William MacNee

Publications (112)669.89 Total impact

• Article: Authors response. The chronic obstructive pulmonary disease (COPD) control panel: towards personalised medicine in COPD.

  Alvar Agusti, William MacNee
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  ABSTRACT: BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease whose assessment and management have traditionally been based on the severity of airflow limitation (forced expiratory volume in 1 s (FEV(1))). Yet, it is now clear that FEV(1) alone cannot describe the complexity of the disease. In fact, the recently released Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2011 revision has proposed a new combined assessment method using three variables (symptoms, airflow limitation and exacerbations). METHODS: Here, we go one step further and propose that in the near future physicians will need a 'control panel' for the assessment and optimal management of individual patients with complex diseases, including COPD, that provides a path towards personalised medicine. RESULTS: We propose that such a 'COPD control panel' should include at least three different domains of the disease: severity, activity and impact. Each of these domains presents information on different 'elements' of the disease with potential prognostic value and/or with specific therapeutic requirements. All this information can be easily incorporated into an 'app' for daily use in clinical practice. CONCLUSION: We recognise that this preliminary proposal needs debate, validation and evolution (eg, including 'omics' and molecular imaging information in the future), but we hope that it may stimulate debate and research in the field.
  Thorax 04/2013; 68(4):389-90. · 6.84 Impact Factor
• Article: Cardiovascular Disease in COPD: Mechanisms.

  John D Maclay, William Macnee
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  ABSTRACT: It is now well established that cardiovascular disease contributes significantly to both morbidity and mortality in COPD. Shared risk factors for cardiovascular disease and COPD, such as smoking, low socioeconomic class, and a sedentary lifestyle contribute to the natural history of each of these conditions. However, it is now apparent that alternative, novel mechanisms are involved in the pathogenesis of cardiovascular disease, and these may play an important role in driving the increased cardiovascular risk associated with COPD. In this article, we discuss the potential mechanisms that link COPD to an increased risk of cardiovascular disease.
  Chest 03/2013; 143(3):798-807. · 5.25 Impact Factor
• Article: Surface functionalization affects the zeta potential, coronal stability and membranolytic activity of polymeric nanoparticles.

  Frank Thielbeer, Ken Donaldson, Mark Bradley, Emma M V Johansson, Wan-Seob Cho, Rodger Duffin, Ian L Megson, William Macnee
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  ABSTRACT: Abstract Nano materials are commonly functionalized to boost their physicochemical properties. However, there is little known about the impact of these modifications on cellular systems. Herein, we synthesized 8 types of polymeric nanoparticles bearing different functional groups, and investigated their effects on interactions with cellular membranes. As models for particle- membrane interactions, hemolysis assays using human red blood cells and culture with A549 cells were utilized. Under protein-free conditions, the nanoparticles showed a wide distribution of zeta potentials which showed a good correlation with their hemolytic potential. However, in the presence of serum or lung lining fluid, the zeta potentials of all nanoparticles coalesced towards a single common negative value and showed neither hemolytic activity nor cytotoxicity to A549 cells. Lipase and protease treatment of the coronated particles did not restore their reactivity. These results imply that particle functionalization influences the stability of the particle corona which, if intact, prevents hemolytic activity and membrane disrupture.
  Nanotoxicology 02/2013; · 5.76 Impact Factor
• Article: Chronic obstructive pulmonary disease and cardiovascular diseases: a "vulnerable" relationship.

  Don D Sin, William Macnee
  American Journal of Respiratory and Critical Care Medicine 01/2013; 187(1):2-4. · 11.08 Impact Factor
• Article: Six Minute Walk Test in COPD: Minimal Clinically Important Difference for Death or Hospitalization.

