928 results found
Lakhdar R, Mumby S, Abubakar-Waziri H, et al., 2022, Lung toxicity of particulates and gaseous pollutants using ex-vivo airway epithelial cell culture systems., Environ Pollut, Vol: 305
Air pollution consists of a multi-faceted mix of gases and ambient particulate matter (PM) with diverse organic and non-organic chemical components that contribute to increasing morbidity and mortality worldwide. In particular, epidemiological and clinical studies indicate that respiratory health is adversely affected by exposure to air pollution by both causing and worsening (exacerbating) diseases such as chronic obstructive pulmonary disease (COPD), asthma, interstitial pulmonary fibrosis and lung cancer. The molecular mechanisms of air pollution-induced pulmonary toxicity have been evaluated with regards to different types of PM of various sizes and concentrations with single and multiple exposures over different time periods. These data provide a plausible interrelationship between cellular toxicity and the activation of multiple biological processes including proinflammatory responses, oxidative stress, mitochondrial oxidative damage, autophagy, apoptosis, cell genotoxicity, cellular senescence and epithelial-mesenchymal transition. However, these molecular changes have been studied predominantly in cell lines rather than in primary bronchial or nasal cells from healthy subjects or those isolated from patients with airways disease. In addition, they have been conducted under different cell culture conditions and generally in submerged culture rather than the more relevant air-liquid interface culture and with a variety of air pollutant exposure protocols. Cell types may respond differentially to pollution delivered as an aerosol rather than being bathed in media containing agglomerations of particles. As a result, the actual pathophysiological pathways activated by different PMs in primary cells from the airways of healthy and asthmatic subjects remains unclear. This review summarises the literature on the different methodologies utilised in studying the impact of submicron-sized pollutants on cells derived from the respiratory tract with an emphasis on data o
Michaeloudes C, Abubakar-Waziri H, Lakhdar R, et al., 2022, Molecular mechanisms of oxidative stress in asthma, Molecular Aspects of Medicine, Vol: 85, ISSN: 0098-2997
The lungs are exposed to reactive oxygen species oxygen (ROS) produced as a result of inhalation of oxygen, as well as smoke and other air pollutants. Cell metabolism and the NADPH oxidases (Nox) generate low levels of intracellular ROS that act as signal transduction mediators by inducing oxidative modifications of histones, enzymes and transcription factors. Redox signalling is also regulated by localised production and sensing of ROS in mitochondria, the endoplasmic reticulum (ER) and inside the nucleus. Intracellular ROS are maintained at low levels through the action of a battery of enzymatic and non-enzymatic antioxidants. Asthma is a heterogeneous airway inflammatory disease with different immune endotypes; these include atopic or non-atopic Th2 type immune response associated with eosinophilia, or a non-Th2 response associated with neutrophilia. Airway remodelling and hyperresponsiveness accompany the inflammatory response in asthma. Over-production of ROS resulting from infiltrating immune cells, particularly eosinophils and neutrophils, and a concomitant impairment of antioxidant responses lead to development of oxidative stress in asthma. Oxidative stress is augmented in severe asthma and during exacerbations, as well as by air pollution and obesity, and causes oxidative damage of tissues promoting airway inflammation and hyperresponsiveness. Furthermore, deregulated Nox activity, mitochondrial dysfunction, ER stress and/or oxidative DNA damage, resulting from exposure to irritants, inflammatory mediators or obesity, may lead to redox-dependent changes in cell signalling. ROS play a central role in airway epithelium-mediated sensing, development of innate and adaptive immune responses, and airway remodelling and hyperresponsiveness. Nonetheless, antioxidant compounds have proven clinically ineffective as therapeutic agents for asthma, partly due to issues with stability and in vivo metabolism of these compounds. The compartmentalised nature of ROS product
Hoda U, Pavlidis S, Bansal AT, et al., 2022, Clinical and transcriptomic features of persistent exacerbation-prone severe asthma in U-BIOPRED cohort, Clinical and Translational Medicine, Vol: 12, ISSN: 2001-1326
Background: Exacerbation-prone asthma is a feature of severe disease. Yet, the basis for its persistency remains unclear. Objectives: To determine the clinical and transcriptomic features of the frequent-exacerbator (FE) and of persistent FEs (PFE) in U-BIOPRED cohort. Methods: We compared features of FE (≥2 exacerbations in past year) to infrequent exacerbators (IE, <2 exacerbations) and of PFE with repeat ≥2 exacerbations during the following year to persistent IE (PIE). Transcriptomic data in blood, bronchial and nasal epithelial brushings, bronchial biopsies and sputum cells were analysed by gene set variation analysis for 103 gene signatures.Results: Of 317 patients, 62.4 % were FE of whom 63.6% were PFE, while 37.6% were IE of whom 61.3% were PIE. Using multivariate analysis, FE was associated with short-acting beta-agonist use, sinusitis and daily oral corticosteroid use, while PFE with eczema, short-acting beta-agonist use and asthma control index. CEA Cell Adhesion Molecule 5 (CEACAM5) was the only differentially-expressed transcript in bronchial biopsies between PE and IE. There were no differentially-expressed genes in the other 4 compartments. There were higher expression scores for Type 2 , T-helper type-17 and Type 1 pathway signatures together with those associated with viral infections in bronchial biopsies from FE compared to IE, while higher expression scores of Type 2, Type 1 and steroid insensitivity pathway signatures in bronchial biopsies of PFE compared to PIE.Conclusion: FE group and its PFE subgroup are associated with poor asthma control while expressing higher Type 1 and Type 2 activation pathways compared to IE and PIE, respectively.
