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Journal articleDoherty DF, Nath S, Poon J, et al., 2019,
Protein Phosphatase 2A Reduces Cigarette Smoke-induced Cathepsin S and Loss of Lung Function
, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 200, Pages: 51-62, ISSN: 1073-449X -
Journal articleSchofield JPR, Burg D, Nicholas B, et al., 2019,
Stratification of asthma phenotypes by airway proteomic signatures
, Journal of Allergy and Clinical Immunology, Vol: 144, Pages: 70-82, ISSN: 0091-6749BACKGROUND: Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy to predict treatment responses and a need for better understanding of the underlying mechanisms. OBJECTIVE: Identify molecular sub-phenotypes of asthma defined by proteomic signatures for improved stratification. METHODS: Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyse the proteomes of sputum supernatants from 246 participants (206 asthmatics) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms. RESULTS: Analysis of the sputum proteome resulted in 10 clusters, proteotypes, based on similarity in proteomics features, representing discrete molecular sub-phenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined three of these as highly eosinophilic, three as highly neutrophilic, and two as highly atopic with relatively low granulocytic inflammation. For each of these three phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms. CONCLUSION: This study provides further stratification of asthma currently classified by quantifying granulocytic inflammation and gives additional insight into their underlying mechanisms which could become targets for novel therapies.
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Journal articleNyga A, Hart A, Tetley TD, 2019,
Molecular analysis of HIF activation as a potential biomarker for adverse reaction to metal debris (ARMD) in tissue and blood samples
, JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS, Vol: 107, Pages: 1352-1362, ISSN: 1552-4973- Author Web Link
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- Citations: 5
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Journal articlePerotin J-M, Schofield JPR, Wilson SJ, et al., 2019,
Epithelial dysregulation in obese severe asthmatics with gastro-oesophageal reflux
, European Respiratory Journal, Vol: 53, ISSN: 0903-1936 -
Journal articleCiano M, Mantellato G, Connolly M, et al., 2019,
EGF receptor (EGFR) inhibition promotes a slow-twitch oxidative, over a fast-twitch, muscle phenotype
, Scientific Reports, Vol: 9, ISSN: 2045-2322A low quadriceps slow-twitch (ST), oxidative (relative to fast-twitch) fiber proportion is prevalent in chronic diseases such Chronic Obstructive Pulmonary Disease (COPD) and is associated with exercise limitation and poor outcomes. Benefits of an increased ST fiber proportion are demonstrated in genetically modified animals. Pathway analysis of published data of differentially expressed genes in mouse ST and FT fibers, mining of our microarray data and a qPCR analysis of quadriceps specimens from COPD patients and controls were performed. ST markers were quantified in C2C12 myotubes with EGF-neutralizing antibody, EGFR inhibitor or an EGFR-silencing RNA added. A zebrafish egfra mutant was generated by genome editing and ST fibers counted. EGF signaling was (negatively) associated with the ST muscle phenotype in mice and humans, and muscle EGF transcript levels were raised in COPD. In C2C12 myotubes, EGFR inhibition/silencing increased ST, including mitochondrial, markers. In zebrafish, egfra depletion increased ST fibers and mitochondrial content. EGF is negatively associated with ST muscle phenotype in mice, healthy humans and COPD patients. EGFR blockade promotes the ST phenotype in myotubes and zebrafish embryos. EGF signaling suppresses the ST phenotype, therefore EGFR inhibitors may be potential treatments for COPD-related muscle ST fiber loss.
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Journal articleFinney LJ, Padmanaban V, Todd S, et al., 2019,
Validity of the diagnosis of pneumonia in hospitalised patients with COPD.
