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A review of the management of COPD is presented, with particular emphasis on the effect on the approach to management of new information which has become available in the 5 [...]

Chronic obstructive pulmonary disease (COPD) is a major public health problem because: (1) it causes significant morbidity and mortality which is expected to increase worldwide in the near future; (1) [...]

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Abstract Background--Neutrophils are likely to play a major role in the inflammatory response seen in chronic obstructive pulmonary disease (COPD). This study sought to address the hypothesis that an enhanced [...]

There is a long history of disease caused by inhaled particles that stretches from Agricola and Paracelsus in the 14th century up to the present. [1] In this century the [...]

Short-acting ß2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled ß2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1(P=2.02 × 10-7) and KCNJ2(P=1.79 × 10-7) were the top associations with BDR. Among African Americans, SNPs in CDH13were significantly associated with BDR (P=5.1 × 10-9). A nominal association with CDH13was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1and KCNJ2). SNPs in CDH13were significantly associated with BDR in African Americans.

We thank Dr Marras for his comment on our review. It is true that we have based our assertions on the use of domiciliary oxygen in patients with mild COPD [...]

As sociedades científicas respiratórias europeia e americana (ERS e ATS) constituíram um grupo de trabalho sobre a “Avaliação dos resultados nos ensaios clínicos na DPOC: da função pulmonar aos marcadores biológicos” para informar a comunidade de investigadores em DPOC sobre o possível uso e limitações dos resultados obtidos e marcadores usados actualmente na avaliação do impacto da terapêutica farmacológica. Com base na revisão da literatura, este documento aborda diferentes secções que avaliam marcadores e resultados específicos: função pulmonar; resultados centrados no doente; exacerbações; nortalidade; impacto social e económico; exames de imagem; marcadores não pulmonares; mínima diferença clinicamente significativa; marcadores biológicos.

To further establish the role of oxidative stress in the pathogenesis of acute bronchial asthma, we investigated the effects of platelet-activating factor (PAF) challenge on systemic oxidant-antioxidant balance in 12 asthmatic patients (age, 25+/-3[sem] yr; FEV"1, 95+/-10% predicted), using a double blinded, controlled with Lyso-PAF (L-PAF), cross-over design. Respiratory system resistance (Rrs), arterial blood gases, peripheral blood neutrophils and oxidant-antioxidant balance, including thiobarbituric acid (TBA)-malondialdehyde (MDA) adducts, protein sulphydryls and Trolox equivalent antioxidant capacity (TEAC), were assessed at baseline and 5, 15 and 45min after PAF and L-PAF (18@mg each) bronchoprovocation. Urinary leukotriene E"4 (uLTE"4) elimination was measured 120min after challenge. Compared with baseline, as expected, PAF increased significantly Rrs and AaPO"2 and decreased PaO"2 and peripheral blood neutrophils along with a rebound neutrophilia and increased uLTE"4. By contrast, markers of systemic oxidative stress remained unaltered throughout the study. Unlike PAF, L-PAF-induced changes were negligible. We conclude that there is no systemic oxidant-antioxidant imbalance during acute bronchoconstriction induced by PAF in these patients with mild asthma.

The severity of chronic obstructive pulmonary disease (COPD) is currently assessed using a single physiological measurement, the forced expiratory volume in 1s (FEV"1). COPD, however, has complex effects on other aspects of respiratory function, and in many patients is associated with important systemic changes. We hypothesized that a multidimensional staging system for COPD could provide a more complete assessment of the disease's impact. We considered over 40 potential staging variables, evaluating them according to sensitivity to change, measured reproducibly, independence of the information they provide and prognostic value. We finally selected three: FEV"1 (including arterial blood gas measurements when FEV"1 falls below 35% predicted), Medical Research Council dyspnea scale and body mass index (BMI). Each measure correlates independently with prognosis in COPD, is supported by a significant body of literature and serves as a surrogate for other potentially important variables. We then used principal components analysis (PCA) to determine the degree of association between 30 of the potential variables measured in 813 stable COPD patients. Using PCA, six groups of measurements defined independent categories of patient information: pulmonary function (including FEV"1), symptoms of cough and sputum, dyspnea, health status, bronchodilator reversibility and BMI. These include the three principal variables selected for the staging system. Although the staging boundaries were based on existing literature, they have proven useful in predicting survival. We conclude that a multidimensional grading system is useful to assess the impact of COPD.

