Mild-moderate COPD Research Articles

Endothelial to mesenchymal transition is an active process in smokers and patients with early COPD contributing to pulmonary arterial pathology.

We have previously reported pulmonary arterial remodelling in smokers and patients with early COPD, which can be attributed to endothelial to mesenchymal transition (EndMT). In this study, we aimed to evaluate if EndMT is an active mechanism in smokers and COPD. Immunohistochemical staining for the EndMT biomarkers CD31, N-cadherin, vimentin and S100A4 was done on lung resection tissue from 49 subjects. These comprised 15 nonsmoker controls (NC), six normal lung function smokers (NLFS), nine patients with small airway disease (SAD), nine current smokers with mild-moderate COPD (COPD-CS) and 10 ex-smokers with COPD (COPD-ES). Pulmonary arteries were analysed using Image ProPlus software v7.0. We noted reduced junctional CD31+ endothelial cells (p<0.05) in the intimal layer of all smoking groups compared to NC. We also observed increased abundance of the mesenchymal markers N-cadherin (p<0.05) and vimentin (p<0.001) in all smoking groups and across all arterial sizes versus NC, except for N-cadherin in large arteries in COPD-CS. The abundance of S100A4 correlated with arterial thickness (small: r=0.29, p=0.05; medium: r=0.33, p=0.03; large: r=0.35, p=0.02). Vimentin in the small arterial wall negatively correlated with forced expiratory volume in 1 s/forced vital capacity (r= -0.35, p=0.02) and forced expiratory flow rate at 25-75% of forced vital capacity (r= -0.34, p=0.03), while increased cytoplasmic CD31 abundance in the intimal layer of medium and large arteries negatively correlated with predicted diffusing capacity of the lung for carbon monoxide (medium: r= -0.35, p=0.04; large: r= -0.39, p=0.03). This is the first study showing the acquisition of mesenchymal traits by pulmonary endothelial cells from NLFS, SAD and mild-moderate COPD patients through EndMT. This informs on the potential early origins of pulmonary hypertension in smokers and patients with early COPD.

Bone Morphogenic Proteins and Their Antagonists in the Lower Airways of Stable COPD Patients.

Bone morphogenic proteins (BMPs) and their antagonists are involved in the tissue development and homeostasis of various organs. To determine transcriptomic and protein expression of BMPs and their antagonists in stable COPD. We measured the expression and localization of BMPs and some relevant antagonists in bronchial biopsies of stable mild/moderate COPD (MCOPD) (n = 18), severe/very severe COPD (SCOPD) (n = 16), control smokers (CS) (n = 13), and control non-smokers (CNS) (n = 11), and in lung parenchyma of MCOPD (n = 9), CS (n = 11), and CNS (n = 9) using immunohistochemistry and transcriptome analysis, in vitro after the stimulation of the 16HBE cells. In bronchial biopsies, BMP4 antagonists CRIM1 and chordin were increased in the bronchial epithelium and lamina propria of COPD patients. BMP4 expression was decreased in the bronchial epithelium of SCOPD and MCOPD compared to CNS. Lung transcriptomic data showed non-significant changes between groups. CRIM1 and chordin were significantly decreased in the alveolar macrophages and alveolar septa in COPD patients. External 16HBE treatment with BMP4 protein reduced the bronchial epithelial cell proliferation. These data show an imbalance between BMP proteins and their antagonists in the lungs of stable COPD. This imbalance may play a role in the remodeling of the airways, altering the regenerative-reparative responses of the diseased bronchioles and lung parenchyma.

A bronchial gene signature specific for severe COPD that is retained in the nose.

A subset of COPD patients develops advanced disease with severe airflow obstruction, hyperinflation and extensive emphysema. We propose that the pathogenesis in these patients differs from mild-moderate COPD and is reflected by bronchial gene expression. The aim of the present study was to identify a unique bronchial epithelial gene signature for severe COPD patients. We obtained RNA sequencing data from bronchial brushes from 123 ex-smokers with severe COPD, 23 with mild-moderate COPD and 23 non-COPD controls. We identified genes specific to severe COPD by comparing severe COPD to non-COPD controls, followed by removing genes that were also differentially expressed between mild-moderate COPD and non-COPD controls. Next, we performed a pathway analysis on these genes and evaluated whether this signature is retained in matched nasal brushings. We identified 219 genes uniquely differentially expressed in severe COPD. Interaction network analysis identified VEGFA and FN1 as the key genes with the most interactions. Genes were involved in extracellular matrix regulation, collagen binding and the immune response. Of interest were 10 genes (VEGFA, DCN, SPARC, COL6A2, MGP, CYR61, ANXA6, LGALS1, C1QA and C1QB) directly connected to fibronectin 1 (FN1). Most of these genes were lower expressed in severe COPD and showed the same effect in nasal brushings. We found a unique severe COPD bronchial gene signature with key roles for VEGFA and FN1, which was retained in the upper airways. This supports the hypothesis that severe COPD, at least partly, comprises a different pathology and supports the potential for biomarker development based on nasal brushes in COPD.