, ERJ Open Research, Vol: 5, Pages: 1-8, ISSN: 2312-0541Rationale: Exacerbations of chronic obstructive pulmonary disease (COPD) and pneumonia are two of the most common reasons for acute hospital admissions. Acute exacerbations and pneumonia present with similar symptoms in COPD patients, representing a diagnostic challenge with a significant impact on patient outcomes. The objectives of this study were to compare the prevalence of radiographic consolidation with the discharge diagnoses of hospitalised COPD patients. Methods: COPD patients admitted to three UK hospitals over a 3-year period were identified. Participants were included if they were admitted with an acute respiratory illness, COPD was confirmed by spirometry and a chest radiograph was performed within 24 h of admission. Pneumonia was defined as consolidation on chest radiograph reviewed by two independent observers. Results: There were 941 admissions in 621 patients included in the final analysis. In 235 admissions, consolidation was present on chest radiography and there were 706 admissions without consolidation. Of the 235 admissions with consolidation, only 42.9% had a discharge diagnosis of pneumonia; 90.7% of patients without consolidation had a discharge diagnosis of COPD exacerbation. The presence of consolidation was associated with increased rate of high-dependency care admission, increased mortality and prolonged length of stay. Inhaled corticosteroid use was associated with recurrent pneumonia. Conclusions: Pneumonia is underdiagnosed in patients with COPD. Radiographic consolidation is associated with worse outcomes and prolonged length of stay. Incorrect diagnosis could result in inappropriate use of inhaled corticosteroids. Future guidelines should specifically address the diagnosis and management of pneumonia in COPD.
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Journal articleFinney LJ, Belchamber KBR, Fenwick PS, et al., 2019,
Human rhinovirus impairs the innate immune response to bacteria in alveolar macrophages in chronic obstructive pulmonary disease
, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 1496-1507, ISSN: 1073-449XRationale Human rhinovirus (HRV) is a common cause of COPD exacerbations. Secondary bacterial infection is associated with more severe symptoms and delayed recovery. Alveolar macrophages clear bacteria from the lung and maintain lung homeostasis through cytokine secretion. These processes are defective in COPD. The effect of HRV on macrophage function is unknown. Objectives To investigate the effect of HRV on phagocytosis and cytokine response to bacteria by alveolar macrophages and monocyte derived macrophages (MDM) in COPD and healthy controls. Methods Alveolar macrophages were obtained by bronchoscopy and MDM by adherence. Macrophages were exposed to HRV 16 (multiplicity of infection 5), polyI:C 30μg/ml, interferon (IFN)-β 10μg/ml, IFN-γ 10μg/ml or medium control for 24 hours. Phagocytosis of fluorescently-labelled Haemophilus influenzae or Streptococcus pneumoniae was assessed by fluorimetry. CXCL8, TNF and IL-10 release was measured by ELISA. Main Results HRV significantly impaired phagocytosis of H. influenzae by 23% in MDM (n=37) and 18% in alveolar macrophages (n=20) in COPD. HRV also significantly reduced phagocytosis of S. pneumoniae by 33% in COPD MDM. There was no effect in healthy controls. Phagocytosis of H. influenzae was impaired by polyI:C but not IFN-β or IFN-γ. HRV significantly reduced cytokine responses to H. influenzae. The IL-10 response to H. influenzae was significantly impaired by polyI:C, IFN-β and IFN-γ. Conclusions HRV impairs phagocytosis of bacteria in COPD which may lead to an outgrowth of bacteria. HRV also impairs cytokine responses to bacteria via the TLR3/IFN pathway which may prevent resolution of inflammation leading to prolonged exacerbations in COPD.
