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Biomedical subjects

Robert A Stockley

Publications and source records attributed to Robert A Stockley.

At least 19 recordsLinked to original sources
PubMed2006

Improved outcomes in patients with chronic obstructive pulmonary disease treated with salmeterol compared with placebo/usual therapy: results of a meta-analysis.

BACKGROUND: Several studies have demonstrated that long-acting beta2-agonists such as salmeterol are beneficial in chronic obstructive pulmonary disease (COPD). A meta-analysis was therefore conducted to review studies in COPD to provide pooled estimates of the effect of salmeterol 50 mcg taken twice daily in addition to usual therapy on several clinically relevant endpoints, when compared with placebo/usual therapy. METHODS: An extensive search of literature and clinical trial databases was conducted using the terms salmeterol, COPD, chronic, obstructive, bronchitis and emphysema. Nine randomized, double-blind, parallel-group, placebo-controlled trials of > or =12 week duration with salmeterol 50 mcg bid treatment in COPD were included (>3500 patients), with a further 14 trials excluded due to study design or reporting timelines. All patients were included, and a sub-group of subjects (84%) with poorly reversible COPD were considered separately. Statistical testing was carried out at the 5% level, except for interaction testing which was carried out at the 10% level. RESULTS: Patients treated with salmeterol over 12 months were less likely to withdraw early from the studies (19% patients compared with 25% on their current usual therapy, p < 0.001), less likely to suffer a moderate/severe exacerbation (34% compared with 39%, p < 0.0001) and had a greater increase in average FEV1 (73 mL difference vs placebo/usual therapy, p < 0.0001). Similar differences were found at 3 and 6 months. At all time points, more patients experienced an improvement in health status and also a greater change with salmeterol than with placebo/usual therapy (p < 0.002). There was no evidence of tachyphylaxis to salmeterol over 12 months. CONCLUSION: The meta-analysis confirmed clinically and statistically significant, sustained and consistent superiority of salmeterol 50 mcg bid over placebo/usual therapy on a broad range of outcome measures.

Albuterol↗
PubMed2006

Inflammation in sputum relates to progression of disease in subjects with COPD: a prospective descriptive study.

BACKGROUND: Inflammation is considered to be of primary pathogenic importance in COPD but the evidence on which current understanding is based does not distinguish between cause and effect, and no single mechanism can account for the complex pathology. We performed a prospective longitudinal study of subjects with COPD that related markers of sputum inflammation at baseline to subsequent disease progression. METHODS: A cohort of 56 patients with chronic bronchitis was characterized in the stable state at baseline and after an interval of four years, using physiological measures and CT densitometry. Sputum markers of airway inflammation were quantified at baseline from spontaneously produced sputum in a sub-group (n = 38), and inflammation severity was related to subsequent disease progression. RESULTS: Physiological and CT measures indicated disease progression in the whole group. In the sub-group, sputum myeloperoxidase correlated with decline in FEV1 (rs = -0.344, p = 0.019, n = 37). LTB4 and albumin leakage correlated with TLCO decline (rs = -0.310, p = 0.033, rs = -0.401, p = 0.008, respectively, n = 35) and IL-8 correlated with progression of lung densitometric indices (rs = -0.464, p = 0.005, n = 38). CONCLUSION: The data support a principal causative role for neutrophilic inflammation in the pathogenesis of COPD and suggest that the measurement of sputum inflammatory markers may have a predictive role in clinical practice.

Aged↗
PubMed2006

The genetics of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease caused by the interaction of genetic susceptibility and environmental influences. There is increasing evidence that genes link to disease pathogenesis and heterogeneity by causing variation in protease anti-protease systems, defence against oxidative stress and inflammation. The main methods of genomic research for complex disease traits are described, together with the genes implicated in COPD thus far, their roles in disease causation and the future for this area of investigation.

Cytokines↗
PubMed2006

Chronic Obstructive Pulmonary Disease, inflammation and co-morbidity--a common inflammatory phenotype?

Chronic Obstructive Pulmonary Disease (COPD) is and will remain a major cause of morbidity and mortality worldwide. The severity of airflow obstruction is known to relate to overall health status and mortality. However, even allowing for common aetiological factors, a link has been identified between COPD and other systemic diseases such as cardiovascular disease, diabetes and osteoporosis. COPD is known to be an inflammatory condition and neutrophil elastase has long been considered a significant mediator of the disease. Pro-inflammatory cytokines, in particular TNF-alpha (Tumour Necrosis Factor alpha), may be the driving force behind the disease process. However, the roles of inflammation and these pro-inflammatory cytokines may extend beyond the lungs and play a part in the systemic effects of the disease and associated co-morbidities. This article describes the mechanisms involved and proposes a common inflammatory TNF-alpha phenotype that may, in part, account for the associations.