The Lognormal Lung: A new approach to quantifying lung inhomogeneity in COPD.

Early diagnosis and disease phenotyping in COPD are currently limited by the use of spirometry, which may remain normal despite significant small-airways disease and which may not fully capture a patient's underlying pathophysiology. In this study we explored the use of a new non-invasive technique that assesses gas-exchange inhomogeneity in patients with COPD of varying disease severity (according to GOLD Stage), compared with age-matched healthy controls. The technique, which combines highly accurate measurement of respiratory gas exchange using a bespoke molecular flow sensor and a mechanistic mathematical model of the lung, provides new indices of lung function: the parameters σCL, σCd, and σVD represent the standard deviations of distributions for alveolar compliance, anatomical deadspace and vascular conductance relative to lung volume, respectively. It also provides parameter estimates for total anatomical deadspace and functional residual capacity (FRC). We demonstrate that these parameters are robust and sensitive, and that they can distinguish between healthy individuals and those with mild-moderate COPD (stage 1-2), as well as distinguish between mild-moderate COPD (stage 1-2) and more severe (stage 3-4) COPD. In particular, σCL, a measure of unevenness in lung inflation/deflation, could represent a more sensitive non-invasive marker of early or mild COPD. In addition, by providing a multi-dimensional assessment of lung physiology, this technique may also give insight into the underlying pathophysiological phenotype for individual patients. These preliminary results warrant further investigation in larger clinical research studies, including interventional trials.

Correlation of Six-Minute Walk Test and COPD Assessment Test (CAT) Scores with Spirometric Indices in Chronic Obstructive Pulmonary Disease Patients

Background: For chronic obstructive pulmonary disease spirometry assessment of post-bronchodilator FEV1 is critical for establishing the diagnosis, staging of the disease, predicting the outcome, and planning treatment. The six-minute walk test (6MWT) is an endurance test used to evaluate functional status of patients with cardiopulmonary disorders. CAT score is a well-established tool for determining the impact of COPD on one's health. Objective: To find out correlation between spirometric indices FEV1, FVC, FEV1/FVC, 6MWT and CAT Scores in COPD patients. Design: Cross sectional study Setting: Conducted from September 2019 to September 2021, for a period of 24 months in a tertiary care hospital in India Materials and Methods: In this study, the correlation between spirometric indices FEV1, FVC, FEV1/FVC, 6MWT and CAT Scores was analyzed in 100 patients diagnosed with COPD. Main outcome measures: 6MWT, CAT Scores and Spirometry values in COPD Sample size: 100 Results: Most patients were males(75%) between the ages of 61-70(36%). Majority were in Stage 3 COPD(55%), followed by stage 2 of GOLD staging(25%). Most of them had CAT score range of 21–30(51%), followed by 10–20(48%) and on 6MWT majority walked a distance of 301-400 meters(43%), followed by &gt; 400 meters(35%). The pulse rate and mean systolic blood pressure increased while mean SpO2 decreased post-6WMT with a statistically significant difference(P&lt;.001). The correlation of 6MWT and spirometry parameters shows there was a strong positive correlation of FEV1, FVC, and FEV1/FVC with 6MWT and correlation of CAT score and spirometry parameters shows there was a strong positive correlation of FEV1, FVC, and FEV1/FVC with 6MWT with a statistically significant difference (P&lt;.0001). There was a strong negative correlation between 6MWT and CAT score with a statistically significant difference (P&lt;.0001) Conclusion: The 6MWT and CAT score can be used as an effective alternative to determine the severity of COPD, according to the findings of this study especially in rural settings where access to spirometry is limited. Limitations: Majority of the individuals in our study had mild–moderate COPD severity, emphasizing that the 6MWT's validity and efficacy should be assessed in all COPD grades. Conflict of interest: None

Sleep quality and architecture in COPD: the relationship with lung function abnormalities.

