R A Stockley

Queen Elizabeth Hospital Birmingham, Birmingham, England, United Kingdom

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Publications (237)1461.9 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Immunesenescence is the functional deterioration of the immune system during natural aging. Despite increased susceptibility to bacterial infections in older adults age-associated changes to neutrophil responses are only partially understood and neutrophil migration has not been characterized in detail. Here we describe reduced chemotaxis but preserved chemokinesis towards a range of inflammatory stimuli in migrating neutrophils isolated from healthy older subjects. Cross-sectional data indicate that migratory behaviour changes in the sixth decade of life. Crucially, aberrant migration may increase "by-stander" tissue damage and heighten inflammation due to excess proteinase release during inaccurate chemotaxis, as well as reducing pathogen clearance. We show evidence of increased neutrophil proteinase activity in older adults, namely raised levels of neutrophil proteinase substrate-derived peptides and evidence of primary granule release, associated with increased systemic inflammation. Inaccurate migration was causally associated with increased constitutive Phosphoinositide 3-kinase (PI3K) signalling; untreated neutrophils from old donors demonstrated significant PI3K activation compared with cells from young donors. PI3K blocking strategies, specifically inhibition of PI3K γ or δ restored neutrophil migratory accuracy while SHIP1 inhibition worsened migratory flaws. Targeting PI3K signalling may therefore offer a new strategy in improving neutrophil functions during infections and reduce inappropriate inflammation in older patients.
    Blood 11/2013; · 9.78 Impact Factor
  • H Stone, A Pye, R A Stockley
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    ABSTRACT: In addition to emphysema alpha-1-antitrypsin deficiency (AATD) has been shown to be associated with several inflammatory conditions, including bronchiectasis, vasculitis, (in particular Wegener's granulomatosis), and panniculitis, suggesting neutrophil proteinases also play a role in their pathophysiology. However, it remains unknown whether other inflammatory diseases are also more prevalent in AATD than the general population. The current study describes the prevalence of other co-morbidities in AATD with particular emphasis on inflammatory bowel disease. The case notes of 651 PiZZ or PiZnull patients attending the UK national centre for AATD between 1996 and 2011 were reviewed. The prevalence of inflammatory bowel disease (1.5%) was higher than that predicted in the UK (0.4%). Ten patients had a confirmed diagnosis of ulcerative colitis, and 1 had Crohn's disease. In 2 cases there was a family history of inflammatory bowel disease and all but 1 patient were ex or never smokers. There was also a higher prevalence of hypothyroidism in this patient group than expected for the UK population - 26 cases (7.2% of females and 1.3% of males). The current study of the UK cohort of patients with AATD confirmed a higher prevalence of ulcerative colitis than would be expected in the general population, providing further evidence of a potential link between these 2 conditions. In addition, the data suggested a potential link between hypothyroidism and AATD.
    Respiratory medicine 10/2013; · 2.33 Impact Factor
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    ABSTRACT: Neutrophil elastase (NE) activity is increased in bronchiectasis and may play a role in this condition. We wished to determine the effect of AZD9668, a selective oral inhibitor of NE. Efficacy and safety of AZD9668 60 mg twice daily over 4 weeks were evaluated in a randomised, double-blind, placebo-controlled, parallel-group, Phase II, signal-searching study in patients with bronchiectasis. Outcome measures included: waking and post-waking sputum neutrophil counts; lung function tests; 24-h sputum weight; BronkoTest(®) diary card data; St George's Respiratory Questionnaire for COPD patients (SGRQ-C); sputum NE activity; inflammatory biomarker levels; desmosine levels; adverse events, safety haematology and biochemistry. AZD9668 levels in plasma and sputum were measured to confirm exposure. Thirty-eight patients were randomised: 16 to placebo and 22 to AZD9668. There was no change in sputum neutrophils with AZD9668. Forced expiratory volume in 1 s improved by 100 mL in the AZD9668 group compared with placebo (p = 0.006). Significant changes (defined a priori as p < 0.1) in favour of AZD9668 were also seen in slow vital capacity, plasma interleukin-8, and post-waking sputum interleukin-6 and Regulated on Activation, Normal T-cell Expressed and Secreted levels. Non-significant changes in favour of AZD9668 were seen in other lung function tests, sputum weight and the SGRQ-C. AZD9668 was well tolerated. In this small signal-searching study, 4 weeks' treatment with AZD9668 improved lung function in patients with bronchiectasis and there were trends for reductions in sputum inflammatory biomarkers. Larger studies of longer duration would be needed to confirm the potential benefits of this agent in bronchiectasis. Registration: NCT00769119.