Chronic obstructive pulmonary disease (COPD) is a general term encompassing several previously used clinical labels such as 'chronic bronchitis and emphysema', 'chronic obstructive airways disease' and 'chronic obstructive lung disease'. COPD is defined by the Global Initiative for Obstructive Lung Disease (GOLD) as 'a disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases'. Few population-based prevalence surveys of COPD have been published. Data based on physician diagnosis from the UK General Practice Research Database indicate a prevalence in 1997 of 1.7% in men and 1.4% in women. The prevalence of COPD in men reached a plateau in the mid-1990s, but continues to increase in women. In the UK, about 30,000 deaths/year are caused by COPD; this accounts for about 6% of all male and 4% of all female deaths. The annual NHS workload for COPD exceeds that of asthma. About 25% of all medical admissions are as a result of respiratory diseases, and more than 50% of these are cases of COPD. In general practice, annual consultation rates for COPD increase with age from 417/10,000 population in 45-64-year-olds to 1032/10,000 population in 75-84-year-olds.

Studies into the effects of ultrafine particles in the lung have shown adverse effects considered to be due in part to the particle size. Air pollution particles (PM10) are associated with exacerbations of respiratory disease and deaths from cardiovascular causes in epidemiological studies and the ultrafine fraction of PM10has been hypothesized to play an important role. The aim of the present study was to investigate proinflammatory responses to various sizes of polystyrene particles as a simple model of particles of varying size including ultrafine. In the animal model, we demonstrated that there was a significantly greater neutrophil influx into the rat lung after instillation of 64-nm polystyrene particles compared with 202- and 535-nm particles and this was mirrored in other parameters of lung inflammation, such as increased protein and lactate dehydrogenase in bronchoalveolar lavage. When surface area instilled was plotted against inflammation, these two variables were directly proportional and the line passed through zero. This suggests that surface area drives inflammation in the short term and that ultrafine particles cause a greater inflammatory response because of the greater surface area they possess. In vitro, we measured the changes in intracellular calcium concentration in mono mac 6 cells in view of the potential role of calcium as a signaling molecule. Calcium changes after particle exposure may be important in leading to proinflammatory gene expression such as chemokines. We demonstrated that only ultrafine polystyrene particles induced a significant increase in cytosolic calcium ion concentration. Experiments using dichlorofluorescin diacetate demonstrated greater oxidant activity of the ultrafine particles, which may explain their activity in these assays. There were significant increases in IL-8 gene expression in A549 epithelial cells after treatment with the ultrafine particles but not particles of other sizes. These findings suggest that ultrafine particles composed of low-toxicity material such as polystyrene have proinflammatory activity as a consequence of their large surface area. This supports a role for such particles in the adverse health effects of PM10.

BackgroundA randomised trial was performed on patients presenting to hospital with an exacerbation of chronic obstructive pulmonary disease (COPD) to compare outcomes in those managed at home with support with those admitted to hospital in the standard manner.MethodsOver an 18 month period all patients presenting to the Royal Infirmary of Edinburgh on weekdays (n=718) with a diagnosis of an exacerbation of COPD were assessed for inclusion in the trial. Patients with impaired level of consciousness, acute confusion, acute changes on radiography, or an arterial pH of <7.35 or with other serious medical or social reasons for admission were excluded. Patients randomised to home support were discharged with an appropriate treatment package (antibiotics, corticosteroids, nebulised bronchodilators and, if necessary, home oxygen). They were visited by a nurse the following day and thereafter at intervals of 2-3 days until recovery when they were discharged from follow up. Parallel observations were made on patients allocated to normal hospital admission up to the point of discharge. Patients in both groups were assessed at home eight weeks after the initial assessment.ResultsAmong weekday patients 353 (50%) were considered obligatory admissions, 140 (19%) were admitted because of co-morbidity, 17 (2%) because of poor social circumstances, and 24 (3%) did not consent to the trial. The remaining 184 (26%) were randomised (2:1) either to home support or to a standard hospital admission. The median time to discharge was 7 days for the home support group and 5 days for the admitted group (p<0.01); 25% of the home support group and 34% of the admitted group were readmitted before the final assessment at eight weeks (p>0.05). There were no significant differences between the groups in attendances by GPs and carers or in health status measured eight weeks after the initial assessment. Satisfaction with the service was good. The mean total health service cost per patient was estimated as £877 for the home support group and £1753 for the admitted group.ConclusionsThis study shows that home supported discharge is a well tolerated, safe, and economic alternative to hospital admission for a proportion of patients referred to hospital for admission for an exacerbation of COPD.