ABSTRACTObjective:Impaired respiratory mechanics and gas exchange may contribute to sleep disturbance in patients with COPD. We aimed to assess putative associations of different domains of lung function (airflow limitation, lung volumes, and gas exchange efficiency) with polysomnography (PSG)-derived parameters of sleep quality and architecture in COPD. Methods:We retrospectively assessed data from COPD 181 patients ≥ 40 years of age who underwent spirometry, plethysmography, and overnight PSG. Univariate and multivariate linear regression models predicted sleep efficiency (total sleep time/total recording time) and other PSG-derived parameters that reflect sleep quality. Results:The severity of COPD was widely distributed in the sample (post-bronchodilator FEV1 ranging from 25% to 128% of predicted): mild COPD (40.3%), moderate COPD (43.1%), and severe-very severe COPD (16.6%). PSG unveiled a high proportion of obstructive sleep apnea (64.1%) and significant nocturnal desaturation (mean pulse oximetry nadir = 82.2% ± 6.9%). After controlling for age, sex, BMI, apnea-hypopnea index, nocturnal desaturation, comorbidities, and psychotropic drug prescription, FEV1/FVC was associated with sleep efficiency (β = 25.366; R2 = 14%; p < 0.001), whereas DLCO predicted sleep onset latency (β = −0.314; R2 = 13%; p < 0.001) and rapid eye movement sleep time/total sleep time in % (β = 0.085; R2 = 15%; p = 0.001). Conclusions:Pulmonary function variables reflecting severity of airflow and gas exchange impairment, adjusted for some potential confounders, were weakly related to PSG outcomes in COPD patients. The direct contribution of the pathophysiological hallmarks of COPD to objectively measured parameters of sleep quality seems to be less important than it was previously assumed.

Novel Respiratory Disability Score Predicts COPD Exacerbations and Mortality in the SPIROMICS Cohort.

RationaleSome COPD patients develop extreme breathlessness, decreased exercise capacity and poor health status yet respiratory disability is poorly characterized as a distinct phenotype.ObjectiveTo define respiratory disability in COPD based on available functional measures and to determine associations with risk for exacerbations and death.MethodsWe analyzed baseline data from a multi-center observational study (SPIROMICS). This analysis includes 2332 participants (472 with severe COPD, 991 with mild/moderate COPD, 726 smokers without airflow obstruction and 143 non-smoking controls).MeasurementsWe defined respiratory disability by ≥4 of 7 criteria: mMRC dyspnea scale ≥3; Veterans Specific Activity Questionnaire <5; 6-minute walking distance <250 m; St George’s Respiratory Questionnaire activity domain >60; COPD Assessment Test >20; fatigue (FACIT-F Trial Outcome Index) <50; SF-12 <20.ResultsUsing these criteria, respiratory disability was identified in 315 (13.5%) participants (52.1% female). Frequencies were severe COPD 34.5%; mild-moderate COPD 11.2%; smokers without obstruction 5.2% and never-smokers 2.1%. Compared with others, participants with disability had more emphysema (13.2 vs. 6.6%) and air-trapping (37.0 vs. 21.6%) on HRCT (P<0.0001). Using principal components analysis to derive a disability score, two factors explained 71% of variance, and a cut point −1.0 reliably identified disability. This disability score independently predicted future exacerbations (ß=0.34; CI 0.12, 0.64; P=0.003) and death (HR 2.97; CI 1.54, 5.75; P=0.001). Thus, participants with disability by this criterion had almost three times greater mortality compared to those without disability.ConclusionOur novel SPIROMICS respiratory disability score in COPD was associated with worse airflow obstruction as well as airway wall thickening, lung parenchymal destruction and certain inflammatory biomarkers. The disability score also proved to be an independent predictor of future exacerbations and death. These findings validate disability as an important phenotype in the spectrum of COPD.

Centrilobular emphysema and coronary artery calcification: mediation analysis in the SPIROMICS cohort