    Respiratory medicine 02/2013; · 2.33 Impact Factor
  • R A Stockley
    COPD Journal of Chronic Obstructive Pulmonary Disease 01/2013; · 2.31 Impact Factor
  • N. J. Sinden, E. Sapey, G. M. Walton, R. A. Stockley
    Thorax 01/2012; 67:A41-A42. · 8.38 Impact Factor
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    ABSTRACT: Small studies have linked α1 antitrypsin (α1AT) deficiency to patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). To test the validity and the mechanism of this association between α1AT and AAV. The distribution of α1AT deficiency alleles Z and S was compared between 856 White Europeans with AAV and 1505 geographic and ethnically matched healthy controls. Genotyping was performed by allelic discrimination assay. were compared between cases and controls using χ(2) tests. The serum and renal biopsies for α1AT polymers were compared using the polymer-specific 2C1 antibody. The role of α1AT polymers in promoting inflammation was investigated by examining their ability to prime neutrophils for ANCA activation as assessed by CD62L shedding, superoxide production and myeloperoxidase degranulation. Results The Z but not the S allele was over-represented in the patients compared with controls (HR=2.25, 95% CI 1.60 to 3.19). Higher concentrations of polymers of α1AT were detected in serum from patients carrying the Z allele than in those not carrying the Z allele (median (IQR) 1.40 (0.91-3.32) mg/dl vs 0.17 (0.06-0.28) mg/dl, p<0.001); polymers of α1AT were also seen in the renal biopsy of a patient with vasculitic glomerulonephritis. Polymers of α1AT primed neutrophils with CD62L shedding and increased superoxide production following ANCA activation. Carriage of the Z allele was not associated with disease severity, survival or relapse. The Z but not the S deficiency allele is associated with AAV. Polymers of α1AT are present in the serum and glomeruli of at least some patients with the Z allele, which may promote inflammation through priming of neutrophils.
    Annals of the rheumatic diseases 08/2011; 70(10):1851-6. · 8.11 Impact Factor
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    ABSTRACT: Vitamin D-binding protein (DBP) genetic polymorphisms have been associated with chronic obstructive pulmonary disease (COPD). DBP has an indirect role in macrophage activation; thus it was hypothesised that DBP is present in the airway and contributes to lung disease by this mechanism. 471 PiZZ subjects with α1-antitrypsin deficiency (AATD) were genotyped for tag single nucleotide polymorphisms (SNPs) covering the DBP gene (GC), together with known functional variants, prior to seeking association with COPD phenotypes. 140 subjects with usual COPD and 480 controls were available for replication. Vitamin D and DBP levels were measured by tandem mass spectrometry and ELISA, respectively, in serum and DBP in the sol phase of sputum in a subset of 60 patients. Concentrations were related to phenotype and to alveolar macrophage activation. rs2070741 was associated with airway bacterial colonisation (p=0.04) and bronchiectasis (p=0.01), as was rs7041 (p=0.03) which also influenced vitamin D concentrations (p=0.01). The GC2 variant predisposed to bronchiectasis in AATD (p=0.04) and protected against COPD (p=0.05); the latter association was replicated in usual COPD versus controls (p=0.04). Circulating DBP related inversely to forced expiratory volume in 1 s (FEV(1)) (p=0.02), in direct contrast to vitamin D, where deficiency related to low FEV(1) (p=0.04). Sol DBP related directly to alveolar macrophage activation (p=0.004). The genetic association of DBP with COPD may be mediated by effects on macrophage activation, since DBP relates to FEV(1), and affects macrophage activation. Vitamin D effects may be independent of this, relating more strongly to innate immunity.