Many ultrafine particles comprised classically of low–toxicity, low–solubility materials such as carbon black and titanium dioxide have been found to have greater toxicity than larger, respirable particles made of the same material. The basis of the increased toxicity of the ultrafine form is not well understood and a programme of research has been carried out in Edinburgh on the toxicology of ultrafines aimed at understanding the mechanism. We used fine and ultrafine carbon black, TiO2and latex and showed that there was an approximately 10–fold increase in inflammation with the same mass of ultrafine compared with fine particles. Using latex particles in three sizes — 64, 202 and 535 nm — revealed that the smallest particles (64 nm) were profoundly inflammogenic but that the 202 and 535 nm particles had much less activity, suggesting that the cut–off for ultrafine toxicity lies somewhere between 64 and 202 nm. Increased oxidative activity of the ultrafine particle surface was shown using the fluorescent molecule dichlorofluorescein confirming that oxidative stress is a likely process by which the ultrafines have their effects. However, studies with transition–metal chelators and soluble extracts showed that the oxidative stress of ultrafine carbon black is not necessarily due to transition metals. Changes in intracellular Ca2levels in macrophage–like cells after ultrafine particle exposure suggested one way by which ultrafines might have their pro–inflammogenic effects.

Exposureto particulate air pollution (PM10) is associated with exacerbations of respiratory diseases and increased cardiopulmonary mortality. PM10induces lung inflammation in rats, which has been attributed to many factors, including the ultrafine components of PM10, endotoxins, and transition metals. In this study, we investigated in alveolar epithelial (A549) cells whether PM10could activate nuclear factor-kappa B (NF-κB), a transcription factor stimulated in response to many proinflammatory agents. Our results show that PM10samples from various sites within the United Kingdom cause nuclear translocation, DNA-binding, and transcriptional activation of NF-κB in A549 cells. Furthermore, increased NF-κB activity was observed in the absence of IκB degradation. To evaluate the role of iron, A549 cells were exposed to PM10previously treated with phosphate-buffered saline (PBS), deferoxamine mesylate, or deferoxamine plus ferrozine. PBS-treated and, to a lesser extent, deferoxamine-treated PM10were able to activate NF-κB, whereas this response was completely abrogated in cells exposed to PM10treated with both deferoxamine and ferrozine. Moreover, we studied the effects of soluble components of PM10on NF-κB activation by exposing alveolar epithelial cells to soluble fractions from PM10treated with PBS or the metal chelators. We found that, compared with fractions from PBS-treated PM10which activated NF-κB, fractions from PM10treated with deferoxamine and ferrozine did not stimulate NF-κB activity above background levels. Coincubation of polymixin B, an endotoxin-binding compound, and PM10did not inhibit NF-κB. In summary, PM10activates NF-κB in A549 cells by an iron-mediated mechanism in the absence of IκB degradation.