BackgroundChronic obstructive pulmonary disease (COPD) is associated with a two-to-five fold increase in the risk of coronary artery disease independent of shared risk factors. This association is hypothesized to be mediated by systemic inflammation but this link has not been established.MethodsWe included 300 participants enrolled in the SPIROMICS cohort, 75 each of lifetime non-smokers, smokers without airflow obstruction, mild-moderate COPD, and severe-very severe COPD. We quantified emphysema and airway disease on computed tomography, characterized visual emphysema subtypes (centrilobular and paraseptal) and airway disease, and used the Weston visual score to quantify coronary artery calcification (CAC). We used the Sobel test to determine whether markers of systemic inflammation mediated a link between spirometric and radiographic features of COPD and CAC.ResultsFEV1/FVC but not quantitative emphysema or airway wall thickening was associated with CAC (p = 0.036), after adjustment for demographics, diabetes mellitus, hypertension, statin use, and CT scanner type. To explain this discordance, we examined visual subtypes of emphysema and airway disease, and found that centrilobular emphysema but not paraseptal emphysema or bronchial thickening was independently associated with CAC (p = 0.019). MMP3, VCAM1, CXCL5 and CXCL9 mediated 8, 8, 7 and 16% of the association between FEV1/FVC and CAC, respectively. Similar biomarkers partially mediated the association between centrilobular emphysema and CAC.ConclusionsThe association between airflow obstruction and coronary calcification is driven primarily by the centrilobular subtype of emphysema, and is linked through bioactive molecules implicated in the pathogenesis of atherosclerosis.Trial RegistrationClinicalTrials.gov: Identifier: NCT01969344.

CORRELATION OF SPECIFIC NK CELL RECEPTOR LIGANDS WITH COPD SEVERITY

SESSION TITLE: Biomarkers in Obstructive Lung Disease SESSION TYPE: Original Investigations PRESENTED ON: 10/10/2018 07:30 AM - 08:30 AM PURPOSE: COPD is the third-leading cause of death in the United States, with few proven disease modifying therapies. Recent studies have focused on the role of immune function in the role of COPD progression after viral exacerbations. Studies of murine COPD models and of COPD patients have shown chronic cigarette smoking primes NK cell activation. The B7 family is a group of cellular receptors that provide both stimulatory and inhibitory signals to NK cells. We looked at B7H3, a direct inhibitor of NK function, and B7H6, a direct activator of NK function, and their soluble ligand levels in never smoking controls and patients with varying degrees of COPD. METHODS: Serum samples were obtained from the COPD VA Cohort. ELISAs for B7H6 (N=73) and B7H3 (N=38) were performed on samples including control patients, former and current smokers, and varying severities of COPD (based on GOLD classification). ELISAs performed according to manufacturer protocol. Results were analyzed with 5-parameter logarithmic regression. RESULTS: We measured the serum levels of B7H3 and B7H6 and evaluated based on correlation with control, current smokers, former smokers, and varying stages of COPD (GOLD I/II based on FEV1 >50% and GOLD III/IV based on FEV1 <50%). We found that there was an inverse relationship between B7H6 levels and COPD severity. Compared with controls and smokers, COPD patients had significantly decreased B7H6 levels as disease severity progressed (p=0.041). We also found that there was a significant decrease in B7H6 between mild-moderate COPD and severe COPD (p=0.032). Our studies found that there was no statistical relationship when comparing B7H3 levels in control, smokers, and COPD patients (p=0.16). CONCLUSIONS: Our study showed that soluble level of B7H3 ligand was not correlated with COPD severity, but that soluble level of B7H6 was inversely correlated with disease progression. This finding fits with our expected theory of NK cell function and COPD progression. As disease progresses and viral exacerbations occur, the body is unable to fight these infections as activating soluble ligands have decreased. A follow-up study using Immunohistochemistry to look at tissue expression of B7H6 may give more insight into why this receptor ligand decreases with disease. CLINICAL IMPLICATIONS: Ultimately the level of B7H6 soluble ligand may be useful as a clinical tool in patients with COPD exacerbations as it may aid in differentiating between viral illnesses and inflammatory exacerbations. Those with viral infections may actually benefit from withholding steroids, as their NK cells respond appropriately to the infection. DISCLOSURES: No relevant relationships by Michael Borchers, source=Web Response No relevant relationships by Jeff Miller, source=Web Response no disclosure on file for Andrew Osterburg

Dietary nitrate improved exercise capacity in COPD but not blood pressure or pulmonary function: a 2 week, double-blind randomised, placebo-controlled crossover trial

Dietary nitrate may improve exercise tolerance in some healthy and clinical populations. Existing data regarding dietary nitrate in COPD is inconsistent. We conducted a 14d double-blind, randomised, placebo-controlled, crossover trial of daily nitrate-rich beetroot juice (BRJ; 12.9 mmol) versus nitrate-depleted BRJ (PL; 0.5 mmol). At baseline and after each condition, we assessed functional capacity (incremental shuttle walk test; ISWT), ambulatory blood pressure, pulmonary function, quality of life as well as exhaled nitric oxide (eNO), and plasma nitrate/nitrite (NOx). Eight subjects with COPD completed the trial. BRJ supplementation was associated with significantly increased NOx (p < .05) and a 14.6% increase in ISWT distance (+56 m, p = .00004) as well as a trend towards increased eNO compared to PL. There was no other differences. Dietary nitrate appears to have ergogenic effect in subjects with mild-moderate COPD. This effect does not appear to be related to altering blood pressure or pulmonary function.