  Michael I Polkey, Martijn A Spruit, Lisa D Edwards, Michael L Watkins, Victor Pinto-Plata, Jørgen Vestbo, Peter M A Calverley, Ruth Tal-Singer, Alvar Agusti, Per S Bakke, Harvey O Coxson, David A Lomas, William Macnee, Stephen Rennard, Edwin K Silverman, Bruce E Miller, Courtney Crim, Julie Yates, Emiel F M Wouters, Bartolome Celli
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  ABSTRACT: Abstract Rationale & OBJECTIVES: Outcomes other than spirometry are required to assess non-bronchodilator therapies for chronic obstructive pulmonary disease. Estimates of the minimal clinically important difference for the six minute walk distance have been derived from narrow cohorts using non-blinded intervention. METHODS: Data from the ECLIPSE cohort were used (N=2112). Death or first hospitalization were index events; we measured change in six minute walk distance in the 12 month period before the event and also related change in six minute walk distance to lung function and St Georges Respiratory Questionnaire (health status). Measurement and MAIN RESULTS: Of subjects with change in the six minute walk distance data, 94 died and 323 were hospitalized. Six minute walk distance fell by 29.7 (SD=82.9)m more in those who died than survivors (P <0.001). A change in distance of more than -30m conferred a hazard ratio of 1.93 (95% confidence interval: 1.29, 2.90; P = 0.001) for death. No significant difference was observed for first hospitalization. Weak relationships only were observed with change in lung function or health status. CONCLUSIONS: A fall in the six minute walk distance of 30m or more is associated with increased risk of death but not hospitalization due to exacerbation in patients with chronic obstructive pulmonary disease and represents a clinically significant minimally important difference.
  American Journal of Respiratory and Critical Care Medicine 12/2012; · 11.08 Impact Factor
• Article: A Guide to Guidelines for Professional Societies and Other Developers of Recommendations: Introduction to Integrating and Coordinating Efforts in COPD Guideline Development. An Official ATS/ERS Workshop Report.

  Holger J Schünemann, Mark Woodhead, Antonio Anzueto, A Sonia Buist, William Macnee, Klaus F Rabe, John Heffner
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  ABSTRACT: Organizations around the world are recognizing that guidelines should be based on the best available evidence, that the development of recommendations needs to be transparent, and that appropriate processes should be followed. In June 2007, we convened an American Thoracic Society (ATS)/European Respiratory Society (ERS)-sponsored workshop with over 60 representatives from 36 international organizations to provide advice to guideline developers about the required steps and processes for guideline development using the management of chronic obstructive pulmonary disease (COPD) as an example. Following the workshop, participants completed a series of 14 review articles that underwent peer review and incorporated key new literature until June 2011 for most articles in this series. The review articles evaluate the guideline cycle including: priority setting, question formulation, managing conflict of interest, defining appropriate outcomes, stakeholder involvement, grading the quality of evidence and strength of recommendations, integration of values and preferences, considering resource use, reporting of guidelines, implementation, and adaptation. In this Introduction we frame the background and methods of these reviews and provide the key conclusions of the workshop. A summary of the workshop's conclusions and recommendations was published in The Lancet. Given the enormous resources that are spent on research and the importance of providing the best guidance to healthcare decision makers, attributing appropriate funds to research syntheses and transparent, independent guidance for the development of evidence-based guidelines is justified. Furthermore, given the immense amount of work that is required, individuals and organizations need to collaborate to achieve the best possible and cost-effective coordination of these efforts.
  Proceedings of the American Thoracic Society 12/2012; 9(5):215-218.
• Article: Deciding What Type of Evidence and Outcomes to Include in Guidelines: Article 5 in Integrating and Coordinating Efforts in COPD Guideline Development. An Official ATS/ERS Workshop Report.