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Journal articleBernabé-Rubio M, Bosch-Fortea M, García E, et al., 2019,
The ciliary membrane of polarized epithelial cells stems from a midbody remnant-associated membrane patch with condensed nanodomains
<jats:title>Abstract</jats:title><jats:p>The primary cilium is a specialized plasma membrane protrusion that harbors receptors involved in important signaling pathways. Despite its central role in regulating cellular behavior, the biogenesis of the primary cilium is not fully understood. In fact, the source of the ciliary membrane remains a mystery in cell types that assemble their primary cilium entirely at the cell surface, such as polarized renal epithelial cells. After cytokinesis, the remnant of the midbody of these cells moves to the center of the apical surface, where it licenses the centrosome for ciliogenesis through an unidentified mechanism. Here, to investigate the origin of the ciliary membrane and the role of the midbody remnant, we analyzed membrane compaction and lipid dynamics at the microscale and nanoscale in living renal epithelial MDCK cells. We found that a specialized patch made of condensed membranes with restricted lipid lateral mobility surrounds the midbody remnant. This patch accompanies the remnant on its journey towards the centrosome and, once the two structures have met, the remnant delivers part of membranes of the patch to build the ciliary membrane. In this way, we have determined the origin of the ciliary membrane and the contribution of the midbody remnant to primary cilium formation in cells whose primary cilium is assembled at the plasma membrane.</jats:p>
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Journal articleKumar R, Fadieieva H, Chipev PM, et al., 2019,
Noninvasive ventilation (advanced): course report
, BREATHE, Vol: 15, Pages: 104-107, ISSN: 1810-6838 -
Journal articlePhilip K, Lewis A, Hopkinson NS, 2019,
Music and dance in chronic lung disease
, Breathe, Vol: 15, Pages: 116-120, ISSN: 1810-6838Arts in Health interventions show potential to improve the quality of life of people with chronic lung disease. Listening to music, making music, and dance have accepted and established roles in the lives of people without chronic disease. However, their potential utility in chronic disease management is infrequently considered by medical professionals. The aim of this review is to examine the use of music and dance in the treatment and self-management of chronic lung disease. Although the evidence base is currently limited, existing research suggests a range of biopsychosocial benefits. As personalised medicine and social prescribing become more prominent, further research is required to establish the role of arts interventions in chronic lung disease.
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Journal articleFarre-Garros R, Lee J, Natanek S, et al., 2019,
Quadriceps miR-542-3p and 5p are elevated in COPD and reduce function by inhibiting ribosomal and protein synthesis
, Journal of Applied Physiology, Vol: 126, Pages: 1514-1524, ISSN: 8750-7587Reduced physical performance reduces quality of life in patients with COPD. Impaired physical performance is, in part, a consequence of reduced muscle mass and function, which is accompanied by mitochondrial dysfunction. We recently showed that miR-542-3p and miR-542-5p were elevated in a small cohort of COPD patients and more markedly in critical care patients. In mice these miRNAs promoted mitochondrial dysfunction suggesting that they would affect physical performance in patients with COPD but we did not explore the association of these miRNAs with disease severity or physical performance further. We therefore quantified miR-542-3p/5p and mitochondrial rRNA expression in RNA extracted from quadriceps muscle of patients with COPD and determined their association with physical performance. As miR-542-3p inhibits ribosomal protein synthesis its ability to inhibit protein synthesis was also determined in vitro.Both miR-542-3p and -5p expression were elevated in patients with COPD (5-fold p<0.001) and the degree of elevation associated with impaired lung function (TLCO% and FEV1%) and physical performance (6-minute walk distance %). In COPD patients, the ratio of 12S rRNA to 16S rRNA was suppressed suggesting mitochondrial ribosomal stress and mitochondrial dysfunction and miR-542-3p/5p expression was inversely associated with mitochondrial gene expression and positively associated with p53 activity. miR-542-3p suppressed RPS23 expression and maximal protein synthesis in vitro. Our data show that miR-542-3p and -5p expression is elevated in COPD patients and may suppress physical performance at least in part by inhibiting mitochondrial and cytoplasmic ribosome synthesis and suppressing protein synthesis.
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Journal articleLaverty AA, Filippidis FT, Taylor-Robinson D, et al., 2019,
Smoking uptake in UK children: Analysis of the UK Millennium Cohort Study.
, Thorax, Vol: 74, Pages: 607-610, ISSN: 0040-6376We used data from 11 577 children in the UK Millennium Cohort Study, collected at approximately 14 years of age (early teens), to assess characteristics associated with smoking, and generated regional estimates of numbers of smokers. 13.8% of UK early teens studied had ever smoked; 1.9% were current smokers. This corresponds to 2 28 136 and 39 653 (13-14 year olds) in the UK, respectively. Ever smoking risk increased if caregivers (26.0% vs 10.9%) or friends smoked (35.1% vs 4.0%), with a dose-response effect for friends' smoking. Caregiver and peer-group smoking remain important drivers of child smoking uptake and thus important targets for intervention.
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Journal articleSmitten KL, Southam HM, Bernardino de la Serna J, et al., 2019,
Using nanoscopy to probe the biological activity of antimicrobial leads that display potent activity against pathogenic, multidrug resistant, gram-negative bacteria.