Background It has been suggested that oxidative stress is an important factor in the pathogenesis of chronic obstructive pulmonary disease (COPD). We have shown that an oxidant/antioxidant imbalance occurs in the distal air spaces of smokers and in patients with COPD which is reflected systemically in the plasma. A study was undertaken to determine whether plasma antioxidant status correlated with lung function as assessed by forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) in smokers and patients with COPD. Methods Plasma antioxidant capacity, assessed by the Trolox equivalent antioxidant capacity (TEAC) as an index of overall systemic oxidative stress, and protein thiol levels were measured in 95 patients with stable COPD, in 82 healthy smokers, and in 37 healthy non-smokers. Results Mean (SE) plasma TEAC levels were significantly decreased in patients with COPD (0.81 (0.03) mmol/l, p<0.001) and in healthy smokers (0.87 (0.04) mmol/l, p<0.001) compared with healthy non-smokers (1.31 (0.11) mmol/l). The mean differences in plasma antioxidant capacity (mM) were (0.81, 95% confidence interval (CI) 0.22 to 1.48), (0.87, 95% CI 0.2 to 1.46), and (1.31, 95% CI 1.09 to 1.58) in patients with COPD, healthy smokers, and healthy non-smokers, respectively. This reduction was associated with a 29% (95% CI 18 to 38) and a 30% (95% CI 19 to 40) decrease in plasma protein thiol levels in COPD patients and smokers, respectively. Current smoking was not the main contributor to the reduction in antioxidant capacity in patients with COPD as those patients who were still smokers had similar TEAC levels (mean (SE) 0.78 (0.05); n = 25) to those who had stopped smoking (0.84 (0.02); n = 70). No significant correlations were found between spirometric data measured as FEV₁ % predicted or FEV₁/FVC % predicted and the plasma levels of TEAC in patients with COPD, healthy smokers, or healthy non-smokers. Similarly, there was no significant correlation between FEV₁ % predicted or FEV₁/FVC % predicted and the levels of plasma protein thiols in the three groups. Conclusions These data confirm decreased antioxidant capacity in smokers and patients with COPD, indicating the presence of systemic oxidative stress. However, no relationship was found between protein thiols or TEAC levels and measurements of airflow limitation in either smokers or in patients with COPD.

Glutathione (GSH) is an important physiological antioxidant in lung epithelial cells and lung lining fluid. We studied the regulation of GSH synthesis in response to the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and the anti-inflammatory agent dexamethasone in human alveolar epithelial cells (A549). TNF-alpha (10 ng/ml) exposure increased GSH levels, concomitant with a significant increase in gamma-glutamylcysteine synthetase (gamma-GCS) activity and the expression of gamma-GCS heavy subunit (gamma-GCS-HS) mRNA at 24 h. Treatment with TNF-alpha also increased chloramphenicol acetyltransferase (CAT) activity of a gamma-GCS-HS 5'-flanking region reporter construct, transfected into alveolar epithelial cells. Mutation of the putative proximal AP-1-binding site (-269 to -263 base pairs), abolished TNF-alpha-mediated activation of the promoter. Gel shift and supershift analysis showed that TNF-alpha increased AP-1 DNA binding which was predominantly formed by dimers of c-Jun. Dexamethasone (3 microM) produced a significant decrease in the levels of GSH, decreased gamma-GCS activity and gamma-GCS-HS mRNA expression at 24 h. The increase in GSH levels, gamma-GCS-HS mRNA, gamma-GCS-HS promoter activity, and AP-1 DNA binding produced by TNF-alpha were abrogated by co-treating the cells with dexamethasone. Thus these data demonstrate that TNF-alpha and dexamethasone modulate GSH levels and gamma-GCS-HS mRNA expression by their effects on AP-1 (c-Jun homodimer). These data have implications for the oxidant/antioxidant balance in inflammatory lung diseases.