  Timothy J Wilt, Gordon Guyatt, Regina Kunz, William Macnee, Milo A Puhan, Giovanni Viegi, Mark Woodhead, Elie A Akl, Holger J Schünemann
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  ABSTRACT: Introduction: Professional societies, like many other organizations around the world, have recognized the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the fifth of a series of 14 articles that were prepared by an international panel to advise guideline developers in respiratory and other diseases on approaches for guideline development. This article focuses on what type of evidence and outcomes to include in guidelines. Methods: In this review we addressed the following topics and questions. (1) What methods should be used to select important outcomes? (2) What types of outcomes should be considered? (3) What sources of evidence should be considered? (4) How should the importance of outcomes be ranked? (5) How to deal with surrogate outcomes. (6) What issues related to outcomes should be considered in the evidence review? (7) What quality of evidence should be used? (8) How to interpret the effect on outcomes. (9) How to incorporate outcomes related to harm. We based our responses on a PubMed literature review, prior reviews, relevant methodological research, and workshop discussions. Results and Discussion: Guideline panels should use transparent and systematic methods to select both the evidence and important outcomes, with input from groups that represent a wide range of expertise and constituencies. Outcomes should address both benefits and downsides, with consideration of the definitions, severity, and time course of the outcomes. Guideline panels should use a transparent approach to rank outcome importance recognizing that stakeholder and patient values and preferences may vary. Intermediate and surrogate outcomes are frequently reported, but their correlation with patient important outcomes may be low. A guideline panel should determine a priori the magnitude of effect judged clinically significant, factors that may influence outcome reporting, and whether different ways of measuring the outcomes permit the outcomes to be combined. Comprehensive identification of the evidence includes the use of multiple data sources. While randomized controlled trials (RCTs) provide the highest quality evidence, reviewers of evidence also need to consider nonrandomized studies such as case series, registries, and case-control studies if randomized trials are not available. This is particularly true for harms. The outcomes reported from RCTs may not always directly apply to clinical practice settings (i.e., they may not be generalizable).
  Proceedings of the American Thoracic Society 12/2012; 9(5):243-250.
• Article: Genome-wide Association Analysis of Blood Biomarkers in COPD.

  Deog Kyeom Kim, Michael H Cho, Craig P Hersh, David A Lomas, Bruce E Miller, Xiangyang Kong, Per Bakke, Amund Gulsvik, Alvar Agusti, Emiel Wouters, [......], William Macnee, Julie C Yates, Stephen Rennard, Augusto Litonjua, Weiliang Qiu, Terri H Beaty, James D Crapo, John H Riley, Ruth Tal-Singer, Edwin K Silverman
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  ABSTRACT: RATIONALE: A genome-wide association study (GWAS) for circulating COPD biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility. OBJECTIVES: To identify genetic variants of circulating protein biomarkers and novel genetic determinants of COPD. METHODS: GWAS was performed for two pneumoproteins, Clara cell secretory protein (CC16) and surfactant protein D (SP-D), and five systemic inflammatory markers (C-reactive protein, fibrinogen, interleukin-6, interleukin-8, and tumor necrosis factor-α) in 1951 COPD subjects. For genome-wide significant SNPs (p < 1 x10-8), association with COPD susceptibility was tested in 2939 COPD cases and 1380 smoking controls. The association of candidate SNPs with mRNA expression in induced sputum was also elucidated. MAIN RESULTS: Genome-wide significant susceptibility loci affecting biomarker levels were found only for the two pneumoproteins. Two discrete loci affecting CC16, one region near the CC16 coding gene (SCGB1A1) on chromosome 11 and another locus ~25 Mb away from SCGB1A1 were identified, whereas multiple SNPs on chromosomes 6 and 16, in addition to SNPs near SFTPD, had genome-wide significant associations with SP-D levels. Several SNPs affecting circulating CC16 levels were significantly associated with sputum mRNA expression of SCGB1A1 (p values 0.009-0.03). Several SNPs highly associated with CC16 or SP-D levels were nominally associated with COPD in a collaborative GWAS (p values 0.001-0.049), although these COPD associations were not replicated in two additional cohorts. CONCLUSION: Distant genetic loci as well as biomarker-coding genes affect circulating levels of COPD-related pneumoproteins. A subset of these protein quantitative trait loci may influence their gene expression in the lung and/or COPD susceptibility.
  American Journal of Respiratory and Critical Care Medicine 11/2012; · 11.08 Impact Factor
• Article: Targeted metabolomics identifies perturbations in amino acid metabolism that sub-classify patients with COPD.