, ACS Nano, Vol: 13, Pages: 5133-5146, ISSN: 1936-0851Medicinal leads that are also compatible with imaging technologies are attractive, as they facilitate the development of therapeutics through direct mechanistic observations at the molecular level. In this context, the uptake and antimicrobial activities of several luminescent dinuclear RuII complexes against E. coli were assessed and compared to results obtained for another ESKAPE pathogen, the Gram-positive major opportunistic pathogen Enterococcus faecalis, V583. The most promising lead displays potent activity, particularly against the Gram-negative bacteria, and potency is retained in the uropathogenic multidrug resistant EC958 ST131 strain. Exploiting the inherent luminescent properties of this complex, super-resolution STED nanoscopy was used to image its initial localization at/in cellular membranes and its subsequent transfer to the cell poles. Membrane damage assays confirm that the complex disrupts the bacterial membrane structure before internalization. Mammalian cell culture and animal model studies indicate that the complex is not toxic to eukaryotes, even at concentrations that are several orders of magnitude higher than its minimum inhibitory concentration (MIC). Taken together, these results have identified a lead molecular architecture for hard-to-treat, multiresistant, Gram-negative bacteria, which displays activities that are already comparable to optimized natural product-based leads.
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Journal articleBenedikz EK, Bailey D, Cook CNL, et al., 2019,
Bacterial flagellin promotes viral entry via an NF-kB and Toll Like Receptor 5 dependent pathway
, SCIENTIFIC REPORTS, Vol: 9, ISSN: 2045-2322- Author Web Link
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- Citations: 15
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Journal articleSharanya A, Ciano M, Withana S, et al., 2019,
Sex differences in COPD-related quadriceps muscle dysfunction and fibre abnormalities
, Chronic Respiratory Disease, Vol: 16, Pages: 1-13, ISSN: 1479-9723Background: In COPD, lower limb dysfunction is associated with reduced exercise capacity, increased hospitalisations and mortality. We investigated sex differences in the prevalence of quadriceps dysfunction and fibre abnormalities in a large COPD cohort, controlling for the normal sex differences in health. Methods: We compared existing data from 76 male and 38 female COPD patients where each variable was expressed as a function of gender-specific normal values (obtained from 16 male and 14 female controls). Results: Female COPD patients had lower quadriceps muscle strength and peak workload on a maximal incremental cycle ergometry protocol compared to male patients. Female patients had a smaller type II fibre cross-sectional area (CSA) compared to male patients, suggesting a greater female preponderance to fibre atrophy, although this result was largely driven by a few male patients with increased type II fibre CSA. Female patients had significantly higher concentrations of a number of plasma pro-inflammatory cytokines including tumor necrosis factor alpha (TNFα) and interleukin 8 (IL8), but not lower levels of physical activity or arterial oxygenation, compared to males. Conclusions: Our data confirms results from a previous small study and suggests that female COPD patients have a greater prevalence of muscle wasting and weakness. Larger studies investigating sex differences in COPD-related muscle atrophy and weakness are needed, as the results will have implications for monitoring in clinical practice and for design of clinical trials evaluating novel muscle anabolic agents.
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Journal articleSingh D, Agusti A, Anzueto A, et al., 2019,
Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: The GOLD Science Committee Report 2019
, European Respiratory Journal, Vol: 53, ISSN: 0903-1936Precision medicine is a patient specific approach that integrates all relevant clinical, genetic and biological information in order to optimise the therapeutic benefit relative to the possibility of side effects for each individual. Recent clinical trials have shown that higher blood eosinophil counts are associated with a greater efficacy of inhaled corticosteroids (ICS) in COPD patients. Blood eosinophil counts are a biomarker with potential to be used in clinical practice, to help target ICS treatment with more precision in COPD patients with a history of exacerbations despite appropriate bronchodilator treatment.The Global initiative for the management of chronic Obstructive Lung Disease (GOLD) 2017 pharmacological treatment algorithms, based on the ABCD assessment, can be applied relatively easily to treatment naïve individuals at initial presentation. However, their use is more problematic during follow up in patients who are already on maintenance treatment. There is a need for a different system to guide COPD pharmacological management during follow up.Recent large randomised controlled trials have provided important new information concerning the therapeutic effects of ICS and long-acting bronchodilators on exacerbations. The new evidence regarding blood eosinophils and inhaled treatments, and the need to distinguish between initial and follow up pharmacological management, led to changes in the GOLD pharmacological treatment recommendations. This paper explains the evidence and rationale for the GOLD 2019 pharmacological treatment recommendations.