Thirty-seven consecutive patients, referred to a respiratory unit with a histological diagnosis of small cell carcinoma of the bronchus, were treated with a combined chemotherapy regime of adriamycin, vincristine and cyclophosphamide. Palliative radiotherapy was given for the control of symptoms. Thirty of 37 patients responded to treatment, 11/37 having a complete and 19/37 a partial response. The median survival of those patients with a complete response was 55 weeks, significantly higher (P<0.01) than either those with partial or no response to treatment. Those patients with limited disease survived longer. A high proportion of patients relapsed at the primary site of the tumour in the lungs.The relationship between the therapeutic response and the histological subtype of small cell carcinoma suffered from the limitations of the available pathological material. However, more of the patients with a complete response were of the lymphocytic-like pattern of small cell carcinoma.Useful survival in these patients with inoperable small cell carcinoma was achieved using this regime of chemotherapy, even in those patients with extensive disease, five of whom had survived for over one year.

1. We assessed lung density, determined by computerized tomography, as a measure of emphysema and related this to lung function and measurement of the elastic recoil of the lung in normal subjects and patients with chronic obstructive lung disease. 2. We found a significant correlation between measurements of elastic recoil pressure at 90% of total lung capacity and both the forced expiratory volume in 1 s (r = 0.80, P <0.001) and the transfer factor for carbon monoxide (r = 0.70, P <0.001). Measurements of elastic recoil of the lung also correlated with lung density as measured by computerized tomography scanning (P <0.001). 3. Multiple regression analysis demonstrated a correlation between the density of the lowest fifth percentile of the computerized tomography lung-density histogram, and both the natural logarithm of the shape parameter of the pressure-volume curve (P <0.01), and the transfer factor for carbon monoxide (P <0.01). However, the mean computerized tomography lung density correlated, in addition, with the elastic recoil pressure of the lungs at 90% of total lung capacity (P <0.001). 4. Since the elastic recoil pressure correlates with computerized tomography lung density, and hence with emphysema, and since elastic recoil pressure also correlates with the forced expiratory volume in 1 s, these results suggest that loss of elastic recoil is one determinant of airflow limitation in patients with chronic obstructive lung disease.

1. The changes in maximum expiratory flow rates after washing out lung air with a helium/oxygen mixture (He/O2, 80: 20) were measured in 24 patients with chronic irreversible airflow obstruction (FEV1 1.77 ± sd 0.39 litres; FVC 3.62 ± 0.59 litres), and in six normal subjects. The percentage increase in flow breathing He/O2 was variable; however, it was similar in normal subjects and in patients with airflow obstruction, and in both groups decreased at low lung volumes. Contrary to previous studies, only three patients with chronic airflow obstruction failed consistently to increase flow rates by 20% when breathing He/O2 at all lung volumes measured. 2. In six normal subjects and 12 patients with chronic airflow obstruction airway gas viscosity was increased by breathing a neon/oxygen mixture (Ne/O2, 80:20). The response to Ne/O2 was again variable (normal subjects δVmax.40 4 ± sd 14%; patients δVmax.40 18 ±8%). Only two normal subjects and one patient with airflow obstruction consistently reduced their flow rates when breathing Ne/O2. 3. These results indicate either that there is no difference in the distribution of airflow resistance in normal subjects and in patients with chronic airflow obstruction, or that density as well as viscosity is an important determinant of flow in very small airways. In either case, He/O2 breathing is not a good discriminator of the site of airflow obstruction.

1. Bronchodilatation was produced in eight normal subjects by inhalation, on separate occasions, of the atropine-like drug ipratropium bromide (0·16 mg by pressurized inhaler; 1 mg nebulized) and the β-sympathomimetic salbutamol (0·8 mg by pressurized inhaler; 5 mg nebulized). 2. Mean specific airways conductance (sGaw) increased from a mean value of ·185 ± se 0·002 to 0·292 ± 0·023 s−1 kPa−1 after ipratropium bromide, and from 0·184 ± 0·020 to 0·303 ± 0·026 s−1 kPa−1 after salbutamol. These increases in sGaw were not significantly different from each other. 3. During both maximal and partial expiratory flow volume manoeuvres similar increases in flow rates were produced by each drug, at all lung volumes, from 40 to 20% of vital capacity. 4. Changes in maximal and partial flow volume curves after washout of lung air with helium/oxygen (4:1) were measured before and after each drug. Flow rates increased in all subjects and the percentage increase in maximum flow when helium was breathed was not significantly different, when repeated after each drug. 5. Thus our results suggest that salbutamol and ipratropium have similar sites of action, both affecting both large and small airways, and produce similar degrees of bronchodilatation. This is supported by our results after the helium/oxygen breathing, where the lack of change in density dependence of maximal flow suggests that there was no change in the distribution of airways resistance after the drugs.