    Thorax 03/2011; 66(3):205-10. · 8.38 Impact Factor
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    ABSTRACT: Liberation of elastin peptides from damaged lung may be a mechanism of autoimmune lung disease. Citrullination, and anti-citrullinated protein antibody formation occurs in smokers, but the role of smoking in autoantibody generation relevant to pulmonary disease is unclear. Anti-elastin, anti-cyclic citrullinated peptide (anti-CCP) and anti-mutated citrullinated vimentin (anti-MCV) antibodies were measured in 257 subjects with α₁-antitrypsin deficiency (AATD), 113 subjects with usual chronic obstructive pulmonary disease (COPD) and 22 healthy nonsmokers. Levels were compared between groups, against phenotypic features and against smoke exposure. Anti-elastin antibodies were higher in controls relative to AATD (p = 0.008) and usual COPD (p < 0.00001), and in AATD relative to usual COPD (p < 0.00001). Anti-elastin levels showed a threshold at 10 pack-yrs, being higher in those who had smoked less (p = 0.004). No relationships between antibody levels and clinical phenotype were seen after adjustment for smoke exposure. Anti-CCP antibodies were higher in usual COPD than AATD (p = 0.002) but the relationship to smoke exposure was less clear. Smoke exposure is the main determinant of anti-elastin antibody levels, which fall after 10 pack-yrs. Local antibody complexes may be a better measure of elastin directed autoimmunity than circulating levels.
    European Respiratory Journal 01/2011; 37(1):32-8. · 6.36 Impact Factor
  • Thorax 01/2011; 66:A59-A59. · 8.38 Impact Factor
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    R A Stockley
    Respiratory medicine 10/2010; 104(12):1956-7. · 2.33 Impact Factor
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    ABSTRACT: There has been much recent interest in the role of the vitamin D axis in lung disease, which includes vitamin D, vitamin D receptor (VDR) and vitamin D-binding protein (VDBP; also known as Gc-globulin). VDBP is a serum protein which has immunomodulatory functions relevant in the lung, predominantly relating to macrophage activation and neutrophil chemotaxis. Variations within its gene are also associated with airways disease, implying a role for the protein product in pathogenesis. Thus far the majority of evidence relates to chronic obstructive pulmonary disease (COPD), but is scant in other airways diseases, such as asthma and bronchiectasis. VDBP also acts as a scavenger protein to clear extracellular G-actin released from necrotic cells, which may be of relevance in severe lung infections and acute lung injury. Vitamin D protects against the development of cancer and tuberculosis, although optimal levels are unknown. The majority of circulating vitamin D is bound to VDBP, and its uptake into cells occurs in both bound and unbound forms, which suggests the role of VDBP warrants further study in these conditions as well. This article reviews the evidence of the role VDBP and its gene (GC) in a range of lung diseases, including asthma, COPD and tuberculosis.
    Thorax 05/2010; 65(5):456-62. · 8.38 Impact Factor
  • A M Wood, P R Newby, S C Gough, R A Stockley
    European Respiratory Journal 02/2010; 35(2):457-8. · 6.36 Impact Factor
  • Hepatology 08/2009; 50(4):1315; author reply 1315-6. · 12.00 Impact Factor
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    ABSTRACT: Four hundred and eighty-eight PiZ alpha-1-antitrypsin deficient patients, who had joined the UK registry over a 9-year period, were followed in an observational study to determine mortality. None had received A1AT augmentation therapy. Cause of death was confirmed from death certification and medical records. Patients were censored according to length of time on the program or until they withdrew from the program. There were 56 deaths of which 30 were attributed to respiratory causes. Of the remaining 26 deaths, 4 were due to complications from lung transplant, 6 due to liver disease (including 2 post-liver transplant) and the other 16 due to a variety of causes. Kaplan-Meier plots indicated a cumulative hazard for mortality of 18.1% in 9 years, correcting for time of follow up. When categorised for FEV1 percent-predicted, the group with severe impairment had increased mortality (p = <0.001) compared with the mild group and there was a direct relationship between severity and mortality. The severe group had increased mortality compared with the mild group when categorised for KCO percent-predicted (p<0.001), RV/TLC ratio (p<0.001) or emphysema score on CT scan (p<0.001 upper zone). Cox regression analyses indicated that these relationships remained when corrected for age. There were no differences in mortality after categorisation for educational level or occupational group. Mortality in a cohort of A1AT deficient patients (PiZ phenotype) in the UK was 2% per year and was associated with lung function impairment and emphysema severity on CT scan, but not social status.