  Baljit K Ubhi, Kian Kai Cheng, Jiyang Dong, Tobias Janowitz, Duncan Jodrell, Ruth Tal-Singer, William Macnee, David A Lomas, John H Riley, Julian L Griffin, Susan C Connor
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  ABSTRACT: Background: COPD, a leading cause of mortality is currently assessed by spirometry (forced expiratory volume in 1 second, FEV(1)). However FEV(1) does not correlate with patient mortality. ECLIPSE (Evaluation of Chronic obstructive pulmonary disease to Longitudinally Identify Predictive Surrogate Endpoints) aims to identify biomarkers that correlate with clinically relevant COPD subtypes, and to assess how these may predict disease progression. New methods were developed and validated to evaluate small molecules as potential diagnostic tools in patients with COPD, COPD related cachexia and cancer related cachexia. Methods and findings: quantitative LC-MS/MS was developed to measure 34 amino acids and dipeptides for stratification of patient groups. Subsets of the ECLIPSE patients were used to assess biomarkers of lung obstruction; GOLD IV (n = 30) versus control (n = 30); emphysema (n = 38) versus airways disease (n = 21) and cachexia (n = 30) versus normal body mass index (n = 30). Serum from cachexic (n = 7) and non-cachexic (n = 5) pancreatic cancer patients were included as controls. Targeted LC-MS/MS distinguished GOLD IV patients from controls, patients with and without emphysema and patients with and without cachexia. Glutamine, aspartate and arginine were significantly increased (p < 0.05; FDR adjustment α < 0.1) in cachexia, emphysema and GOLD IV patients and aminoadipate was decreased. Several amino acid concentrations were significantly altered in patients with COPD but not patients with pancreatic cancer (serine, sarcosine, tryptophan, BCAAs and 3-methylhistdine). Increased γ-aminobutyrate (GABA, p < 0.01) levels were specific to cachexia in patients with pancreatic cancer. β-aminoisobutyrate, 1-methylhistidine and asparagine (p < 0.05) were common across the patients with cachexia from both the COPD and pancreatic cancer cohorts. Conclusion: these results demonstrate that a metabolomic fingerprint has potential to stratify patients for the treatment of COPD and may provide a means of assessing response to therapy. GOLD IV patients were distinguished from smoker control subjects, patients with emphysema were distinguished from those without emphysema and COPD patients displaying cachexia were distinguished from those not displaying cachexia. General markers of cachexia were discovered reflecting both COPD- and pancreatic cancer-related cachexia (increased glutamine, aspartate, arginine, and asparagine and decreased aminoadipate, β-aminoisobutyrate and 1-methylhistidine). Metabolomic biomarkers, particularly altered levels of GABA, could be exploited as a way of monitoring treatment efficacy and tumour recurrence for patients with pancreatic cancer experiencing cachexia.
  Molecular BioSystems 10/2012; · 3.53 Impact Factor
• Article: Neuromuscular electrical stimulation prevents muscle function deterioration in exacerbated COPD: a pilot study.

  Santiago Giavedoni, Andrew Deans, Paul McCaughey, Ellen Drost, William MacNee, Roberto A Rabinovich
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  ABSTRACT: COPD is a condition with systemic effects of which peripheral muscle dysfunction is a prominent contributor to exercise limitation, health related quality of life (HRQoL) impairment, and is an independent predictor of morbidity and mortality. Pulmonary rehabilitation (PR) is a successful strategy to improve exercise tolerance and HRQoL through the improvement of muscle function in patients with stable COPD or early after severe exacerbations of COPD (SECOPD). However, muscle function further deteriorates during SECOPD before early PR programmes commence. We aimed to investigate the feasibility and efficacy of quadriceps neuromuscular electrical stimulation (NMES) applied during a SECOPD to prevent muscle function deterioration. We have conducted a pilot study in eleven COPD patients (FEV(1) 41.3 ± 5.6 % pred) admitted to hospital with a SECOPD. We randomly allocated one leg to receive NMES (once a day for 14 days) with the other leg as a control (non-stimulated leg). We measured the change in quadriceps maximal voluntary contraction (ΔQMVC) as the main outcome. Mean quadriceps muscle strength decreased in control legs (ΔQMVC -2.9 ± 5.3 N, p = ns) but increased in the stimulated legs (ΔQMVC 19.2 ± 6.1 N, p < 0.01). The difference in ΔQMVC between groups was statistically significant (p < 0.05). The effect of NMES was directly related to the stimulation intensity (∑mA) applied throughout the 14 sessions (r = 0.76, p < 0.01). All patients tolerated NMES without any side effects. NMES is a feasible and effective treatment to prevent quadriceps muscle strength derangement during severe exacerbations of COPD and may be used to compliment early post-exacerbation pulmonary rehabilitation.
  Respiratory medicine 06/2012; 106(10):1429-34. · 2.33 Impact Factor
• Article: Bronchodilator responsiveness as a phenotypic characteristic of established chronic obstructive pulmonary disease.