Human peripheral blood neutrophils were exposed in vitro, in a tonometer, to two different fractions of cigarette smoke-designated particulate phase and vapor phase. The proteolytic activity of the cells following exposure was assessed by measuring their elastase release and ability to degrade fibronectin. At levels of smoke exposure that were physiologically attainable, neither smoke fraction caused an increase in elastase release or fibronectin degradation. In most experiments, fibronectin proteolysis was suppressed by smoke exposure-an effect that was reversible on treatment with phorbol myristate acetate. These data provide evidence that the proteolytic activity of neutrophils is not enhanced by a direct effect of cigarette smoke on these cells.

AbstractBackgroundAn oxidant/antioxidant imbalance is thought to occur in patients with chronic obstructive pulmonary disease (COPD). It has recently been shown that during exacerbations of COPD the antioxidant capacity and protein sulfhydryls of plasma are lower and the levels of products of lipid peroxidation are higher than in age matched healthy subjects. The aims of this study were to confirm these data and to measure the time course of these changes.MethodsThe plasma Trolox equivalent antioxidant capacity (TEAC), protein sulfhydryls, and products of lipid peroxidation were measured throughout the course of treatment in 13 patients who presented with an acute exacerbation of COPD.ResultsTEAC values (mmol/l) were low on admission (mean 0.67, 95% confidence interval (CI) 0.32 to 0.88; p&lt;0.05) and had increased by discharge (0.98, 95% CI 0.88 to 1.2; p&lt;0.05) but still remained lower than in healthy subjects (1.33, 95% CI 1.11 to 1.65). There was also restoration of plasma protein sulfhydryl levels (mmol/l) from admission (0.32, 95% CI 0.20 to 0.43) to discharge (0.49, 95% CI 0.42 to 0.62, p &lt;0.001) to levels similar to those in healthy subjects (0.52, 95% CI 0.43 to 0.65). Products of lipid peroxidation, measured as thiobarbituric acid-malondialdehyde adducts (lmol/l), were significantly higher (2.08, 95% CI 1.8 to 2.5) than in control subjects (1.3, 95% CI 0.85 to 1.32; p&lt;0.01) and returned to normal values by the time of discharge (1.2, 95% CI 0.88 to 1.29).ConclusionsThese data confirm the presence of a profound oxidant/antioxidant imbalance in the blood of patients with acute exacerbations of COPD which returns towards normal values during the course of treatment.

Abstract: Pulmonary arterial pressure predicts survival in patients with hypoxic chronic obstructive pulmonary disease as does the presence of cor pulmonale. Thus, cardiac catheterization has been performed prior to treatment for long-term oxygen therapy (LTOT) in order to 1) assess the suitability of patients for LTOT, 2) predict survival in patients receiving LTOT and 3) for research in cor pulmonale. In this review I will submit the evidence which suggests that these indications for measurement of pulmonary haemodynamics are not justified, and measurements of arterial blood gas values and assessment of airflow limitation are all that is necessary prior to LTOT.

The ability of peripheral blood neutrophils to injure elements of the alveolar septum was assessed. Experiments consisted of activating previously isolated neutrophils (PMNs) with a soluble (phorbol myristate acetate, PMA) and a particulate (zymosan) trigger, and measuring detachment of51Cr-labeled epithelial cells. In addition, the mechanisms of epithelial injury were investigated by including anti-proteinase and antioxidants in the system. Untriggered PMNs produced only slight detachment injury to epithelial cells at two effector-target cell ratios, this effect being dramatically increased after triggering with PMA; zymosan caused triggering but less than was produced by PMA. Alpha-1-protease inhibitor produced a decrease in detachment when both PMA- and zymosan-triggered cells were the effectors; superoxide dismutase did not significantly reduce detachment. The ability of triggered PMNs to cause proteolysis of fibronectin, as measured in a radiolabeled fibronectin matrix degradation assay, was related to their triggerability in the detachment assay, zymosan being largely ineffective in triggering enhanced proteoiysis. These findings suggest that fibronectin is important in maintaining the integrity of the alveolar epithelial surfaces. Furthermore, in inflamed alveoli, activated PMNs can release proteinases, which cause degradation of this matrix component leading to compromise of the alveolar epithelial barrier.