Bronchodilator Responses in Respiratory Impedance, Hyperinflation and Gas Trapping in COPD

ABSTRACTHyperinflation, gas trapping and their responses to long-acting bronchodilator are clinically important in COPD. The forced oscillation technique (FOT) measures of respiratory system resistance and reactance are sensitive markers of bronchodilator response in COPD. The relationships between changes in resistance and reactance, and changes in hyperinflation and gas trapping, following long-acting bronchodilator (LA-BD) have not been studied.15 subjects with mild-moderate COPD underwent FOT, spirometry then body plethysmography, before and 2 hours after a single 150 microg dose of the LA-BD indacaterol. Hyperinflation was quantified as the inspiratory capacity to total lung capacity ratio (IC/TLC), and gas trapping as residual volume to TLC ratio (RV/TLC).At baseline, FOT parameters were moderately correlated with IC/TLC (|r| 0.53–0.73, p < 0.05). At 2 hours post-LA-BD, there were moderate correlations between change in FOT and change in RV/TLC (|r| 0.60–0.82, p < 0.05). Baseline FOT parameters also correlated with the subsequent post-LA-BD change in both IC/TLC (|r| 0.54–0.62, p < 0.05) and RV/TLC (|r| 0.57–0.76, p < 0.05).FOT impedance reflects hyperinflation and gas trapping in COPD, and the potential for long-acting bronchodilator responsiveness. These results provide us with further insight into the physiological mechanisms of action of long-acting bronchodilator treatment, and may be clinically useful for predicting treatment responses.

Distinct emphysema subtypes defined by quantitative CT analysis are associated with specific pulmonary matrix metalloproteinases.

BackgroundEmphysema is characterised by distinct pathological sub-types, but little is known about the divergent underlying aetiology. Matrix-metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix and have been identified as potentially important in the development of emphysema. However, the relationship between MMPs and emphysema sub-type is unknown. We investigated the role of MMPs and their inhibitors in the development of emphysema sub-types by quantifying levels and determining relationships with these sub-types in mild-moderate COPD patients and ex/current smokers with preserved lung function. MethodsTwenty-four mild-moderate COPD and 8 ex/current smokers with preserved lung function underwent high resolution CT and distinct emphysema sub-types were quantified using novel local histogram-based assessment of lung density. We analysed levels of MMPs and tissue inhibitors of MMPs (TIMPs) in bronchoalveolar lavage (BAL) and assessed their relationship with these emphysema sub-types.ResultsThe most prevalent emphysema subtypes in COPD subjects were mild and moderate centrilobular (CLE) emphysema, while only small amounts of severe centrilobular emphysema, paraseptal emphysema (PSE) and panlobular emphysema (PLE) were present. MMP-3, and -10 associated with all emphysema sub-types other than mild CLE, while MMP-7 and -8 had associations with moderate and severe CLE and PSE. MMP-9 also had associations with moderate CLE and paraseptal emphysema. Mild CLE occurred in substantial quantities irrespective of whether airflow obstruction was present and did not show any associations with MMPs.ConclusionMultiple MMPs are directly associated with emphysema sub-types identified by CT imaging, apart from mild CLE. This suggests that MMPs play a significant role in the tissue destruction seen in the more severe sub-types of emphysema, whereas early emphysematous change may be driven by a different mechanism.Trial registrationTrial registration number NCT01701869.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0402-z) contains supplementary material, which is available to authorized users.

