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1.  Biological clustering supports both “Dutch” and “British” hypotheses of asthma and chronic obstructive pulmonary disease 
Background
Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases.
Objective
We sought to determine, in terms of their sputum cellular and mediator profiles, the extent to which they represent distinct or overlapping conditions supporting either the “British” or “Dutch” hypotheses of airway disease pathogenesis.
Methods
We compared the clinical and physiological characteristics and sputum mediators between 86 subjects with severe asthma and 75 with moderate-to-severe COPD. Biological subgroups were determined using factor and cluster analyses on 18 sputum cytokines. The subgroups were validated on independent severe asthma (n = 166) and COPD (n = 58) cohorts. Two techniques were used to assign the validation subjects to subgroups: linear discriminant analysis, or the best identified discriminator (single cytokine) in combination with subject disease status (asthma or COPD).
Results
Discriminant analysis distinguished severe asthma from COPD completely using a combination of clinical and biological variables. Factor and cluster analyses of the sputum cytokine profiles revealed 3 biological clusters: cluster 1: asthma predominant, eosinophilic, high TH2 cytokines; cluster 2: asthma and COPD overlap, neutrophilic; cluster 3: COPD predominant, mixed eosinophilic and neutrophilic. Validation subjects were classified into 3 subgroups using discriminant analysis, or disease status with a binary assessment of sputum IL-1β expression. Sputum cellular and cytokine profiles of the validation subgroups were similar to the subgroups from the test study.
Conclusions
Sputum cytokine profiling can determine distinct and overlapping groups of subjects with asthma and COPD, supporting both the British and Dutch hypotheses. These findings may contribute to improved patient classification to enable stratified medicine.
doi:10.1016/j.jaci.2014.06.035
PMCID: PMC4282726  PMID: 25129678
Asthma and COPD overlap; cytokines; factor and cluster analyses; COPD, Chronic obstructive pulmonary disease; ROC, Receiver operating characteristic; ROC AUC, Area under the receiver operating characteristic curve
2.  Computational modeling of the obstructive lung diseases asthma and COPD 
Journal of Translational Medicine  2014;12(Suppl 2):S5.
Asthma and chronic obstructive pulmonary disease (COPD) are characterized by airway obstruction and airflow limitation and pose a huge burden to society. These obstructive lung diseases impact the lung physiology across multiple biological scales. Environmental stimuli are introduced via inhalation at the organ scale, and consequently impact upon the tissue, cellular and sub-cellular scale by triggering signaling pathways. These changes are propagated upwards to the organ level again and vice versa. In order to understand the pathophysiology behind these diseases we need to integrate and understand changes occurring across these scales and this is the driving force for multiscale computational modeling.
There is an urgent need for improved diagnosis and assessment of obstructive lung diseases. Standard clinical measures are based on global function tests which ignore the highly heterogeneous regional changes that are characteristic of obstructive lung disease pathophysiology. Advances in scanning technology such as hyperpolarized gas MRI has led to new regional measurements of ventilation, perfusion and gas diffusion in the lungs, while new image processing techniques allow these measures to be combined with information from structural imaging such as Computed Tomography (CT). However, it is not yet known how to derive clinical measures for obstructive diseases from this wealth of new data. Computational modeling offers a powerful approach for investigating this relationship between imaging measurements and disease severity, and understanding the effects of different disease subtypes, which is key to developing improved diagnostic methods.
Gaining an understanding of a system as complex as the respiratory system is difficult if not impossible via experimental methods alone. Computational models offer a complementary method to unravel the structure-function relationships occurring within a multiscale, multiphysics system such as this. Here we review the current state-of-the-art in techniques developed for pulmonary image analysis, development of structural models of the respiratory system and predictions of function within these models. We discuss application of modeling techniques to obstructive lung diseases, namely asthma and emphysema and the use of models to predict response to therapy. Finally we introduce a large European project, AirPROM that is developing multiscale models to investigate structure-function relationships in asthma and COPD.
doi:10.1186/1479-5876-12-S2-S5
PMCID: PMC4255909  PMID: 25471125
3.  Statistical Cluster Analysis of the British Thoracic Society Severe Refractory Asthma Registry: Clinical Outcomes and Phenotype Stability 
PLoS ONE  2014;9(7):e102987.
Background
Severe refractory asthma is a heterogeneous disease. We sought to determine statistical clusters from the British Thoracic Society Severe refractory Asthma Registry and to examine cluster-specific outcomes and stability.
Methods
Factor analysis and statistical cluster modelling was undertaken to determine the number of clusters and their membership (N = 349). Cluster-specific outcomes were assessed after a median follow-up of 3 years. A classifier was programmed to determine cluster stability and was validated in an independent cohort of new patients recruited to the registry (n = 245).