  Paul Albert, Alvar Agusti, Lisa Edwards, Ruth Tal-Singer, Julie Yates, Per Bakke, Bartolome R Celli, Harvey O Coxson, Courtney Crim, David A Lomas, William Macnee, Bruce Miller, Stephen Rennard, Edwin K Silverman, Jørgen Vestbo, Emiel Wouters, Peter Calverley
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  ABSTRACT: Bronchodilator responsiveness is a potential phenotypic characteristic of chronic obstructive pulmonary disease (COPD). We studied whether change in lung function after a bronchodilator is abnormal in COPD, whether stable responder subgroups can be identified, and whether these subgroups experience different clinical outcomes. 1831 patients with COPD, 285 smoking (SC) and 228 non-smoking (NSC) controls from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort. Spirometric reversibility to 400 μg inhaled salbutamol was assessed on four occasions over 1 year. Forced expiratory volume in 1 s (FEV(1)) increase after salbutamol was similar in SC (mean 0.14 litres (SD 0.15)) and COPD (0.12 litres (0.15)) and was significantly greater than NSC (0.08 litres (0.14)). Reversibility status varied with repeated testing in parallel with the day-to-day variation in pre-bronchodilator FEV(1), which was similar in control subjects and patients with COPD. Absolute FEV(1) change decreased by Global initiative for chronic Obstructive Lung Disease (GOLD) stage in patients with COPD (GOLD II, mean 0.16 litres (SD 0.17); III, 0.10 litres (0.13); IV, 0.05 litres (0.08) as did chances of being classified as reversible. CT-defined emphysema was weakly related to the absolute change in FEV(1) post salbutamol. Consistently reversible patients (n=227) did not differ in mortality, hospitalisation or exacerbation experience from irreversible patients when allowing for differences in baseline FEV(1). Reversibility only assessed with salbutamol and defined by FEV(1) criteria. The COPD population was older than the control populations. Post-salbutamol FEV(1) change is similar in patients with COPD and smoking controls but is influenced by baseline lung function and the presence of emphysema. Bronchodilator reversibility status varies temporally and does not distinguish clinically relevant outcomes, making it an unreliable phenotype.
  Thorax 06/2012; 67(8):701-8. · 6.84 Impact Factor
• Article: The threshold length for fiber-induced acute pleural inflammation: shedding light on the early events in asbestos-induced mesothelioma.

  Anja Schinwald, Fiona A Murphy, Adriele Prina-Mello, Craig A Poland, Fiona Byrne, Dania Movia, James R Glass, Janet C Dickerson, David A Schultz, Chris E Jeffree, William Macnee, Ken Donaldson
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  ABSTRACT: Suspicion has been raised that high aspect ratio nanoparticles or nanofibers might possess asbestos-like pathogenicity. The pleural space is a specific target for disease in individuals exposed to asbestos and by implication of nanofibers. Pleural effects of fibers depends on fiber length, but the key threshold length beyond which adverse effects occur has never been identified till now because all asbestos and vitreous fiber samples are heterogeneously distributed in their length. Nanotechnology advantageously allows for highly defined length distribution of synthetically engineered fibers that enable for in-depth investigation of this threshold length. We utilized the ability to prepare silver nanofibers of five defined length classes to demonstrate a threshold fiber length for acute pleural inflammation. Nickel nanofibers and carbon nanotubes were then used to strengthen the relationship between fiber length and pleural inflammation. A method of intrapleural injection of nanofibers in female C57Bl/6 strain mice was used to deliver the fiber dose, and we then assessed the acute pleural inflammatory response. Chest wall sections were examined by light and scanning electron microscopy to identify areas of lesion; furthermore, cell-nanowires interaction on the mesothelial surface of the parietal pleura in vivo was investigated. Our results showed a clear threshold effect, demonstrating that fibers beyond 4 µm in length are pathogenic to the pleura. The identification of the threshold length for nanofiber-induced pathogenicity in the pleura has important implications for understanding the structure-toxicity relationship for asbestos-induced mesothelioma and consequent risk assessment with the aim to contribute to the engineering of synthetic nanofibers by the adoption of a benign-by-design approach.
  Toxicological Sciences 05/2012; 128(2):461-70. · 4.65 Impact Factor
• Article: Abnormal lung aging in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.