Pinkerton JW, Kim RY, Brown AC, et al., 2022, Relationship between type 2 cytokine and inflammasome responses in obesity-associated asthma, Journal of Allergy and Clinical Immunology, Vol: 149, Pages: 1270-1280, ISSN: 0091-6749
BACKGROUND: Obesity is a risk factor for asthma, and obese asthmatic individuals are more likely to have severe, steroid-insensitive disease. How obesity affects the pathogenesis and severity of asthma is poorly understood. Roles for increased inflammasome-mediated neutrophilic responses, type 2 immunity, and eosinophilic inflammation have been described. OBJECTIVE: We investigated how obesity affects the pathogenesis and severity of asthma and identified effective therapies for obesity-associated disease. METHODS: We assessed associations between body mass index and inflammasome responses with type 2 (T2) immune responses in the sputum of 25 subjects with asthma. Functional roles for NLR family, pyrin domain-containing (NLRP) 3 inflammasome and T2 cytokine responses in driving key features of disease were examined in experimental high-fat diet-induced obesity and asthma. RESULTS: Body mass index and inflammasome responses positively correlated with increased IL-5 and IL-13 expression as well as C-C chemokine receptor type 3 expression in the sputum of subjects with asthma. High-fat diet-induced obesity resulted in steroid-insensitive airway hyperresponsiveness in both the presence and absence of experimental asthma. High-fat diet-induced obesity was also associated with increased NLRP3 inflammasome responses and eosinophilic inflammation in airway tissue, but not lumen, in experimental asthma. Inhibition of NLRP3 inflammasome responses reduced steroid-insensitive airway hyperresponsiveness but had no effect on IL-5 or IL-13 responses in experimental asthma. Depletion of IL-5 and IL-13 reduced obesity-induced NLRP3 inflammasome responses and steroid-insensitive airway hyperresponsiveness in experimental asthma. CONCLUSION: We found a relationship between T2 cytokine and NLRP3 inflammasome responses in obesity-associated asthma, highlighting the potential utility of T2 cytokine-targeted biologics and inflammasome inhibitors.
Mortaz E, Nomani M, Adcock I, et al., 2022, Galactooligosaccharides and 2'-fucosyllactose can directly suppress growth of specific pathogenic microbes and affect phagocytosis of neutrophils., Nutrition, Vol: 96
OBJECTIVES: Non-digestible oligosaccharides such as milk oligosaccharides (MOS) can regulate and influence immune function. As an example, galactooligosaccharides (GOS), and 2'-fucosyllactose (2'-FL; a specific human MOS) regulate immune development and functionality. Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA), both serious pathogens, can cause severe and life-threatening infections. The aim of this study was to examine the effects of GOS and 2'-FL on bacterial growth and on polymorphonuclear (PMN) phagocytosis. METHODS: PMNs were isolated from heparinized whole human blood before treatment/incubation with GOS (0.0625-10%), 2'-FL (0.5-2.5%) and/or GOS combined with 2'-FL (GOS 10%/2'-FL 2.5%; GOS 0.0625%/2'-FL 0.5%) and incubation with green florescent protein (GFP)-labeled SA or PA for 60 h. GFP-relative fluorescent units (GFP-RFU) was measured ≤60 h using a plate reader. Bacterial lag time was determined by the time to onset of exponential bacterial fluorescence/growth alone or after co-culture of bacteria and PMN. Viable bacterial colony-forming units (CFUs) were determined after 60 h. RESULTS: SA and PA growth lag time was suppressed by co-incubation with GOS in a concentration-dependent manner. This was significant for both SA and PA at concentrations >2.5% GOS (P ≤ 0.05 for both SA and PA) but only for SA at 1% GOS (P ≤ 0.05). 1.5% 2'-FL significantly suppressed the lag time of SA growth (P ≤ 0.05) and was effective against SA and PA at 2.5% (P ≤ 0.01 and P ≤ 0.01, respectively). GOS (10%, 5%) and 2.5% 2'-FL significantly decreased SA and PA bacterial growth/CFUs (P ≤ 0.05). CONCLUSION: The data suggests that both GOS and 2'-FL can suppress growth of serious pathogens and enhance phagocytosis.