Findings
Five clusters were identified. Cluster 1 (34%) were atopic with early onset disease, cluster 2 (21%) were obese with late onset disease, cluster 3 (15%) had the least severe disease, cluster 4 (15%) were the eosinophilic with late onset disease and cluster 5 (15%) had significant fixed airflow obstruction. At follow-up, the proportion of subjects treated with oral corticosteroids increased in all groups with an increase in body mass index. Exacerbation frequency decreased significantly in clusters 1, 2 and 4 and was associated with a significant fall in the peripheral blood eosinophil count in clusters 2 and 4. Stability of cluster membership at follow-up was 52% for the whole group with stability being best in cluster 2 (71%) and worst in cluster 4 (25%). In an independent validation cohort, the classifier identified the same 5 clusters with similar patient distribution and characteristics.
Interpretation
Statistical cluster analysis can identify distinct phenotypes with specific outcomes. Cluster membership can be determined using a classifier, but when treatment is optimised, cluster stability is poor.
doi:10.1371/journal.pone.0102987
PMCID: PMC4109965  PMID: 25058007
4.  Elevated Sputum Interleukin-5 and Submucosal Eosinophilia in Obese Individuals with Severe Asthma 
Rationale: The relationship between airway inflammation and obesity in severe asthma is poorly understood.
Objectives: We sought to determine the relationship between sputum mediator profiles and the distribution of eosinophilic inflammation and obesity in people with severe asthma.
Methods: Clinical parameters and eight mediators in sputum were assessed in 131 subjects with severe asthma from a single center categorized into lean, overweight, and obese groups defined by their body mass index. In an independent group of people with severe asthma (n = 45) and healthy control subjects (n = 19) eosinophilic inflammation was enumerated in bronchial submucosa, blood, and sputum and related to their body mass index.
Measurements and Main Results: Sputum IL-5 geometric mean (95% confidence interval) (pg/ml) was elevated in the obese (1.8 [1.2–2.6]) compared with overweight (1.1 [0.8–1.3]; P = 0.025) and lean (0.9 [0.6–1.2]; P = 0.018) subjects with asthma and was correlated with body mass index (r = 0.29; P < 0.001). There was no relationship among body mass index, the sputum cell count, or other sputum mediators. In the bronchoscopy group the submucosal eosinophil number in the subjects with asthma was correlated with body mass index (Spearman rank correlation, rs = 0.38; P = 0.013) and the median (interquartile range) number of submucosal eosinophils was increased in obese (19.4 [11.8–31.2]) (cells per square millimeter) versus lean subjects (8.2 [5.4–14.6]) (P = 0.006). There was no significant association between sputum or peripheral blood eosinophil counts and body mass index.
Conclusions: Sputum IL-5 and submucosal eosinophils, but not sputum eosinophils, are elevated in obese people with severe asthma. Whether specific antieosinophilic therapy is beneficial, or improved diet and lifestyle in obese asthma has antiinflammatory effects beyond weight reduction, requires further study.
doi:10.1164/rccm.201208-1470OC
PMCID: PMC3826183  PMID: 23590263
asthma; obesity; cytokines; phenotypes; eosinophil
5.  Increased Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Expression Mediates Intrinsic Airway Smooth Muscle Hypercontractility in Asthma 
Rationale: Asthma is characterized by disordered airway physiology as a consequence of increased airway smooth muscle contractility. The underlying cause of this hypercontractility is poorly understood.
Objectives: We sought to investigate whether the burden of oxidative stress in airway smooth muscle in asthma is heightened and mediated by an intrinsic abnormality promoting hypercontractility.
Methods: We examined the oxidative stress burden of airway smooth muscle in bronchial biopsies and primary cells from subjects with asthma and healthy controls. We determined the expression of targets implicated in the control of oxidative stress in airway smooth muscle and their role in contractility.
Measurements and Main Results: We found that the oxidative stress burden in the airway smooth muscle in individuals with asthma is heightened and related to the degree of airflow obstruction and airway hyperresponsiveness. This was independent of the asthmatic environment as in vitro primary airway smooth muscle from individuals with asthma compared with healthy controls demonstrated increased oxidative stress–induced DNA damage together with an increased production of reactive oxygen species. Genome-wide microarray of primary airway smooth muscle identified increased messenger RNA expression in asthma of NADPH oxidase (NOX) subtype 4. This NOX4 overexpression in asthma was supported by quantitative polymerase chain reaction, confirmed at the protein level. Airway smooth muscle from individuals with asthma exhibited increased agonist-induced contraction. This was abrogated by NOX4 small interfering RNA knockdown and the pharmacological inhibitors diphenyleneiodonium and apocynin.