  Rosa Faner, Mauricio Rojas, William Macnee, Alvar Agustí
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  ABSTRACT: Aging is a natural process characterized by progressive functional impairment and reduced capacity to respond appropriately to environmental stimuli and injury. The incidence of two common chronic respiratory diseases (chronic obstructive pulmonary disease [COPD] and idiopathic pulmonary fibrosis [IPF]) increases with advanced age. It is plausible, therefore, that abnormal regulation of the mechanisms of normal aging may contribute to the pathobiology of both COPD and IPF. This review discusses the available evidence supporting a number of aging mechanisms, including oxidative stress, telomere length regulation, cellular and immunosenescence, as well as changes in a number of antiaging molecules and the extracellular matrix, which are abnormal in COPD and/or IPF. A better understanding of these abnormalities may help in the design of novel and better therapeutic interventions for these patients.
  American Journal of Respiratory and Critical Care Medicine 05/2012; 186(4):306-13. · 11.08 Impact Factor
• Source

  Available from: Grant Mair

  Article: Emphysema distribution assessed using CT: A clinical review

  Grant Mair, William MacNee
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  ABSTRACT: Computed tomography (CT) thoracic imaging provides accurate assessment of both the extent and distribution of emphysema. These measurements have been used to describe chronic obstructive pulmonary disease (COPD) phenotypes and have been related to clinical outcomes in COPD.
  The Annals of Respiratory Medicine. 03/2012;
• Article: Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease.

  Bartolome R Celli, Nicholas Locantore, Julie Yates, Ruth Tal-Singer, Bruce E Miller, Per Bakke, Peter Calverley, Harvey Coxson, Courtney Crim, Lisa D Edwards, David A Lomas, Annelyse Duvoix, William MacNee, Stephen Rennard, Edwin Silverman, Jørgen Vestbo, Emiel Wouters, Alvar Agustí
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  ABSTRACT: Accurate prediction of mortality helps select patients for interventions aimed at improving outcome. Because chronic obstructive pulmonary disease is characterized by low-grade systemic inflammation, we hypothesized that addition of inflammatory biomarkers to established predictive factors will improve accuracy. A total of 1,843 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study were followed for 3 years. Kaplan-Meier curves, log-rank analysis, and Cox proportional hazards analyses determined the predictive value for mortality of clinical variables, while C statistics assessed the added discriminative power offered by addition of biomarkers. At recruitment we measured anthropometrics, spirometry, 6-minute walk distance, dyspnea, BODE index, history of hospitalization, comorbidities, and computed tomography scan emphysema. White blood cell and neutrophil counts, serum or plasma levels of fibrinogen, chemokine ligand 18, surfactant protein D, C-reactive protein, Clara cell secretory protein-16, IL-6 and -8, and tumor necrosis factor-α were determined at recruitment and subsequent visits. A total of 168 of the 1,843 patients (9.1%) died. Nonsurvivors were older and had more severe airflow limitation, increased dyspnea, higher BODE score, more emphysema, and higher rates of comorbidities and history of hospitalizations. The best predictive model for mortality using clinical variables included age, BODE, and hospitalization history (C statistic of 0.686; P < 0.001). One single biomarker (IL-6) significantly improved the C statistic to 0.708, but this was further improved to 0.726 (P = 0.003) by the addition of all biomarkers. The addition of a panel of selected biomarkers improves the ability of established clinical variables to predict mortality in chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT00292552).
  American Journal of Respiratory and Critical Care Medicine 03/2012; 185(10):1065-72. · 11.08 Impact Factor
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  Available from: Edwin van Beek

  Article: Systemic elastin degradation in chronic obstructive pulmonary disease.