Pillar A, Brown A, Mayall J, et al., 2022, Relationship between interleukin-13 and transferrin receptor-1 responses in asthma pathogenesis, Publisher: WILEY, Pages: 105-105, ISSN: 1323-7799
Adcock IM, Bhatt SP, Balkissoon R, et al., 2022, The Use of Inhaled Corticosteroids for Patients with COPD Who Continue to Smoke Cigarettes: An Evaluation of Current Practice., Am J Med, Vol: 135, Pages: 302-312
The use of inhaled corticosteroids (ICS) in combination with inhaled bronchodilators for patients with chronic obstructive pulmonary disease (COPD) is a common practice in primary care settings. However, ICS-containing therapies may be less effective in patients with COPD compared with asthma, and in individuals with COPD who continue to smoke cigarettes. Preclinical studies suggest that inflammation in COPD is very different from in asthma. Glucocorticoid receptor functioning and other innate anti-inflammatory mechanisms are altered in cells exposed to cigarette smoke. COPD may be relatively insensitive to ICS, especially in individuals who continue to smoke. ICS-containing therapies in patients with asthma who continue to smoke may also be less effective compared with patients who do not smoke. ICS-containing therapies may be inappropriately used in some patients with COPD, and their long-term use is associated with an increased risk for side effects, including pneumonia and bone fractures in some patients. Treatment for patients with COPD should be carefully evaluated, and anti-inflammatory/bronchodilatory strategies should be chosen based on individual patient characteristics and recommendations in current guidelines.
Tiotiu A, Badi Y, Kermani NZ, et al., 2022, Association of Differential Mast Cell Activation with Granulocytic Inflammation in Severe Asthma, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 205, Pages: 397-+, ISSN: 1073-449X
There is no justification for a therapeutic nihilism in clinical practice because current management (pharmacological and non-pharmacological) of the patients with chronic obstructive pulmonary disease (COPD) according to treatable traits is effective in decreasing their respiratory symptoms, increasing their exercise tolerance and capacity, improving their quality of life, preventing (and treating) many of their exacerbations and decreasing their mortality.
Nucera F, Mumby S, Paudel KR, et al., 2022, Role of oxidative stress in the pathogenesis of COPD., Minerva Medica, ISSN: 0026-4806
Chronic inhalation of cigarette smoke is a prominent cause of chronic obstructive pulmonary disease (COPD) and provides an important source of exogenous oxidants. In addition, several inflammatory and structural cells are a source of endogenous oxidants in the lower airways of COPD patients, even in former smokers. This suggests that oxidants play a key role in the pathogenesis of COPD. This oxidative stress is counterbalanced by the protective effects of the various endogenous antioxidant defenses of the lower airways. A large amount of data from animal models and patients with COPD have shown that both the stable phase of the disease, and during exacerbations, have increased oxidative stress in the lower airways compared with age-matched smokers with normal lung function. Thus, counteracting the increased oxidative stress may produce clinical benefits in COPD patients. Smoking cessation is currently the most effective treatment of COPD patients and reduces oxidative stress in the lower airways. In addition, many drugs used to treat COPD have some antioxidant effects, however, it is still unclear if their clinical efficacy is related to pharmacological modulation of the oxidant/antioxidant balance. Several new antioxidant compounds are in development for the treatment of COPD.
The characteristic features of chronic obstructive pulmonary disease (COPD) include inflammation and remodelling of the lower airways and lung parenchyma together with activation of inflammatory and immune processes. Due to the increasing habit of cigarette smoking worldwide COPD prevalence is increasing globally. Current therapies are unable to prevent COPD progression in many patients or target many of its hallmark characteristics which may reflect the lack of adequate biomarkers to detect the heterogeneous clinical and molecular nature of COPD. In this chapter we review recent molecular data that may indicate novel pathways that underpin COPD subphenotypes and indicate potential improvements in the classes of drugs currently used to treat COPD. We also highlight the evidence for new drugs or approaches to treat COPD identified using molecular and other approaches including kinase inhibitors, cytokine- and chemokine-directed biologicals and small molecules, antioxidants and redox signalling pathway inhibitors, inhaled anti-infectious agents and senolytics. It is important to consider the phenotypes/molecular endotypes of COPD patients together with specific outcome measures to target new therapies to particular COPD subtypes. This will require greater understanding of COPD molecular pathologies and a focus on biomarkers of predicting disease subsets and responder/non-responder populations.
Luecken MD, Zaragosi L-E, Madissoon E, et al., 2022, The discovAIR project: a roadmap towards the Human Lung Cell Atlas., Eur Respir J
The Human Cell Atlas (HCA) consortium aims to establish an atlas of all organs in the healthy human body at single-cell resolution to increase our understanding of basic biological processes that govern development, physiology and anatomy, and to accelerate diagnosis and treatment of disease. The lung biological network of the HCA aims to generate the Human Lung Cell Atlas as a reference for the cellular repertoire, molecular cell states and phenotypes, and the cell-cell interactions that characterise normal lung homeostasis in healthy lung tissue. Such a reference atlas of the healthy human lung will facilitate mapping the changes in the cellular landscape in disease. The discovAIR project is one of six pilot actions for the HCA funded by the European Commission in the context of the H2020 framework program. DiscovAIR aims to establish the first draft of an integrated Human Lung Cell Atlas, combining single-cell transcriptional and epigenetic profiling with spatially resolving techniques on matched tissue samples, as well as including a number of chronic and infectious diseases of the lung. The integrated Lung Cell Atlas will be available as a resource for the wider respiratory community, including basic and translational scientists, clinical medicine, and the private sector, as well as for patients with lung disease and the interested lay public. We anticipate that the Lung Cell Atlas will be the founding stone for a more detailed understanding of the pathogenesis of lung diseases, guiding the design of novel diagnostics and preventive or curative interventions.