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Journal articlePostma DS, Brightling C, Baldi S, et al., 2019,
Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort study
, LANCET RESPIRATORY MEDICINE, Vol: 7, Pages: 402-416, ISSN: 2213-2600 -
Journal articleCryer AM, Chan C, Eftychidou A, et al., 2019,
Tyrosine kinase inhibitor gold nanoconjugates for the treatment of non-small cell lung cancer
, ACS Applied Materials and Interfaces, Vol: 11, Pages: 16336-16346, ISSN: 1944-8244Gold nanoparticles (AuNPs) have emerged as promising drug delivery candidates that can be leveraged for cancer therapy. Lung cancer (LC) is a heterogeneous disease that imposes a significant burden on society, with an unmet need for new therapies. Chemotherapeutic drugs such as afatinib (Afb), which is clinically approved for the treatment of epidermal growth factor receptor positive LC, is hydrophobic and has low bioavailability leading to spread around the body, causing severe side effects. Herein, we present a novel afatinib-AuNP formulation termed Afb-AuNPs, with the aim of improving drug efficacy and biocompatibility. This was achieved by synthesis of an alkyne-bearing Afb derivative and reaction with azide functionalized lipoic acid using copper catalyzed click chemistry, then conjugation to AuNPs via alkylthiol-gold bond formation. The Afb-AuNPs were found to possess up to 3.7-fold increased potency when administered to LC cells in vitro and were capable of significantly inhibiting cancer cell proliferation, as assessed by MTT assay and electric cell-substrate impedance sensing respectively. Furthermore, when exposed to Afb-AuNPs, human alveolar epithelial type I-like cells, a model of the healthy lung epithelium, maintained viability and were found to release less pro-inflammatory cytokines when compared to free drug, demonstrating the biocompatibility of our formulation. This study provides a new platform for the development of non-traditional AuNP conjugates which can be applied to other molecules of therapeutic or diagnostic utility, with potential to be combined with photothermal therapy in other cancers.
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Journal articleCalderazzo MA, Trujillo-Torralbo M-B, Finney LJ, et al., 2019,
Inflammation and infections in unreported chronic obstructive pulmonary disease exacerbations
, International Journal of Chronic Obstructive Pulmonary Disease, Vol: 2019, Pages: 823-832, ISSN: 1176-9106Purpose: COPD patients often do not report acute exacerbations to healthcare providers – unreported exacerbations. It is not known whether variances in symptoms, airway obstruction, aetiology and inflammatory responses account for differences in reporting of COPD exacerbations. The aims of the study were to compare symptoms, lung function changes, aetiology and inflammatory markers between exacerbations that were reported to healthcare providers or treated, with those that were unreported and untreated.Patients and methods: We recruited a cohort of COPD patients and collected clinical data and blood and airway samples when stable and during acute exacerbations. Virological and bacterial analyses were carried out and inflammatory markers measured.Results: We found no differences in symptoms, lung function, incidence of infection and inflammatory markers between reported and unreported exacerbations. Subjects who reported all exacerbations had higher BODE scores, lower FEV1 and more exacerbations compared with those who did not.Conclusion: The failure to report exacerbations is not related to the severity, aetiology or inflammatory profile of the exacerbation. Patients with less severe COPD and less frequent exacerbations are less likely to report exacerbations. The decision to report an exacerbation is not an objective marker of exacerbation severity and therefore studies that do not count unreported exacerbations will underestimate the frequency of clinically significant exacerbations. A better understanding of the factors that determine non-reporting of exacerbations is required to improve exacerbation reporting.
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Journal articleSmith JA, McGarvey L, Morice AH, et al., 2019,
The Effect of Aclidinium on Symptoms Including Cough in COPD: A Phase IV, DoubleBlind, Placebo-Controlled, Parallel-Group Study.
, Am J Respir Crit Care Med
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