Peripheral blood neutrophils were harvested and exposed acutely in vitro to physiologically attainable levels of cigarette smoke. The adherence of radiolabeled neutrophils subsequently to alveolar epithelial cell monolayers was measured. In contrast to control cells, smoke-exposed neutrophils were significantly less adherent and failed to increase their adherence following stimulation with phorbol ester or f-met-leu-phe (fMLP). Flow cytometric analysis of the cell surface adhesion protein CD18 demonstrated no significant change in expression following in vitro smoke exposure and, furthermore, no increase in surface CD18 of smoke-exposed cells following consecutive fMLP stimulation was demonstrated. Acute in vivo cigarette smoking of up to 4 cigarettes also did not alter peripheral blood neutrophil CD 18 expression. Cell spreading and chemokinesis, but not chemotaxis, was also impaired following in vitro smoke exposure. These data suggest that acute cigarette smoke may impair the crucial neutrophil functions of adherence and movement. However, the chronic effects of cigarette smoke exposure may clearly differ.

LIPOCORTN 1 (Lc1) is an anti-inflammatory protein, which, given systemically, inhibits polymorphonuclear neutrophil (PMN) emigration from the circulation to sites of inflammation; delivery of Lc1 to the inflamed site is ineffective. We have examined the effect of Lc1 on changes in PMN deformability, and observed a consistent improvement in the deformability of unstimulated PMN; N-formyl-methionyl-leucyl-phenylalanine (fMLP)-activated cell deformability was unaltered. A Lc1-induced increase in cell deformability may reduce PMN sequestration so contributing to the anti-migratory effects of systemic Lc1 previously demonstrated in vivo .

BackgroundAdvanced glycation endproducts (AGE) in patients with chronic obstructive pulmonary disease (COPD) has been considered in the pathology of the disease and as a biomarker of emphysema severity. In addition, AGE has been implicated in cardiovascular (CV) disease, a common comorbidity in COPD. Whether the soluble receptor for AGE (sRAGE) predicts CV status in COPD is unclear.ObjectiveThe aim of this study was to assess the associations between sRAGE and measures of both lung and CV function in patients with COPD from the ERICA cohort.MethodsPatients with confirmed COPD performed spirometry, blood pressure, aortic pulse wave velocity (PWV), carotid intima media thickness (CIMT) at clinical stability. Blood for sRAGE was taken.ResultsOf the 729 subjects in ERICA, 677 patients had a sRAGE result. 417 patients were male; mean (SD) age was 67.4 (7.8) years and 31% were current smokers. There was a weak association of sRAGE with age (r=0.16, p<0.001), FEV1% predicted (r=0.12, p<0.05) and FEV1/FVC (r=0.15, p<0.001). There was no difference in sRAGE in current or ex-smokers. In multiple linear regression, a lower sRAGE was associated with more severe lung function: FEV1% predicted, (B 4.3 [95% CI 1.6, 6.8, p=0.0012]. No significant relationship was observed between sRAGE and cardiovascular variables: aortic PWV (p=0.418) and CIMT (p=0.596) in the multivariate models. sRAGE in those with concurrent presence of CV disease, diabetes or cerebrovascular disease or not was not different (p=0.579).ConclusionDespite literature supporting the role of AGE in both lung and CV disease, there was no apparent association of sRAGE with CV status in patients with COPD in the ERICA cohort. There were associations with spirometry variables of FEV1% predicted and FEV1/FVC.