Mortaz E, Jamaati H, Roofchayee ND, et al., 2022, Decreased serum levels of angiotensin converting enzyme (ACE)2 and enhanced cytokine levels with severity of COVID-19: normalisation upon disease recovery, HELIYON, Vol: 8
Aliee H, Massip F, Qi C, et al., 2022, Determinants of expression of SARS-CoV-2 entry related genes in upper and lower airways., Allergy, Vol: 77, Pages: 690-694, ISSN: 0105-4538
Sparreman Mikus M, Kolmert J, Andersson LI, et al., 2022, Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation., Eur Respir J, Vol: 59
RATIONALE: Asthma phenotyping requires novel biomarker discovery. OBJECTIVES: To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). METHODS: An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. RESULTS: In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. CONCLUSIONS: The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2-independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA.
Patel B, Mumby S, Johnson N, et al., 2022, Decision support system to evaluate ventilation in the acute respiratory distress syndrome (DeVENT study)-trial protocol, Trials, Vol: 23, Pages: 1-18, ISSN: 1745-6215
BackgroundThe acute respiratory distress syndrome (ARDS) occurs in response to a variety of insults, and mechanical ventilation is life-saving in this setting, but ventilator-induced lung injury can also contribute to the morbidity and mortality in the condition. The Beacon Caresystem is a model-based bedside decision support system using mathematical models tuned to the individual patient’s physiology to advise on appropriate ventilator settings. Personalised approaches using individual patient description may be particularly advantageous in complex patients, including those who are difficult to mechanically ventilate and wean, in particular ARDS.MethodsWe will conduct a multi-centre international randomised, controlled, allocation concealed, open, pragmatic clinical trial to compare mechanical ventilation in ARDS patients following application of the Beacon Caresystem to that of standard routine care to investigate whether use of the system results in a reduction in driving pressure across all severities and phases of ARDS.DiscussionDespite 20 years of clinical trial data showing significant improvements in ARDS mortality through mitigation of ventilator-induced lung injury, there remains a gap in its personalised application at the bedside. Importantly, the protective effects of higher positive end-expiratory pressure (PEEP) were noted only when there were associated decreases in driving pressure. Hence, the pressures set on the ventilator should be determined by the diseased lungs’ pressure-volume relationship which is often unknown or difficult to determine. Knowledge of extent of recruitable lung could improve the ventilator driving pressure. Hence, personalised management demands the application of mechanical ventilation according to the physiological state of the diseased lung at that time. Hence, there is significant rationale for the development of point-of-care clinical decision support systems which help personalise ventilatory strateg
Abdel-Aziz MI, Vijverberg SJH, Neerincx AH, et al., 2022, A multi-omics approach to delineate sputum microbiome-associated asthma inflammatory phenotypes, EUROPEAN RESPIRATORY JOURNAL, Vol: 59, ISSN: 0903-1936
Patel B, Mumby S, Johnson N, et al., 2021, Decision support system to evaluate VENTilation in the Acute Respiratory Distress Syndrome (DeVENT study) – Trial Protocol, Trials, ISSN: 1745-6215
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The Acute Respiratory Distress Syndrome (ARDS) occurs in response to a variety of insults, and mechanical ventilation is life-saving in this setting, but ventilator induced lung injury can also contribute to the morbidity and mortality in the condition. The Beacon Caresystem is a model-based bedside decision support system using mathematical models tuned to the individual patient’s physiology to advise on appropriate ventilator settings. Personalised approaches using individual patient description may be particularly advantageous in complex patients, including those who are difficult to mechanically ventilate and wean, in particular ARDS.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We will conduct a multi-centre international randomised, controlled, allocation concealed, open, pragmatic clinical trial to compare mechanical ventilation in ARDS patients following application of the Beacon Caresystem to that of standard routine care to investigate whether use of the system results in a reduction in driving pressure across all severities and phases of ARDS.</jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>Despite 20 years of clinical trial data showing significant improvements in ARDS mortality through mitigation of ventilator induced lung injury, there remains a gap in its personalised application at the bedside. Importantly, the protective effects of higher positive end-expiratory pressure (PEEP) were noted only when there were associated decreases in driving pressure. Hence, the pressures set on the ventilator should be determined by the diseased lungs’ pressure-volume relationship which is often unknown or difficult to determine. Knowledge of extent of recruitable lung could improve the ventilator driving pressure. H
Zhang H, Li C, Song X, et al., 2021, Integrated analysis reveals lung fibrinogen gamma chain as a biomarker for chronic obstructive pulmonary disease, Annals of Translational Medicine, Vol: 24, Pages: 1-17, ISSN: 2305-5839
Background: Chronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable airway disease. This study aimed to identify key genes related to COPD pathogenesis through an integrated transcriptomic and proteomic analysis of lung tissue from COPD subjects undergoing lung resection for malignancy.Methods: We performed RNA sequencing, gene expression analysis, and gene set enrichment analysis (GSEA) on lung tissue in 13 non-smokers, 16 smokers, and 16 COPD patients. Key genes were verified by RT-qPCR, immunohistochemistry and Western blot in human lung tissues, cigarette smoke extract (CSE)-exposed human bronchial epithelial cell line (BEAS-2B cells), and a cigarette smoke (CS)-induced mouse model.Results: There were 521 differentially expressed genes between non-smokers and smokers, 57 genes between smokers and COPD patients, and 860 genes between non-smokers and COPD patients. Fibrinogen gamma chain (FGG) was highly expressed in COPD patients versus smokers and in COPD patients versus healthy controls. GSEA of the COPD patients with the highest FGG expression were enriched in the B cell receptor signaling pathway, pantothenate and CoA biosynthesis, Fc epsilon RI signaling pathway, and the Toll-like receptor (TLR) signaling pathway. RT-PCR analysis confirmed enhanced FGG mRNA levels in the lungs of both smokers and COPD patients compared to non-smokers and in CSE-exposed cells compared to control cells. FGG protein levels were elevated in the lungs of COPD patients and smokers compared to non-smokers and in the lungs of CS-exposed mice compared to control mice.Conclusions: FGG may serve as a biomarker for COPD and may play an important role in its pathogenesis.