Regional Heterogeneity of Chronic Obstructive Pulmonary Disease Phenotypes: Pulmonary 3He Magnetic Resonance Imaging and Computed Tomography

Pulmonary ventilation may be visualized and measured using hyperpolarized 3He magnetic resonance imaging (MRI) while emphysema and its distribution can be quantified using thoracic computed tomography (CT). Our objective was to phenotype ex-smokers with COPD based on the apical-to-basal distribution of ventilation abnormalities and emphysema to better understand how these phenotypes change regionally as COPD progresses. We evaluated 100 COPD ex-smokers who provided written informed consent and underwent spirometry, CT and 3He MRI. 3He MRI ventilation imaging was used to quantify the ventilation defect percent (VDP) for whole-lung and individual lung lobes. Regional VDP was used to generate the apical-lung (AL)-to-basal-lung (BL) difference (ΔVDP); a positive ΔVDP indicated AL-predominant and negative ΔVDP indicated BL-predominant ventilation defects. Emphysema was quantified using the relative-area-of-the-lung ≤−950HU (RA950) of the CT density histogram for whole-lung and individual lung lobes. The AL-to-BL RA950 difference (ΔRA950) was generated with a positive ΔRA950 indicating AL-predominant emphysema and a negative ΔRA950 indicating BL-predominant emphysema. Seventy-two ex-smokers reported BL-predominant MRI ventilation defects and 71 reported AL-predominant CT emphysema. BL-predominant ventilation defects (AL/BL: GOLD I = 18%/82%, GOLD II = 24%/76%) and AL-predominant emphysema (AL/BL: GOLD I = 84%/16%, GOLD II = 72%/28%) were the major phenotypes in mild-moderate COPD. In severe COPD there was a more uniform distribution for ventilation defects (AL/BL: GOLD III = 40%/60%, GOLD IV = 43%/57%) and emphysema (AL/BL: GOLD III = 64%/36%, GOLD IV = 43%/57%). Basal-lung ventilation defects predominated in mild-moderate GOLD grades, and a more homogeneous distribution of ventilation defects was observed in more advanced grade COPD; these differences suggest that over time, regional ventilation abnormalities become more homogenously distributed during disease progression.

The effect of dietary nitrate supplementation on the oxygen cost of cycling, walking performance and resting blood pressure in individuals with chronic obstructive pulmonary disease: A double blind placebo controlled, randomised control trial

BackgroundChronic obstructive pulmonary disease (COPD) results in exercise intolerance. Dietary nitrate supplementation has been shown to lower blood pressure (BP), reduce the oxygen cost of exercise, and enhance exercise tolerance in healthy volunteers. This study assessed the effects of dietary nitrate on the oxygen cost of cycling, walking performance and BP in individuals with mild–moderate COPD. MethodsThirteen patients with mild–moderate COPD were recruited. Participants consumed 70 ml of either nitrate-rich (6.77 mmol nitrate; beetroot juice) or nitrate-depleted beetroot juice (0.002 mmol nitrate; placebo) twice a day for 2.5 days, with the final supplement ~3 hours before testing. BP was measured before completing two bouts of moderate-intensity cycling, where pulmonary gas exchange was measured throughout. The six-minute walk test (6MWT) was completed 30 minutes subsequent to the second cycling bout. ResultsPlasma nitrate concentration was significantly elevated following beetroot juice vs. placebo (placebo; 48 ± 86 vs. beetroot juice; 215 ± 84 µM, P = 0.002). No significant differences were observed between placebo vs. beetroot juice for oxygen cost of exercise (933 ± 323 vs. 939 ± 302 ml: min−1; P = 0.88), distance covered in the 6MWT (456 ± 86 vs. 449 ± 79 m; P = 0.37), systolic BP (123 ± 14 vs. 123 ± 14 mmHg; P = 0.91), or diastolic BP (77 ± 9 vs. 79 ± 9 mmHg; P = 0.27). ConclusionDespite a large rise in plasma nitrate concentration, two days of nitrate supplementation did not reduce the oxygen cost of moderate intensity cycling, increase distance covered in the 6MWT, or lower BP.

Norman Lawrence

<b>Background:</b> Despite having similar mild-moderate airflow obstruction some individuals report a greater burden of symptoms and exacerbations. <b>Aims:</b> Explore factors associated with self-reported symptom severity and exacerbation history in mild-moderate...