Conclusions: Our findings support a critical role for NOX4 overexpression in asthma in the promotion of oxidative stress and consequent airway smooth muscle hypercontractility. This implicates NOX4 as a potential novel target for asthma therapy.
doi:10.1164/rccm.201107-1281OC
PMCID: PMC3402550  PMID: 22108207
asthma; airway smooth muscle; airway hyperresponsiveness; NOX4; SOD2
6.  Integrin αVβ5 Mediated TGF-β Activation by Airway Smooth Muscle Cells in Asthma 
Severe asthma is associated with airway remodelling, characterised by structural changes including increased smooth muscle mass and matrix deposition in the airway, leading to deteriorating lung function. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine leading to increased synthesis of matrix molecules by human airway smooth muscle cells (HASMs) and is implicated in asthmatic airway remodelling. TGF-β is synthesised as a latent complex, sequestered in the extracellular matrix, and requires activation for functionality. Activation of latent TGF-β is the rate-limiting step in its bioavailability. This study investigated the effect of the contraction agonists LPA and methacholine on TGF-β activation by HASMs and its role in the development of asthmatic airway remodelling. The data presented show that LPA and methacholine induced TGF-β activation by HASMs via the integrin αVβ5. Our findings highlight the importance of the β5 cytoplasmic domain since a polymorphism in the β5 subunit rendered the integrin unable to activate TGF-β. This is the first description of a biologically relevant integrin that is unable to activate TGF-β. These data demonstrate for the first time that murine airway smooth muscle (ASM) cells express αVβ5 integrins and activate TGF-β. Finally, these data show that inhibition, or genetic loss, of αVβ5 reduces allergen-induced increases in airway smooth muscle thickness in two models of asthma. These data highlight a hitherto un-described mechanism of TGF-β activation in asthma and support the hypothesis that bronchoconstriction may promote airway remodelling via integrin mediated TGF-β activation.
doi:10.4049/jimmunol.1003507
PMCID: PMC3242066  PMID: 22025551
7.  Clinical management and outcome of refractory asthma in the UK from the British Thoracic Society Difficult Asthma Registry 
Thorax  2012;67(8):754-756.
Refractory asthma represents a significant unmet clinical need. Data from a national online registry audited clinical outcome in 349 adults with refractory asthma from four UK specialist centres in the British Thoracic Society Difficult Asthma Network. At follow-up, lung function improved, with a reduction in important healthcare outcomes, specifically hospital admission, unscheduled healthcare visits and rescue courses of oral steroids. The most frequent therapeutic intervention was maintenance oral corticosteroids and most steroid sparing agents (apart from omalizumab) demonstrated minimal steroid sparing benefit. A significant unmet clinical need remains in this group, specifically a requirement for therapies which reduce systemic steroid exposure.
doi:10.1136/thoraxjnl-2012-201869
PMCID: PMC3402747  PMID: 22581823
Refractory asthma; national registry; clinical assessment and outcome; asthma phenotypes; asthma; asthma epidemiology; asthma guidelines; allergic lung disease; eosinophil biology; occupational lung disease; airway epithelium; asthma mechanisms; asthma pharmacology; COPD epidemiology; COPD exacerbations
8.  Functional KCa3.1 K+ channels are required for human fibrocyte migration 
Background
Fibrocytes are bone marrow–derived CD34+ collagen I–positive cells present in peripheral blood that develop α-smooth muscle actin expression and contractile activity in tissue culture. They are implicated in the pathogenesis of tissue remodeling and fibrosis in both patients with asthma and those with idiopathic pulmonary fibrosis. Targeting fibrocyte migration might therefore offer a new approach for the treatment of these diseases. Ion channels play key roles in cell function, but the ion-channel repertoire of human fibrocytes is unknown.
Objective
We sought to examine whether human fibrocytes express the KCa3.1 K+ channel and to determine its role in cell differentiation, survival, and migration.
Methods
Fibrocytes were cultured from the peripheral blood of healthy subjects and patients with asthma. Whole-cell patch-clamp electrophysiology was used for the measurement of ion currents, whereas mRNA and protein were examined to confirm channel expression. Fibrocyte migration and proliferation assays were performed in the presence of KCa3.1 ion-channel blockers.
Results
Human fibrocytes cultured from the peripheral blood of both healthy control subjects and asthmatic patients expressed robust KCa3.1 ion currents together with KCa3.1 mRNA and protein. Two specific and distinct KCa3.1 blockers (TRAM-34 and ICA-17043) markedly inhibited fibrocyte migration in transwell migration assays. Channel blockers had no effect on fibrocyte growth, apoptosis, or differentiation in cell culture.