Roofchayee ND, Adcock IM, Marjani M, et al., 2021, T helper cell subsets in the pleural fluid of tuberculous patients differentiate patients with non-tuberculous pleural effusions, Frontiers in Immunology, Vol: 12, Pages: 1-10, ISSN: 1664-3224
Background: Tuberculous pleural effusion (TPE) is one of the most common forms of extrapulmonary tuberculosis (Tb). Patients with TPE or malignant pleural effusions (MPE) frequently have a similar lymphocytic pleural fluid profile. Since the etiology of PE in various diseases is different, identifying the cellular components may provide diagnostic clues for understanding the pathogenesis.Objective: We determined the frequency of T helper (Th) subtypes in the PEs for differentiation of Tb and non-Tb patients.Methods: Thirty patients with TPE, 30 patients with MPE, 14 patients with empyema (EMP), and 14 patients with parapneumonic effusion (PPE) were enrolled between December 2018 and December 2019. Five-milliliter fresh PE in tubes containing heparin as an anticoagulant was obtained from patients. The frequencies of CD4+IL-9+, CD4+IL-22+, CD+IL-17+, and regulatory T-cells CD4+CD25+ FOXP3+ (Treg) were determined by flow cytometry.Results: Treg cells have a lower frequency in TPE patients [4.2 (0.362–17.24)] compared with non-TPE patients [26.3 (3.349–76.93, p < 0.0001)]. The frequency of CD4+IL-9+ cells was significantly lower in TPE patients [3.67 (0.87–47.83)] compared with non-TPE groups [13.05 (1.67–61.45), p < 0.0001]. On the contrary, there was no significant difference in the frequency of CD4+IL-17+ and CD4+IL-22+ cells between TPE and non-TPE patients (p = 0.906 and p = 0.2188). Receiver-operator curve (ROC) analysis demonstrated that CD4+CD25+FOXP3+ T cells [optimal cutoff value = 13.6 (%), sensitivity 90%, specificity 75.86%] could be considered as predictor for TPE. However, adenosine deaminase [cutoff value 27.5 (IU/l), sensitivity 90%, specificity 96.5%] levels had an even greater predictive capacity.Conclusion: ADA, Treg cells, and CD4+IL-9+ cells may differentiate TPE from non-TPE patients. However, these results need validation in an independent large cohort.
Hashemian SM, Shafigh N, Afzal G, et al., 2021, Plasmapheresis reduces cytokine and immune cell levels in COVID-19 patients with acute respiratory distress syndrome (ARDS), Pulmonology, Vol: 27, Pages: 486-492, ISSN: 2531-0437
BACKGROUND: In December 2019, pneumonia associated with a novel coronavirus (COVID-19) was reported in Wuhan, China. Acute respiratory distress syndrome (ARDS) is the most frequently observed complication in COVID-19 patients with high mortality rates. OBJECTIVE OF STUDY: To observe the clinical effect of plasmapheresis on excessive inflammatory reaction and immune features in patients with severe COVID-19 at risk of ARDS. MATERIALS AND METHODS: In this single-center study, we included 15 confirmed cases of COVID-19 at Masih Daneshvari Hospital, in March 2020 in Tehran, Iran. COVID-19 cases were confirmed by RT-PCR and CT imaging according to WHO guidelines. Plasmapheresis was performed to alleviate cytokine-induced ARDS. The improvement in oxygen delivery (PaO2/FiO2), total number of T cells, liver enzymes, acute reaction proteins, TNF-α and IL-6 levels were evaluated. RESULTS: Inflammatory cytokine levels (TNF-α, IL-6), and acute phase reaction proteins including ferritin and CRP were high before plasmapheresis. After plasmapheresis, the levels of PaO2/FiO2, acute phase reactants, inflammatory mediators, liver enzymes and bilirubin were significantly reduced within a week (p < 0.05). In contrast, although the number of T helper cells decreased immediately after plasmapheresis, they rose to above baseline levels after 1 week. Nine out of fifteen patients on non-invasive positive-pressure ventilation (NIPPV) survived whilst the six patients undergoing invasive mechanical ventilation (IMV) died. CONCLUSION: Our data suggests that plasmapheresis improves systemic cytokine and immune responses in patients with severe COVID-19 who do not undergo IMV. Further controlled studies are required to explore the efficacy of plasmapheresis treatment in patients with COVID-19.