Serum ghrelin and adiponectin levels are increased but serum leptin level is unchanged in low weight Chronic Obstructive Pulmonary Disease patients

BackgroundWeight loss and muscle wasting are common features reported in COPD patients and they are all related with systemic inflammation. In this study, the relationship between pulmonary functions and inflammatory and metabolic parameters in low weight COPD patients were investigated. MethodsFifty male COPD patients were grouped according to the Global Initiative for Chronic Obstructive Lung Disease criteria. Group 1: Mild–moderate COPD patients (n=18; with a mean age of 66.4±9.2yrs; body mass index (BMI):19.7±1.5kg/m2), group 2: Severe–very severe COPD patients (n=32; with a mean age of 65.9±10.0yrs; BMI:19.3±1.6kg/m2), group 3: Control group composed of healthy nonsmoking males (n=17; with a mean age of 50.2±8.4yrs; BMI:21.85±1.5kg/m2). Anthropometric parameters, serum levels of adiponectin (ApN), ghrelin, leptin, hsCRP, IL-6, IL-1β, IL-8, TNF-α and pulmonary functions were compared. ResultsAdiponectin concentration was higher in group 1 (43.3±28.6ng/mL; p<0.05) and group 2 (59.9±31.8ng/mL; p<0.001) when compared with the control group (23.5±13.6ng/mL). Ghrelin concentrations were higher in COPD groups (1281.0±1173.7 and 1840.0±403.6pg/mL; p<0.05) compared to the control subjects (554.0±281.9pg/mL). When the groups were compared, no significant difference was found for leptin, IL-1β, TNF-α, and IL-8. Interleukin-6 and hsCRP levels were higher in group 1 than in the control group. ApN was negatively correlated with BMI and FEV1. In all groups, FEV1 showed positive correlation with BMI, skinfold thicknesses, insulin and triglyceride; negative correlation with age, pack/years, HDL-Chol and ApN.Increased SHBG with decreased insulin level and HOMA-IR may indicate increased insulin sensitivity in COPD groups. ConclusionThe anti-inflammatory effect of ApN and ghrelin is more evident in severe–very severe COPD patients.

Abstract A4: SNP-SNP interaction and nongenetic risk factors combine to identify lung cancer susceptibility: Validation in a prospective study

Abstract Introduction: Key risk indicators for lung cancer include a smoking history, genetic factors, increasing age, family history and impaired lung function (COPD). In a case-control study, 20 genetic markers associated with lung cancer were combined with non-genetic risks to derive a lung cancer susceptibility score (LCSS). The aim of this prospective follow up study was to compare the LCSS in a cohort of very high risk smokers, with and without lung cancer. Methods: A cohort of 728 high risk individuals (smoker/ex-smokers, &amp;gt;40 yrs old, &amp;gt;20 pack years, with spirometric confirmed COPD) were recruited and followed for a mean of 5 years. All volunteers underwent spirometry, completed a modified ATS respiratory questionnaire and gave blood for DNA. These volunteers were recruited from the community (N=420) and a COPD outpatient clinic (N=308). To date, we have identified 53 cases of lung cancer (histology confirmed) in this cohort (24 community and 28 clinic). The 20 SNP panel was genotyped using the iPLEX system. Each subjects' genotypes were combined, in a predefined algorithm, to derive the lung cancer susceptibility score. Results: COPD patients subsequently diagnosed with lung caner were comparable to those with no lung cancer for age, gender, smoking exposure. The mean LCSS, was higher in those who developed lung cancer than those who did not (LCSS 7.0 vs 5.7, P=0.06), and significantly higher than those recruited from the community with mild-moderate COPD (LCSS 7.0 vs 4.7, P&amp;lt;0.001). The performance characteristics of the LCSS reported here, confirms its utility in high risk smokers, to target lung cancer screening and/or diagnostic approaches (using molecular, cytological and/or radiological based tools). Conclusion: We show, in a prospectively recruited high risk cohort, that our LCSS identifies those with mild-moderate COPD at greatest risk of lung cancer. Such a group might benefit from aggressive screening/diagnostic approaches, so that their lung cancer is diagnosed in stage 1 when survival has been shown to be dramatically improved. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A4.

Trace elements as a component of oxidative stress in COPD.