  John D Maclay, David A McAllister, Roberto Rabinovich, Imran Haq, Scott Maxwell, Stephen Hartland, Martin Connell, John T Murchison, Edwin J R van Beek, Robert D Gray, Nicholas L Mills, William Macnee
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  ABSTRACT: Development of emphysema and vascular stiffness in chronic obstructive pulmonary disease (COPD) may be due to a common mechanism of susceptibility to pulmonary and systemic elastin degradation. To investigate whether patients with COPD have evidence of systemic elastin degradation in the skin. The authors measured cutaneous elastin degradation using immunohistochemistry (percentage area of elastin fibres) in sun-exposed (exposed) and non-sun-exposed (non-exposed) skin biopsies in 16 men with COPD and 15 controls matched for age and cigarette smoke exposure. Quantitative PCR of matrix metalloproteinase (MMP)-2, -9, -12 and tissue inhibitor of metalloproteinase-1 mRNA and zymography for protein expression of MMP-2 and -9 were performed on homogenised skin. Arterial stiffness and emphysema severity were measured using carotid-femoral pulse wave velocity and quantitative CT scanning. Skin elastin degradation was greater in exposed and non-exposed skin of patients with COPD compared with controls (exposed, mean (SD); 43.5 (12.1)% vs 26.3 (6.9)%, p<0.001; non-exposed 22.4 (5.2)% vs 18.1 (4.3)%, p=0.02). Cutaneous expression of MMP-9 mRNA and proMMP-9 concentrations was increased in exposed skin of COPD patients (p=0.004 and p=0.02, respectively) and was also associated with increased skin elastin degradation (r=0.62, p<0.001 and r=0.47, p=0.01, respectively). In the entire cohort of ex-smokers, cutaneous elastin degradation was associated with emphysema severity, FEV(1) and pulse wave velocity. Patients with COPD have increased skin elastin degradation compared with controls, which is related to emphysema severity and arterial stiffness. Systemic elastin degradation due to increased proteolytic activity may represent a novel shared mechanism for the pulmonary, vascular and cutaneous features of COPD.
  Thorax 02/2012; 67(7):606-12. · 6.84 Impact Factor
• Article: Antioxidant pharmacological therapies for COPD.

  Irfan Rahman, William MacNee
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  ABSTRACT: Increased oxidative stress occurs in the lungs and systemically in COPD, which plays a role in many of the pathogenic mechanisms in COPD. Hence, targeting local lung and systemic oxidative stress with agents that modulate the antioxidants/redox system or boost endogenous antioxidants would be a useful therapeutic approach in COPD. Thiol antioxidants (N-acetyl-l-cysteine [NAC] and N-acystelyn, carbocysteine, erdosteine, and fudosteine) have been used to increase lung thiol content. Modulation of cigarette smoke (CS) induced oxidative stress and its consequent cellular changes have also been reported to be effected by synthetic molecules, such as spin traps (α-phenyl-N-tert-butyl nitrone), catalytic antioxidants (superoxide dismutase [ECSOD] mimetics), porphyrins, and lipid peroxidation and protein carbonylation blockers/inhibitors (edaravone and lazaroids/tirilazad). Preclinical and clinical trials have shown that these antioxidants can reduce oxidative stress, affect redox and glutathione biosynthesis genes, and proinflammatory gene expression. In this review the approaches to enhance lung antioxidants in COPD and the potential beneficial effects of antioxidant therapy on the course of the disease are discussed.
  Current Opinion in Pharmacology 02/2012; 12(3):256-65. · 6.86 Impact Factor
• Article: Zeta potential and solubility to toxic ions as mechanisms of lung inflammation caused by metal/metal oxide nanoparticles.