Animals↗
PubMed2006

Wnt signalling in lung development and diseases.

There are several signalling pathways involved in lung organogenesis including Notch, TGFbeta/BMP, Sonic hedgehog (Shh), FGF, EGF, and Wnt. Despite the widely acknowledged significance of Wnt signalling in embryonic lung development, the role of different Wnt pathways in lung pathologies has been slow to emerge. In this review, we will present a synopsis of current Wnt research with particular attention paid to the role of Wnt signals in lung development and in pulmonary diseases.

Animals↗
PubMed2006

Alpha-1-antitrypsin replacement therapy: current status.

PURPOSE OF REVIEW: Alpha-1-antitrypsin deficiency is a relatively common genetic disease that predisposes to the development of early-onset emphysema and, in some instances, liver disease. The use of alpha-1-antitrypsin replacement therapy in the treatment of alpha-1-antitrypsin deficiency related emphysema is much debated and the purpose of this review is to examine the results of recent studies. We will comment briefly on the pathogenesis and epidemiology of the disease together with new therapeutic approaches currently under intense research. RECENT FINDINGS: Several nonrandomized observational studies and one meta-analysis on the clinical effectiveness of alpha-1-antitrypsin replacement treatment showed a favourable result towards reducing forced expiratory volume in 1 s (FEV1) deterioration in alpha-1-antitrypsin-deficient individuals with moderate lung disease or accelerated FEV1 decline. Improved ways of monitoring disease progression, including computed tomography scanning and exacerbations, are being proposed as primary endpoints. Apart from one small randomized, placebo-controlled trial using computed tomography scanning, which showed a trend toward preservation of lung density on scanning with treatment, the literature lacks proof of effectiveness from large randomized trials. SUMMARY: There might be a possible, but so far unproven, role of alpha-1-antitrypsin augmentation therapy in reducing the progression of emphysema in subsets of patients with alpha-1-antitrypsin deficiency. Placebo-controlled, randomized clinical trials are required to draw firm conclusions. Recent advances in the understanding of the molecular pathology provide opportunities for development of new therapeutic targets for this genetic disorder.

Clinical Trials as Topic↗
PubMed2005

IgA1 protease.

IgA1 proteases are proteolytic enzymes that cleave specific peptide bonds in the human immunoglobulin A1 (IgA1) hinge region sequence. Several species of pathogenic bacteria secrete IgA1 proteases at mucosal sites of infection to destroy the structure and function of human IgA1 thereby eliminating an important aspect of host defence. IgA1 proteases are known as autotransporter proteins as their gene structure encodes the information to direct their own secretion out of the bacterial cell. The iga gene structure is also thought to contribute to the antigenic heterogeneity demonstrated by the IgA1 proteases during infections and the cleavage specificity of the IgA1 proteases for human IgA1. The IgA1 proteases have therefore been implicated as important virulence factors that contribute to bacterial infection and colonisation. The development of strategies to inactivate these IgA1 proteases has become the subject of recent research, as this has the potential to reduce bacterial colonisation at mucosal surfaces.

Bacterial Infections↗
PubMed2005

Effect of expectoration on inflammation in induced sputum in alpha-1-antitrypsin deficiency.

It is unclear how chronic expectoration influences airway inflammation in patients with chronic lung disease. The aim of this study was to investigate factors influencing inflammation in induced sputum samples, including, in particular, chronic sputum production. Myeloperoxidase, interleukin-8, leukotriene B4 (LTB4), neutrophil elastase, secretory leukoprotease inhibitor (SLPI) and protein leakage were compared in induced sputum samples from 48 patients (36 with chronic expectoration) with COPD (with and without alpha-1-antitrypsin deficiency; AATD), 9 individuals with AATD but without lung disease and 14 healthy controls. There were no differences in inflammation in induced sputum samples from healthy control subjects and from AATD deficient patients with normal lung function but without chronic expectoration (P>0.05). Inflammation in induced sputum from AATD patients with airflow obstruction and chronic sputum expectoration was significantly greater than for similar patients who did not expectorate: Interleukin-8 (P<0.01), elastase activity (P=0.01), and protein leakage (P<0.01). The presence of spontaneous sputum expectoration in AATD patients with airflow obstruction was associated with increased neutrophilic airway inflammation in induced sputum samples. The presence of chronic expectoration in some patients will clearly complicate interpretation of studies employing sputum induction where this feature has not been identified.

Adult↗
PubMed2005

Exacerbations of COPD diagnosed in primary care: changes in spirometry and relationship to symptoms.

