care and quality of dying. Secondary outcomes include concordance between patient's preferences for end-of-life care and received end-of-life care, and psychological distress in bereaved family members of deceased patients. Intervention and control groups will be compared using univariate analyses and clustered regression analysis.
Ethics and dissemination
Ethical approval was received from the Medical Ethical Committee of the Catharina Hospital Eindhoven, the Netherlands (NL42437.060.12). The current project provides recommendations for guidelines on palliative care in COPD and supports implementation of ACP in the regular clinical care.
Clinical trial registration number
PMCID: PMC3902375  PMID: 24384905
Advance Care Planning; End-of-life Care; Palliative Care; COPD

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