  Wan-Seob Cho, Rodger Duffin, Frank Thielbeer, Mark Bradley, Ian L Megson, William Macnee, Craig A Poland, C Lang Tran, Ken Donaldson
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  ABSTRACT: The toxicology of nanoparticles (NPs) is an area of intense investigation that would be greatly aided by improved understanding of the relationship between NP structure and inflammogenicity. To evaluate how their physicochemical parameters influence toxicity, we assembled a panel of 15 metal/metal oxide NPs and attempted to relate various physicochemical parameters, including zeta potential (ζP) and solubility, to lung inflammogenicity. The acute pulmonary inflammogenicity of the 15 NPs showed a significant correlation with one of two structural parameters-ζP under acid conditions for low-solubility NPs and solubility to toxic species for high-solubility NPs. ζP is the electrical potential created between the surface of a particle, with its associated ions, and the medium it exists in and provides information concerning the particle surface charge. We suggest that inside the phagolysosome under acid conditions, a high positive ζP may allow NPs to damage the integrity of the phagolysosomal membrane leading to inflammation. In the case of high-solubility NPs, inflammogenicity depends on the ions that are produced during dissolution of NP inside the acidic phagolysosomes; if the ions are toxic, then phagolysosomes will be destabilized and cause inflammation. These two parameters may have utility in preliminary assessment of the potential lung inflammation hazard of the large number of NPs that require testing.
  Toxicological Sciences 01/2012; 126(2):469-77. · 4.65 Impact Factor
• Source

  Available from: Ruth Tal-Singer

  Article: Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype.

  Alvar Agustí, Lisa D Edwards, Stephen I Rennard, William MacNee, Ruth Tal-Singer, Bruce E Miller, Jørgen Vestbo, David A Lomas, Peter M A Calverley, Emiel Wouters, Courtney Crim, Julie C Yates, Edwin K Silverman, Harvey O Coxson, Per Bakke, Ruth J Mayer, Bartolome Celli
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  ABSTRACT: Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies. To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552). Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-α levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years. We found that, at baseline, 30% of COPD patients did not show evidence of systemic inflammation whereas 16% had persistent systemic inflammation. Even though pulmonary abnormalities were similar in these two groups, persistently inflamed patients during follow-up had significantly increased all-cause mortality (13% vs. 2%, p<0.001) and exacerbation frequency (1.5 (1.5) vs. 0.9 (1.1) per year, p<0.001) compared to non-inflamed ones. As a descriptive study our results show associations but do not prove causality. Besides this, the inflammatory response is complex and we studied only a limited panel of biomarkers, albeit they are those investigated by the majority of previous studies and are often and easily measured in clinical practice. Overall, these results identify a novel systemic inflammatory COPD phenotype that may be the target of specific research and treatment.
  PLoS ONE 01/2012; 7(5):e37483. · 4.09 Impact Factor
• Article: Graphene-based nanoplatelets: a new risk to the respiratory system as a consequence of their unusual aerodynamic properties.

  Anja Schinwald, Fiona A Murphy, Alan Jones, William MacNee, Ken Donaldson
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  ABSTRACT: Graphene is a new nanomaterial with unusual and useful physical and chemical properties. However, in the form of nanoplatelets this new, emerging material could pose unusual risks to the respiratory system after inhalation exposure. The graphene-based nanoplatelets used in this study are commercially available and consist of several sheets of graphene (few-layer graphene). We first derived the respirability of graphene nanoplatelets (GP) from the basic principles of the aerodynamic behavior of plate-shaped particles which allowed us to calculate their aerodynamic diameter. This showed that the nanoplatelets, which were up to 25 μm in diameter, were respirable and so would deposit beyond the ciliated airways following inhalation. We therefore utilized models of pharyngeal aspiration and direct intrapleural installation of GP, as well as an in vitro model, to assess their inflammatory potential. These large but respirable GP were inflammogenic in both the lung and the pleural space. MIP-1α, MCP-1, MIP-2, IL-8, and IL-1β expression in the BAL, the pleural lavage, and cell culture supernatant from THP-1 macrophages were increased with GP exposure compared to controls but not with nanoparticulate carbon black (CB). In vitro, macrophages exposed to GP showed expression of IL-1β. This study highlights the importance of nanoplatelet form as a driver for in vivo and in vitro inflammogenicity by virtue of their respirable aerodynamic diameter, despite a considerable 2-dimensional size which leads to frustrated phagocytosis when they deposit in the distal lungs and macrophages attempt to phagocytose them. Our data suggest that nanoplatelets pose a novel nanohazard and structure-toxicity relationship in nanoparticle toxicology.
  ACS Nano 12/2011; 6(1):736-46. · 10.77 Impact Factor