The study objective was to assess spirometric changes during resolution of acute exacerbations of COPD diagnosed and treated in primary care and their relationship to clinical features. Spirometry was carried out on 101 patients with AECOPD presenting to a primary care physician on the day of presentation, days 5, 10-14, 28, and 56 after presentation and traces were analyzed including quality and reproducibility. Eighty-three patients produced at least one technically acceptable spirometer trace at presentation and 60 patients produced acceptable traces at all time points. The increase in FEV1 and VC occurred during the first 5 days after presentation, with a median increase in postbronchodilator FEV1 of 55 ml (IQR, -63 to 128, p = 0.003) and VC of 90 ml (IQR -78 to 308 ml, p < 0.001). The improvement in prebronchodilator values related to the bronchodilator reversibility at presentation and was strongest for VC (by day 28: r = 0.522, p < 0.001). Patients presenting with purulent sputum demonstrated improvements in FEV1 and VC but this was limited to FEV1 in those with mucoid sputum. The initial dyspnoea score related to the changes in spirometry. It is possible to obtain clinically useful spirometric traces in most patients presenting with an acute exacerbation in primary care. Some patients present with changes in sputum characteristics and cough without increased breathlessness. However, exacerbations characterized by increased breathlessness are associated with increases in airflow obstruction that may be influenced by sputum characteristics and/or changes in airway reactivity.

Adult↗
PubMed2005

Variability in densitometric assessment of pulmonary emphysema with computed tomography.

OBJECTIVES: The objectives of this study were to investigate whether computed tomography (CT) densitometry can be applied consistently in different centers; and to evaluate the reproducibility of densitometric quantification of emphysema by assessment of different sources of variation, ie, intersite, interscan and inter- and intraobserver variability, in comparison with intersubject variability. MATERIALS AND METHODS: In 5 different hospitals, 119 patients with emphysema were scanned using standardized protocols. In each site, an observer performed a quantitative densitometric analysis (including blood recalibration) on the corresponding patient group (n=23-25) and one observer analyzed the entire group of 119 patients. After several months, the latter observer analyzed all data for a second time. Subsequently, different sources of variation were assessed by variance component analysis with and without volume correction of the data. RESULTS: Inter- and intraobserver variability marginally contributes to the total variability (<0.001%). The interscan variability was 0.02% of the total variation after application of volume correction. The intersite variability was 48% as a result of one deviating CT scanner. Air recalibration normalized deviating air densities in CT scanners. Within sites, the intersubject variability ranged between 93% and 99% based on the analysis of 2 subsequent CT scans of the patients. CONCLUSIONS: Almost all variability in the density measurement of emphysema originates from differences between scanners and from differences in severity of emphysema between patients. Lung densitometry with multislice CT scanners is a highly reproducible measurement, especially if corrected for lung volume, because this reduces interscan variability.

Absorptiometry, Photon↗
PubMed2004

Pattern of emphysema distribution in alpha1-antitrypsin deficiency influences lung function impairment.

FEV(1) is fundamental to the diagnosis and staging of chronic obstructive pulmonary disease. In emphysema, airflow obstruction usually coexists with impairment of gas exchange, but discordance is not infrequent. We hypothesized that variations in the distribution of emphysema would be associated with functional differences and therefore account for discordant physiology. We used quantitative computed tomography to assess emphysema severity and distribution in 119 subjects with alpha1-antitrypsin deficiency (PiZ phenotype) and grouped them according to distribution pattern. In the 102 subjects with emphysema, 65 had a predominantly basal pattern ("basal"), but 37 (36%) had greater involvement of the upper regions ("apical"). Subjects from each group were matched for total volume of emphysema and age, and matched pairs analysis was used to relate emphysema distribution to clinical phenotype. Basal distribution was associated with greater impairment of FEV(1) (mean difference, 9.9% predicted; 95% confidence interval, 3.8 to 16.0; p = 0.002) but less impairment of gas exchange (Pa(O(2)) mean difference, 0.5 kPa, 0.03 to 0.1; p = 0.016) and alveolar-arterial oxygen gradient (mean difference, 0.7 kPa; 0.2 to 1.2; p = 0.007) than the apical distribution. Emphysema distribution correlated with physiologic discordance (r = -0.409, p < 0.001). The use of single physiologic parameters as a surrogate measure of emphysema severity may introduce systematic bias in the staging of subjects with emphysema.

Adult↗
PubMed2004

Influence of calibration on densitometric studies of emphysema progression using computed tomography.