IntroductionChronic Obstructive Pulmonary Disease (COPD) is a major cause of death worldwide. Research shows people with severe COPD have unmet needs, and the traditional cancer palliative care model is not appropriate.Aim(s) and method(s)To pilot and evaluate HELP-COPD - a community-based proactive holistic assessment of needs. The intervention comprised a home visit by a respiratory nurse, following discharge from hospital after an exacerbation, to discuss social/psychological/spiritual/physical needs, provide advice/information and make further referrals. A HELP_COPD Action Plan was completed and given to the patient and general practitioner. Follow-up included three phone calls over six months.Qualitative evaluation of HELP-COPD comprised interviews with participating patients, lay-carers and health professionals, alongside documentary analysis of completed action plans. Interviews were recorded, transcribed and entered into NVivo for thematic analysis.Results23 patients, from two hospitals, completed action plans. 31 interviews were completed. Patients were generally positive, openly discussing concerns and coping strategies in all domains. Professionals considered the intervention feasible and potentially valuable. Actions included facilitating discussion with their GP on palliative use of opiates, reinforcing referral to pulmonary rehabilitation and providing details of local voluntary services. However, fewer unmet needs were identified than expected, and some patients declined proffered services/information. Participants highlighted overlap with discharge planning and case management provided by community teams.Conclusion(s)HELP COPD was feasible and generally welcomed by patients. Fewer actions were identified than anticipated due to a combination of inappropriate timing, reluctance to accept social services, duplication by existing services and long-term adaptation reducing recognition of need and of the seriousness of the condition.

IntroductionBlood eosinophils level in Chronic Obstructive Pulmonary Disease (COPD) is a candidate biomarker for Regulatory qualification as a drug development tool identifying individuals who may benefit from targeted therapies. Current evidence focused on association with exacerbations and response to therapy, however the association of eosinophilia with cardiorespiratory physiology has not been determined.MethodsThe ERICA (Evaluating the Role of Inflammation in Chronic Airway Disease) study is a large multicentre study of patients with COPD.1Aortic pulse wave velocity (PWV), carotid intimal thickness (CIMT) and spirometry were measured. Health Status (CAT) was recorded. From the full blood count, both absolute and percentage eosinophil counts were considered. We used previously validated cut offs2of 0.3 × 109 cells/L and 2% to compare aortic PWV, CIMT and spirometry variables using a Student’s t-test. A multivariate model was then built to examine the effect after adjusting for confounding factors.Results519 subjects were included in this analysis. Of these, 58% were men, mean (SD) age of 66.9 (7.6) years with a median smoking history of 42 pack years. Mean (SD) resting heart rate was 75 (13)bpm, mean arterial pressure 104 (12) mmHg and percentage predicted FEV152.5 (16.1)%. When comparing high and low eosinophil groups at both 0.3 × 109 cells/L and 2% cut-offs there was no difference in smoking status or pack years, spirometry variables or CAT score. There was no difference in prevalence of ischaemic heart disease, stroke or diabetes. Aortic PWV or CIMT were not different between groups. Multiple regression confirmed this (Table).Abstract P94 Table 1Cardiorespiratory variables *Absolute eosinophil countPercentage eosinophil countBeta co-efficient95% CIp-valueBeta co-efficient 95% CIp-valueAortic PWV(m/s)0.23−1.3 to 1.70.770.090−0.29 to 0.470.64CIMT(mm) Diameter right Diameter left0.16 0.17−0.60 to 0.91 −0.56 to 0.890.69 0.650.04 0.05−0.15 to 0.23 −0.13 to 0.230.71 0.59FEV1(L)0.10−0.11 to 0.510.210.06−0.02 to 0.130.15FVC (L)0.17−0.29 to 0.640.460.120.01 to 0.230.04*Adjustment for sex, age, MAP, HR, FEV1, FVC, smoking pack years, history of diabetes and peripheral vascular diseaseConclusionsA phenotype defined by blood eosinophilia does not relate to cardiorespiratory physiological variables in subjects with COPD.ReferencesMohan Det al. Journal of COPD2015.Negewo Net al. Respirology2017.