The purpose of this study was to assess the serum concentrations of those trace elements that act as a component of oxidative stress in COPD patients. Clinically stable COPD outpatients (n = 26) and healthy controls (n = 24) were studied. Serum concentrations of copper (Cu) and zinc (Zn) were determined using a Varian Spectra AA220 flame atomic absorption spectrophotometer. Serum concentration of iron (Fe) was measured by the ferene assay, using a commercially available kit (IL Test Iron) with the ILAb 900 autoanalyser. The lipid peroxidation product malondialdehyde (MDA) in serum samples was measured spectrophotometrically in terms of TBARS (thiobarbituric acid reactive substances). The serum MDA concentration in COPD patients was found to be similar to the control group (0.68 +/- 0.15 nmol/mL vs 0.62 +/- 0.13 nmol/mL, respectively; P= 0.163). The serum concentrations of the trace elements in both study groups were in the normal reference range. There was no difference in Fe concentration between COPD patients and the control group (0.81 +/- 0.38 micro g/mL vs 0.92 +/- 0.41 micro g/mL; P= 0.360). Copper concentrations were higher (1.06 +/- 0.26 microg/mL vs 0.92 +/- 0.19 microg/mL; P <0.040); while zinc was lower in the COPD group compared to the controls (0.83 +/- 0.25 microg/mL vs 1.03 +/- 0.23 microg/mL; P= 0.006). Serum Zn concentrations were lower in the severe COPD patients compared to mild-moderate COPD patients (P = 0.038). The results of this study indicate that there are alterations in serum concentrations of trace elements in COPD patients, suggesting that they may play a role in the pathophysiology of this disease by virtue of their role in oxidative stress. We recommend further studies on the role of trace elements in the pathophysiology of COPD, their association with markers of oxidant/antioxidant status and on the clinical significance of their deficiency.

Rapid protective effect of inhaled fluticasone on airway hyperresponsiveness to AMP in asthma but not in COPD

Rationale Airway hyperresponsiveness (AHR) to adenosine 5'-monophosphate (AMP) occursin patients with asthma and COPD. In patients with asthma, but not with COPD, AHR to AMP is reduced by long-term treatment with inhaled steroids. In addition recently it has been shown that one single dose of fluticasone attenuates, after 2 h, AHR to AMP in mild asthma. The aim of this study was to establish whether or not this rapid protective effect of inhaled fluticasone occurs in patients with COPD. Methods We therefore compared changes in AHR to AMP after one single dose of inhaled fluticasone (1000 μg) in 13 non smokers with mild asthma and in 14 smokers with mild-moderate COPD. The study was conducted according to a randomized, double-blind, placebo-controlled protocol. Patients were in stable clinical condition and no inhaled/oral steroid was used in the last month before the study. Inhaled B 2-agonists were discontinuated at least 24 h before the study. In each study day the patients, underwent bronchial challenge with AMP, 2 hours after inhalation of either placebo or fluticasone. Results The mean PC 20 AMP significantly increased from 15.2 ± 8.04 mg/ml after placebo to 79.10 ± 119.8 mg/ml after fluticasone (P<0.001) in asthmatics, whereas no significant change was observed in COPD patients their PC 20 AMP being 79.3 ± 14.7 mg/ml and 93.2 ± 31.3 mg/ml after placebo and fluticasone respectively (P=NS). Conclusions A single dose of inhaled fluticasone rapidly improves AHR to AMP in asthmatics but not in patients with COPD. This may provide a convenient way by which provocation challenge with inhaled AMP may be useful in discriminating asthma from COPD.

Benefits of Oxygen on Exercise Performance and Pulmonary Hemodynamics in Patients With COPD With Mild Hypoxemia

To clarify the effects of oxygen on exercise performance and pulmonary hemodynamics during exercise in patients with COPD with mild hypoxemia at rest. Seventy-five male patients with stable COPD ("pink puffer" type), accompanied by mild hypoxemia (> 60 mm Hg) at rest and with mild (percentage of predicted FEV1 [%FEV1] > 50%, n = 16), moderate (%FEV1 > 35% to < or = 50%, n = 25), and severe (%FEV1 < or =35%, n = 34) airflow obstruction were recruited from an outpatient clinic. A 6-min walking distance (6MD) test was administered to 75 patients, and the pulmonary hemodynamics of 43 subjects were determined during exercise on a supine bicycle ergometer at 25 W and breathing compressed air and oxygen at 2 L/min. Supplemental oxygen resulted in a significant increase in 6MD, except for patients with mild airflow obstruction and mild desaturation. This increase in 6MD produced by oxygen was greater as the restriction of the airflow was more severe, and correlated negatively with %FEV1, but not with PaO2 at rest or exercise hypoxemia. Pulmonary artery pressure (Ppa) and pulmonary artery occlusion pressure (Pop) increased with exercise, while the rates of increase in both types of pressure were significantly higher for severe COPD than for mild COPD and moderate COPD. Oxygen inhalation significantly reduced the increases in Ppa and Pop during exercise in patients with moderate-to-severe COPD, and the effect of oxygen on the increase in Pop correlated positively with airtrapping (vital capacity - FVC). These findings suggest that supplemental oxygen benefits patients with COPD with moderate-to-severe airflow obstruction and mild hypoxemia at rest, as reflected in improvement in exercise performance and pulmonary hypertension during exercise.