Reinke SN, Naz S, Chaleckis R, et al., 2021, Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study., Eur Respir J
INTRODUCTION: Asthma is a heterogeneous disease with poorly defined phenotypes. Severe asthmatics often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. Here, we aimed to identify dysregulated metabolic processes in relation to asthma severity and medication. METHODS: Baseline urine was collected prospectively from healthy participants (n=100), mild-to-moderate asthmatics (n=87) and severe asthmatics (n=418) in the cross-sectional U-BIOPRED cohort; 12-18-month longitudinal samples were collected from severe asthmatics (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods. RESULTS: Ninety metabolites were identified, with 40 significantly altered (p<0.05, FDR<0.05) in severe asthma and 23 by OCS use. Multivariate modelling showed that observed metabotypes in healthy participants and mild-to-moderate asthmatics differed significantly from severe asthmatics (p=2.6×10-20), OCS-treated asthmatics differed significantly from non-treated (p=9.5×10-4), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings. CONCLUSIONS: This is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the necessity to evaluate potential modulating effects on a treatment- and metabolite-specific basis. Altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS tre
Reinke S, Naz S, Kermani N, et al., 2021, The carnitine pathway is dysregulated in asthma in an oral corticosteroid-independent mechanism, 2021 ERS International Congress, Publisher: European Respiratory Society, ISSN: 0903-1936
Background: Asthma is a heterogeneous disease with poorly defined phenotypes.Aim: To identify metabolic dysregulations associated with asthma severity and evaluate the effects of asthma medication upon observed metabotypes.Methods: Baseline urine was collected from healthy controls (HC, n=108), mild-to-moderate asthmatics (MMA, n=87) and severe asthmatics (SA, n=418) from the U-BIOPRED cohort. 12-18 month longitudinal samples were collected from the SA cohort (n=305). Metabolomic data were acquired using mass spectrometry and analyzed using multivariate statistics. Gene set variation analysis (GSVA) was performed on bronchial brushing transcriptomic data.Results: 90 metabolites were identified with 40 altered in asthma (FDR<0.1). Multivariate modeling showed that HC and MMA differed significantly from all SA (p=1.4 ×10-14) and that oral corticosteroid (OCS)-treated asthmatics differed significantly from non-treated (p=9.52 ×10-4). Longitudinal samples were metabolically stable relative to baseline. OCS affected the levels of 25% of the metabolites, while theophylline affected 12%, and omalizumab had a minimal effect. Carnitine levels decreased in SA in an OCS-independent fashion. Carnitine is involved in long-chain fatty acid metabolism in mitochondria, which decreased along with levels of the carnitine transporter SLC22A5 in association with asthma severity in bronchial brushings, with differences strengthened by Th2 high/low stratification.Conclusions: SA have a dysregulated urinary metabolic profile that is strongly confounded by OCS treatment. Altered carnitine metabolism is independent of OCS and associated with mitochondrial dysfunction, presenting a potential target for intervention.
Mortaz E, Jamaati H, Roofchayee ND, et al., 2021, Decreased serum levels of angiotensin converting enzyme (ACE)2 and enhanced cytokine levels with severity of COVID-19: normalisation upon disease recovery, Publisher: Elsevier BV
Background:SARS-CoV-2 causes coronavirus disease 2019 (COVID-19). Circulating soluble angiotensin-converting enzyme (sACE2), the main receptor for SARS-CoV-2, together with components of the renin-angiotensin system promote infection and disease severity. Objective: In this pilot study we followed the time-course of sACE2 levels in relation to systemic cytokines in severe and moderate COVID-19 patients treated with remdesivir/dexamethasone in combination.Methods: Peripheral blood was obtained upon admission from 30 patients (12 with moderate disease and 18 with severe disease) and 14 patients with PCR-confirmed mild COVID-19. Severe and moderate patients were treated with remdesivir (200mg/first day and 100mg/day for the remaining days ) and dexamethasone (100mg/day ). 6 healthy control subjects (HC) were also enrolled. Serum interleukin (IL)-6 and IL-8 and sACE2 levels were measured by ELISA at baseline and during treatment in severe and moderate patients and at baseline in mild and HCs.Results: Baseline sACE2 levels were lower in severe (p=0.0005) and moderate (p=0.0022) patients than in patients with mild COVID-19 and in HC (p=0.0023 and p=0.0012 respectively). Serum sACE2 levels increased in patients with severe disease recovered over time compared with moderate (p=0.0021) and severe (p=0.0411) COVID-19 subjects at baseline. Systemic IL-6 and IL-8 levels were higher in all patient groups compared with HC and were not significantly affected over time or by remdesivir/dexamethasone treatment for 5 days.Conclusion: Serum sACE2 levels increase in severe COVID-19 patients as they recover over time whilst circulating cytokines are unaffected. Future studies should link these results to clinical outcomes.Funding: IMA is financially supported by the Welcome Trust (093080/Z/10/Z), the EPSRC (EP/T003189/1), and the Community Jameel Imperial College COVID-19 Excellence Fund (G26290) and by the UK MRC (MR/T010371/1). SM is supported by EU project 853850.Declaration of Inter