    Respiratory medicine 06/2009; 103(10):1540-7. · 2.33 Impact Factor
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    ABSTRACT: Wegener granulomatosis (WG) has previously been associated with increased nasal carriage of Staphylococcus aureus, but no studies have investigated the occurrence of pathogen growth in the lower airways. To culture bronchoalveolar lavage fluid (BALF) from patients with WG, patients with idiopathic pulmonary fibrosis (IPF) and normal controls. 33 patients with WG, 22 with IPF and 8 normal controls underwent bronchoscopy and bronchoalveolar lavage. Quantitative culture established bacterial levels in the lower airways. Culture experiments were designed to investigate whether BALF is a supportive environment for S aureus growth. BALF cytokines were measured by ELISA. Pathogens were commonly grown from BALF of patients with WG and those with IPF. S aureus was particularly associated with patients with WG both in relapse and in remission. BALF levels of interleukin 1 receptor antagonist (IL1ra) were statistically significantly elevated in those patients who grew a pathogen from lavage fluid. BALF from patients with WG and IPF stimulated S aureus growth compared with normal lavage fluid. Pathogens are more commonly isolated from BALF from patients with WG than from that of patients with IPF or normal controls, and with a different culture profile. IL1ra was associated with pathogen growth in WG and IPF. WG BALF is a trophic environment for S aureus growth. Pulmonologists treating patients with acute or relapsing WG should consider bronchoscopic microbiological sampling and consider antibiotics with antistaphylococcal activity.
    Thorax 05/2009; 64(8):692-7. · 8.38 Impact Factor
  • R A Stockley, A Pye
    Respiratory medicine 04/2009; 103(6):939-40. · 2.33 Impact Factor
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    ABSTRACT: The aim of this study was to determine whether long-term air pollution exposure is associated with clinical phenotype in alpha(1)-antitrypsin deficiency. In total, 304 PiZZ subjects underwent full lung function testing and quantitative high-resolution computed tomography to identify the presence and severity of the disease. Mean annual air pollutant data for 2006 was matched to the location of patients' houses and used in regression models to identify phenotypic associations with pollution, controlling for covariates. Relative trends in pollution levels were assessed to validate use of a single year's data to indicate long-term exposure. Pollutant levels correlated significantly with one another, with higher levels of primary particles, SO(2) and NO(2) being associated with lower ozone levels. Regression models showed that estimated higher exposure to ozone was associated with worse gas transfer and more severe emphysema. Regression parameters suggested that significance from other pollutants was due to collinearity with ozone. The 2006 pollutant levels showed linear relationships with cumulative years, thus validating the model. Higher exposures to ozone may be associated with worse respiratory status in alpha(1)-antitrypsin deficiency, identifying a group susceptible to ambient air pollution.
    European Respiratory Journal 04/2009; 34(2):346-53. · 6.36 Impact Factor
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    ABSTRACT: Assessment of emphysema-modifying therapy is difficult, but newer outcome measures offer advantages over traditional methods. The EXAcerbations and Computed Tomography scan as Lung End-points (EXACTLE) trial explored the use of computed tomography (CT) densitometry and exacerbations for the assessment of the therapeutic effect of augmentation therapy in subjects with alpha(1)-antitrypsin (alpha(1)-AT) deficiency. In total, 77 subjects (protease inhibitor type Z) were randomised to weekly infusions of 60 mg x kg(-1) human alpha(1)-AT (Prolastin) or placebo for 2-2.5 yrs. The primary end-point was change in CT lung density, and an exploratory approach was adopted to identify optimal methodology, including two methods of adjustment for lung volume variability and two statistical approaches. Other end-points were exacerbations, health status and physiological indices. CT was more sensitive than other measures of emphysema progression, and the changes in CT and forced expiratory volume in 1 s were correlated. All methods of densitometric analysis concordantly showed a trend suggestive of treatment benefit (p-values for Prolastin versus placebo ranged 0.049-0.084). Exacerbation frequency was unaltered by treatment, but a reduction in exacerbation severity was observed. In patients with alpha(1)-AT deficiency, CT is a more sensitive outcome measure of emphysema-modifying therapy than physiology and health status, and demonstrates a trend of treatment benefit from alpha(1)-AT augmentation.