Conclusions
The K+ channel KCa3.1 plays a key role in human fibrocyte migration. Currently available KCa3.1-channel blockers might therefore attenuate tissue fibrosis and remodeling in patients with diseases such as idiopathic pulmonary fibrosis and asthma through the inhibition of fibrocyte recruitment.
doi:10.1016/j.jaci.2011.07.047
PMCID: PMC3526791  PMID: 21872912
Pulmonary fibrosis; asthma; fibrocyte; cell migration; ion channel; KCa3.1; patch clamp electrophysiology; 1-EBIO, 1-Ethyl-2-benzimidazolinone; αSMA, α-Smooth muscle actin; ASM, Airway smooth muscle; IPF, Idiopathic pulmonary fibrosis; Kd, Concentration producing 50% block
9.  Systems medicine and integrated care to combat chronic noncommunicable diseases 
Genome Medicine  2011;3(7):43.
We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.
doi:10.1186/gm259
PMCID: PMC3221551  PMID: 21745417
10.  Chromosome 17q21 SNP and Severe Asthma 
Journal of human genetics  2010;56(1):97-98.
doi:10.1038/jhg.2010.134
PMCID: PMC3027598  PMID: 20981039
severe asthma; 17q21; ORMDL3
11.  Refractory asthma in the UK: cross-sectional findings from a UK multicentre registry 
Thorax  2010;65(9):787-794.
Introduction
Refractory asthma represents a significant unmet clinical need where the evidence base for the assessment and therapeutic management is limited. The British Thoracic Society (BTS) Difficult Asthma Network has established an online National Registry to standardise specialist UK difficult asthma services and to facilitate research into the assessment and clinical management of difficult asthma.
Methods
Data from 382 well characterised patients, who fulfilled the American Thoracic Society definition for refractory asthma attending four specialist UK centres—Royal Brompton Hospital, London, Glenfield Hospital, Leicester, University Hospital of South Manchester and Belfast City Hospital—were used to compare patient demographics, disease characteristics and healthcare utilisation.
Results
Many demographic variables including gender, ethnicity and smoking prevalence were similar in UK centres and consistent with other published cohorts of refractory asthma. However, multiple demographic factors such as employment, family history, atopy prevalence, lung function, rates of hospital admission/unscheduled healthcare visits and medication usage were different from published data and significantly different between UK centres. General linear modelling with unscheduled healthcare visits, rescue oral steroids and hospital admissions as dependent variables all identified a significant association with clinical centre; different associations were identified when centre was not included as a factor.
Conclusion
Whilst there are similarities in UK patients with refractory asthma consistent with other comparable published cohorts, there are also differences, which may reflect different patient populations. These differences in important population characteristics were also identified within different UK specialist centres. Pooling multicentre data on subjects with refractory asthma may miss important differences and potentially confound attempts to phenotype this population.
doi:10.1136/thx.2010.137414
PMCID: PMC2975949  PMID: 20805172
Refractory asthma; National registry; clinical assessment; asthma phenotypes; asthma epidemiology; asthma
12.  Engagement of the EP2 prostanoid receptor closes the K+ channel KCa3.1 in human lung mast cells and attenuates their migration 
European Journal of Immunology  2008;38(9):2548-2556.
Human lung mast cells (HLMC) express the Ca2+-activated K+ channel KCa3.1, which plays a crucial role in their migration to a variety of diverse chemotactic stimuli. KCa3.1 activation is attenuated by the β2-adrenoceptor and the adenosine A2A receptor through a Gs-coupled mechanism independent of cyclic AMP. Prostaglandin E2 promotes degranulation and migration of mouse bone marrow-derived mast cells through the Gi-coupled EP3 prostanoid receptor, and induces LTC4 and cytokine secretion from human cord blood-derived mast cells. However, PGE2 binding to the Gs-coupled EP2 receptor on HLMC inhibits their degranulation. We show that EP2 receptor engagement closes KCa3.1 in HLMC. The EP2 receptor-specific agonist butaprost was more potent than PGE2 in this respect, and the effects of both agonists were reversed by the EP2 receptor antagonist AH6809. Butaprost markedly inhibited HLMC migration induced by chemokine-rich airway smooth muscle-conditioned media. Interestingly, PGE2 alone was chemotactic for HLMC at high concentrations (1 µM), but was a more potent chemoattractant for HLMC following EP2 receptor blockade. Therefore, the Gs-coupled EP2 receptor closes KCa3.1 in HLMC and attenuates both chemokine- and PGE2-dependent HLMC migration. EP2 receptor agonists with KCa3.1 modulating function may be useful for the treatment of mast cell-mediated disease.
doi:10.1002/eji.200738106
PMCID: PMC2699428  PMID: 18792407
Chemotaxis; Ion channel; KCa3.1; Mast cell; Prostaglandin E2

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