van de Wetering C, Manuel AM, Sharafi M, et al., 2021, Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2, Redox Biology, Vol: 47, Pages: 1-11, ISSN: 2213-2317
BackgroundInterleukin-1-dependent increases in glycolysis promote allergic airways disease in mice and disruption of pyruvate kinase M2 (PKM2) activity is critical herein. Glutathione-S-transferase P (GSTP) has been implicated in asthma pathogenesis and regulates the oxidation state of proteins via S-glutathionylation. We addressed whether GSTP-dependent S-glutathionylation promotes allergic airways disease by promoting glycolytic reprogramming and whether it involves the disruption of PKM2.MethodsWe used house dust mite (HDM) or interleukin-1β in C57BL6/NJ WT or mice that lack GSTP. Airway basal cells were stimulated with interleukin-1β and the selective GSTP inhibitor, TLK199. GSTP and PKM2 were evaluated in sputum samples of asthmatics and healthy controls and incorporated analysis of the U-BIOPRED severe asthma cohort database.ResultsAblation of Gstp decreased total S-glutathionylation and attenuated HDM-induced allergic airways disease and interleukin-1β-mediated inflammation. Gstp deletion or inhibition by TLK199 decreased the interleukin-1β-stimulated secretion of pro-inflammatory mediators and lactate by epithelial cells. 13C-glucose metabolomics showed decreased glycolysis flux at the pyruvate kinase step in response to TLK199. GSTP and PKM2 levels were increased in BAL of HDM-exposed mice as well as in sputum of asthmatics compared to controls. Sputum proteomics and transcriptomics revealed strong correlations between GSTP, PKM2, and the glycolysis pathway in asthma.ConclusionsGSTP contributes to the pathogenesis of allergic airways disease in association with enhanced glycolysis and oxidative disruption of PKM2. Our findings also suggest a PKM2-GSTP-glycolysis signature in asthma that is associated with severe disease.
Adcock I, Dezfuli NK, Alipoor SD, et al., 2021, Evaluation expression of miR-146a and miR-155 in non-small cell lung cancer patients, Frontiers in Oncology, Vol: 11, Pages: 1-12, ISSN: 2234-943X
Background: Non−small-cell lung cancer (NSCLC) is the major type of lung cancer. MicroRNAs (miRNAs) are novel markers and targets in cancer therapy and can act as both tumor suppressors and oncogenes and affect immune function. The aim of this study was to investigate the expression of miR146a and miR155 in linked to blood immune cell phenotypes and serum cytokines in NSCLC patients.Methods: Thirty-three NSCLC patients and 30 healthy subjects were enrolled in this study. The allele frequencies of potential DNA polymorphisms were studied using polymerase chain reaction (PCR)–restriction fragment length polymorphism (PCR-RFLP) analysis in peripheral blood samples. Quantitative reverse transcription PCR (qRT-PCR) was used to measure the expression of miR-146a and miR-155 in peripheral blood mononuclear cells (PBMCs). Serum cytokine (IL-1β, IL-6, TNF-α, TGF-β, IL-4, IFN-γ) levels were determined by ELISA. The frequency of circulating CD3+CTLA-4+ and CD4+CD25+FOXP3+ (T regulatory cells/Treg) expression was measured by flow cytometry.Results: miR-146a was significantly downregulated in PBMC of NSCLC patients (P ≤ 0.001). Moreover, IL-6 and TGF-β levels were elevated in NSCLC patients (P ≤ 0.001, P ≤ 0.018, respectively). CD3+ CTLA-4+ and Treg cells frequencies were higher in patients than in control subjects (P ≤ 0.0001, P ≤ 0.0001, respectively). There was a positive correlation between miR-155 and IL-1β levels (r=0.567, p ≤ 0.001) and a negative correlation between miR-146a and TGF-β levels (r=-0.376, P ≤ 0.031) in NSCLC patients. No significant differences were found in the relative expression of miR-146a and miR-155, cytokine levels or immune cell numbers according to miR-146a and miR-155 (GG/GC/CC, TT/AT/AA) genotypes. However, there was a positive correlation between miR-146a and IL-1β levels (r=0.74, P ≤ 0.009) in GG subjects and a positive correlation between miR-146a expression and CD3+
Zhou Y, Qiao Y, Adcock IM, et al., 2021, FIZZ2 as a Biomarker for Acute Exacerbation of Chronic Obstructive Pulmonary Disease, LUNG, Vol: 199, Pages: 629-638, ISSN: 0341-2040
Portelli MA, Rakkar K, Hu S, et al., 2021, Translational analysis of moderate to severe asthma GWAS signals into candidate causal genes and their functional, tissue-dependent and disease-related associations, Frontiers in Allergy, Vol: 2, ISSN: 2673-6101