The fundamental importance of calibration for any measuring device is indisputable, but computed tomography (CT) calibration in longitudinal lung densitometry studies is largely unexplored. Although the validity of CT as a measure of emphysema has been confirmed in cross-sectional studies, there are limited data on long-term reproducibility, and this is critically important for validating its use as an outcome measure in therapeutic trials. A general understanding of the strengths and pitfalls of CT densitometry is critical for physicians reviewing the published literature using this methodology. In our study of 57 patients with alpha-1 antitrypsin deficiency (phenotype PiZ), progression of voxel index determined from three successive annual scans acquired with a fully calibrated scanner was intimately associated with changes in CT air densitometry, sampled from patient images. Images were therefore reanalyzed, using a correction technique validated in phantom studies that adjusted for changes in measured air density, and the reliability of the voxel index as a measure of emphysema progression was improved. Comparison of adjusted voxel index thresholds indicated the optimum threshold was -950 Hounsfield units. Internal air calibration is therefore critical in longitudinal and multicenter lung densitometry studies of emphysema and incorporation of a correction factor is essential for quantitative image analysis.

Absorptiometry, Photon↗
PubMed2004

Comparison of the sensitivities of 5 different computed tomography scanners for the assessment of the progression of pulmonary emphysema: a phantom study.

RATIONALE AND OBJECTIVES: To compare the sensitivities of 5 different computed tomography scanners (4 multislice CT [MSCT] and 1 single-slice CT) in the assessment of the progression of pulmonary emphysema. METHODS: A Perspex cylinder phantom was constructed containing small pieces of polythene foam with densities representative of lung. Changing the cylinder's volume simulated subtle lung density changes. The sensitivity to density changes was defined by the variation in the residual errors from the linear regression line between time and density. RESULTS: The single-slice CT scanner was significantly less sensitive to density changes than MSCT scanners. Also, among MSCT scanners, small but significant differences were found when the standardized acquisition protocol was used. CONCLUSIONS: Considering the large sensitivity differences between single- and multislice CT scanners, we would recommended using MSCT scanners in clinical multicenter trials in emphysema. The protocol standardization of MSCT scanners can still be further improved.

Humans↗
PubMed2003

Myeloid related protein-8/14 stimulates interleukin-8 production in airway epithelial cells.

Excessive neutrophil recruitment is implicated in the pathogenesis of chronic lung diseases by causing collateral tissue damage. The cells move from the circulation in response to chemokines, such as interleukin (IL)-8, that are secreted by several lung cell types including epithelial cells. This study has investigated factors present in bronchial secretions that are responsible for IL-8 expression and secretion by epithelial cells and hence initiate or perpetuate the recruitment of neutrophils. A549 epithelial cells were stimulated with proinflammatory molecules likely to be of relevance in the lung. Tumor necrosis factor-alpha, IL-1beta, and lipopolysaccharide stimulated IL-8 production from epithelial cells in a dose- and time-dependent manner, and these effects were abrogated by specific antibodies or inhibitors. Bronchial secretions also stimulated IL-8 production, and lipopolysaccharide accounted for approximately 33% of this activity. An abundant 32-kD protein capable of stimulating IL-8 production was isolated from the secretion and identified as neutrophil cytoplasmic protein myeloid-related protein (MRP)-14, which is the heavy polypeptide chain in the MRP-8/14 heterodimer. Abrogation of MRP-14 activity with a specific antibody also reduced the IL-8-stimulating potential of bronchial secretions, suggesting it was a significant stimulus to IL-8 production in the lung and may amplify the neutrophilic inflammation seen in bronchial disease.

Antibodies↗
PubMed2002

The effect of augmentation therapy on bronchial inflammation in alpha1-antitrypsin deficiency.

alpha1-Antitrypsin (AAT) deficiency predisposes to bronchitis and emphysema associated with neutrophilic airway inflammation. The efficacy of augmentation therapy has not been proven clinically or by demonstrating an effect on airway inflammation. We treated 12 patients with four infusions of Prolastin (60 mg/kg) at weekly intervals and monitored both the serum and secretion concentrations of AAT as well as markers of neutrophilic inflammation, including myeloperoxidase, elastase, and the neutrophil chemoattractants interleukin-8 and leukotriene B(4). Serum AAT rose and was maintained above the protective threshold. In addition, AAT concentrations in the sputum rose from a mean of 0.17 microM (SEM +/- 0.04) before therapy to concentrations similar to nondeficient subjects (0.43 +/- 0.12) 1 week after the first infusion (p < 0.01). This was associated with a reduction in elastase activity (p < 0.002) and the chemoattractant leukotriene B(4) (p < 0.02), which fell from a median baseline value of 13.46 nM (range, 4.17-55.00) to 8.62 nM (4.23-21.59) the day following the last infusion. Although median values for myeloperoxidase and interleukin-8 also fell, the changes failed to achieve statistical significance. In summary, short-term therapy with AAT increased lung secretion concentrations and was associated with a fall in leukotriene B(4), which is thought to be central to the airway inflammation of AAT deficiency.

Biomarkers↗