    European Respiratory Journal 03/2009; 33(6):1345-53. · 6.36 Impact Factor
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    ABSTRACT: The aim of the present study was to identify alpha(1)-antitrypsin (alpha(1)-AT)-deficient patients who had rapidly progressive disease. PiZ patients (n = 101) underwent annual lung function measurements over a 3-yr period, and the results were related to factors that may influence decline. The mean annual decline in forced expiratory volume in 1 s (FEV(1)) was 49.9 mL. The greatest FEV(1) decline occurred in the moderate severity group (FEV(1) 50-80% of the predicted value), with a mean annual decline of 90.1 mL, compared with 8.1 mL in the very severe group (FEV(1) <30% pred). However, annual decline in transfer coefficient of the lung for carbon monoxide (K(CO)) was greatest in the severe and very severe groups. When the whole group was divided into tertiles of FEV(1) decline, the fast tertile compared with the slow tertile had more patients with bronchodilator reversibility (BDR) (73 versus 41%; p = 0.010), more males (79 versus 56%; p = 0.048) and lower body mass index (BMI) (24.0 versus 26.1; p = 0.042). Logistic regression analyses confirmed that FEV(1) decline was independently associated with BMI, BDR, exacerbation rate and high physical component 36-item short-form health survey scores. In PiZ alpha(1)-AT-deficient patients, FEV(1) decline was greatest in moderate disease, unlike K(CO) decline, which was greatest in severe disease. The FEV(1) decline showed associations with BDR, BMI, sex and exacerbation rate.
    European Respiratory Journal 01/2009; 33(6):1338-44. · 6.36 Impact Factor
  • Source
    E Sapey, D Bayley, A Ahmad, R Stockley
    European Respiratory Journal 12/2008; 32(5):1408-9; author reply 1409. · 6.36 Impact Factor

Publication Stats

5k Citations
1,461.90 Total Impact Points

Institutions

  • 1987–2013
    • Queen Elizabeth Hospital Birmingham
      Birmingham, England, United Kingdom
  • 1978–2013
    • University of Birmingham
      • • School of Clinical and Experimental Medicine
      • • College of Medical and Dental Sciences
      • • School of Immunity and Infection
      Birmingham, England, United Kingdom
  • 2009
    • Copenhagen University Hospital Gentofte
      Hellebæk, Capital Region, Denmark
  • 1999–2009
    • University Hospitals Birmingham NHS Foundation Trust
      • Department of Respiratory Medicine
      Birmingham, England, United Kingdom
    • Washington University in St. Louis
      San Luis, Missouri, United States
  • 2005
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 2002
    • Policlinico San Matteo Pavia Fondazione IRCCS
      Ticinum, Lombardy, Italy
    • Royal United Hospital Bath NHS Trust
      Bath, England, United Kingdom
  • 1998
    • The Queen Elizabeth Hospital
      Tarndarnya, South Australia, Australia
  • 1995
    • Papworth Hospital NHS Foundation Trust
      Papworth, England, United Kingdom
  • 1994–1995
    • University of Cambridge
      • • Department of Medicine
      • • Department of Haematology
      Cambridge, ENG, United Kingdom
  • 1987–1994
    • The Royal Orthopaedic Hospital NHS Foundation Trust
      Birmingham, England, United Kingdom
  • 1993
    • University of Queensland 
      • School of Medicine
      Brisbane, Queensland, Australia
  • 1990
    • Barnes Jewish Hospital
      San Luis, Missouri, United States
  • 1980
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States