Asthma affects more than 300 million people globally and is both under diagnosed and under treated. The most recent and largest genome-wide association study investigating moderate to severe asthma to date was carried out in 2019 and identified 25 independent signals. However, as new and in-depth downstream databases become available, the translational analysis of these signals into target genes and pathways is timely. In this study, unique (U-BIOPRED) and publicly available datasets (HaploReg, Open Target Genetics and GTEx) were investigated for the 25 GWAS signals to identify 37 candidate causal genes. Additional traits associated with these signals were identified through PheWAS using the UK Biobank resource, with asthma and eosinophilic traits amongst the strongest associated. Gene expression omnibus dataset examination identified 13 candidate genes with altered expression profiles in the airways and blood of asthmatic subjects, including MUC5AC and STAT6. Gene expression analysis through publicly available datasets highlighted lung tissue cell specific expression, with both MUC5AC and SLC22A4 genes showing enriched expression in ciliated cells. Gene enrichment pathway and interaction analysis highlighted the dominance of the HLA-DQA1/A2/B1/B2 gene cluster across many immunological diseases including asthma, type I diabetes, and rheumatoid arthritis. Interaction and prediction analyses found IL33 and IL18R1 to be key co-localization partners for other genes, predicted that CD274 forms co-expression relationships with 13 other genes, including the HLA-DQA1/A2/B1/B2 gene cluster and that MUC5AC and IL37 are co-expressed. Drug interaction analysis revealed that 11 of the candidate genes have an interaction with available therapeutics. This study provides significant insight into these GWAS signals in the context of cell expression, function, and disease relationship with the view of informing future research and drug development efforts for moderate-severe asthma.
Adcock I, Mortaz E, Bakhtiari Z, et al., 2021, Angiogenic effects of cell therapy within a biomaterial scaffold in a rat hind limb ischemia model, Scientific Reports, Vol: 11, Pages: 1-10, ISSN: 2045-2322
Critical limb ischemia (CLI) is a life- and limb-threatening condition affecting 1–10% of humans worldwide with peripheral arterial disease. Cellular therapies, such as bone marrow-derived mesenchymal stem cells (MSCs) have been used for the treatment of CLI. However, little information is available regarding the angiogenic potency of MSCs and mast cells (MC) in angiogenesis. The aim of this study was to evaluate the ability of MCs and MSCs to induce angiogenesis in a rat model of ischemic hind limb injury on a background of a tissue engineered hydrogel scaffold. Thirty rats were randomly divided into six control and experimental groups as follows: (a) Control healthy (b) Ischemic positive control with right femoral artery transection, (c) ischemia with hydrogel scaffold, (d) ischemia with hydrogel plus MSC, (e) ischemia with hydrogel plus MC and (f) ischemia with hydrogel plus MSC and MCs. 106 of each cell type, isolated from bone marrow stroma, was injected into the transected artery used to induce hind limb ischemia. The other hind limb served as a non-ischemic control. After 14 days, capillary density, vascular diameter, histomorphometry and immunohistochemistry at the transected location and in gastrocnemius muscles were evaluated. Capillary density and number of blood vessels in the region of the femoral artery transection in animals receiving MSCs and MCs was increased compared to control groups (P < 0.05). Generally the effect of MCs and MSCs was similar although the combined MC/MSC therapy resulted in a reduced, rather than enhanced, effect. In the gastrocnemius muscle, immunohistochemical and histomorphometric observation showed a great ratio of capillaries to muscle fibers in all the cell-receiving groups (P < 0.05). The data indicates that the combination of hydrogel and cell therapy generates a greater angiogenic potential at the ischemic site than cell therapy or hydrogels alone.
Yang Y, Man J, Yingwei O, et al., 2021, Mechanisms and biomarkers of airway epithelial cell damage in asthma: a review, The Clinical Respiratory Journal, Vol: 15, Pages: 1027-1045, ISSN: 1752-6981
Bronchial asthma is a heterogeneous disease with complex pathological mechanisms representing different phenotypes, including severe asthma. The airway epithelium is a major site of complex pathological changes in severe asthma due, in part, to activation of inflammatory and immune mechanisms in response to noxious agents. Current imaging procedures are unable to accurately measure epithelial and airway remodeling. Damage of airway epithelial cells occurs is linked to specific phenotypes and endotypes which provides an opportunity for the identification of biomarkers reflecting epithelial, and airway, remodeling. Identification of patients with more severe epithelial disruption using biomarkers may also provide personalized therapeutic opportunities and/or markers of successful therapeutic intervention. Here, we review the evidence for ongoing epithelial cell dysregulation in the pathogenesis of asthma, the sentinel role of the airway epithelium and how understanding these molecular mechanisms provides the basis for the identification of candidate biomarkers for asthma prediction, prevention, diagnosis, treatment and monitoring.
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