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1. A comparison of treatment response to biologics in asthma-COPD overlap and pure asthma: Findings from the PRISM study

Author

Ji-Su Shim, MD, PhD, Hyunkyoung Kim, MS, Jae-Woo Kwon, MD, PhD, So-Young Park, MD, PhD, Sujeong Kim, MD, PhD, Byung-Keun Kim, MD, PhD, Young-Hee Nam, MD, PhD, Min-Suk Yang, MD, PhD, Mi-Yeong Kim, MD, PhD, Sae-Hoon Kim, MD, PhD, Byung-Jae Lee, MD, PhD, Taehoon Lee, MD, PhD, Sang-Ha Kim, MD, PhD, So Young Park, MD, PhD, Young-Joo Cho, MD, PhD, Chan Sun Park, MD, PhD, Jae-Woo Jung, MD, PhD, Han-Ki Park, MD, PhD, Joo-Hee Kim, MD, PhD, Jeong-Hee Choi, MD, PhD, Ji-Yong Moon, MD, PhD, Ian Adcock, MD, PhD, Kian Fan Chung, MD, PhD, Min-Hye Kim, MD, PhD, and Tae-Bum Kim, MD, PhD

Subjects
Asthma-COPD overlap, Asthma, Biologics, Monoclonal antibodies, Treatment response, Immunologic diseases. Allergy, RC581-607
Abstract

Background: Despite the increasing use of biologics in severe asthma, there is limited research on their use in asthma-chronic obstructive pulmonary disease overlap (ACO). We compared real-world treatment responses to biologics in ACO and asthma. Methods: We conducted a multicenter, retrospective, cohort study using data from the Precision Medicine Intervention in Severe Asthma (PRISM). ACO was defined as post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) 10 pack-years. Physicians selected biologics (omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab) based on each United States Food & Drug Administration (FDA) approval criteria. Results: After six-month treatment with biologics, both patients with ACO (N = 13) and asthma (N = 81) showed positive responses in FEV1 (10.69 ± 17.17 vs. 11.25 ± 12.87 %, P = 0.652), Asthma Control Test score (3.33 ± 5.47 vs. 5.39 ± 5.42, P = 0.290), oral corticosteroid use (−117.50 ± 94.38 vs. −115.06 ± 456.85 mg, P = 0.688), fractional exhaled nitric oxide levels (−18.62 ± 24.68 vs. −14.66 ± 45.35 ppb, P = 0.415), sputum eosinophils (−3.40 ± 10.60 vs. −14.48 ± 24.01 %, P = 0.065), blood eosinophils (−36.47 ± 517.02 vs. −363.22 ± 1294.59, P = 0.013), and exacerbation frequency (−3.07 ± 4.42 vs. −3.19 ± 5.11, P = 0.943). The odds ratio for exacerbation and time-to-first exacerbation showed no significant difference after full adjustments, and subgroup analysis according to biologic type was also showed similar results. Conclusions: Biologics treatment response patterns in patients with ACO and asthma were comparable, suggesting that biologics should be actively considered for ACO patients as well.

Published
2023
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2. SARS-CoV2 in public spaces in West London, UK during COVID-19 pandemic

Author

Prashant Kumar, Kian Fan Chung, Ian Adcock, Pankaj K Bhavsar, Hisham Abubakar-Waziri, Gopinath Kalaiarasan, Rebecca Wawman, Faye Hobbs, Claire Dilliway, Fangxin Fang, Christopher Pain, Alexandra Porter, Emma Ransome, and Vincent Savolainen

Subjects
Medicine, Diseases of the respiratory system, RC705-779
Abstract

Background Spread of SARS-CoV2 by aerosol is considered an important mode of transmission over distances >2 m, particularly indoors.Objectives We determined whether SARS-CoV2 could be detected in the air of enclosed/semi-enclosed public spaces.Methods and analysis Between March 2021 and December 2021 during the easing of COVID-19 pandemic restrictions after a period of lockdown, we used total suspended and size-segregated particulate matter (PM) samplers for the detection of SARS-CoV2 in hospitals wards and waiting areas, on public transport, in a university campus and in a primary school in West London.Results We collected 207 samples, of which 20 (9.7%) were positive for SARS-CoV2 using quantitative PCR. Positive samples were collected from hospital patient waiting areas, from hospital wards treating patients with COVID-19 using stationary samplers and from train carriages in London underground using personal samplers. Mean virus concentrations varied between 429 500 copies/m3 in the hospital emergency waiting area and the more frequent 164 000 copies/m3 found in other areas. There were more frequent positive samples from PM samplers in the PM2.5 fractions compared with PM10 and PM1. Culture on Vero cells of all collected samples gave negative results.Conclusion During a period of partial opening during the COVID-19 pandemic in London, we detected SARS-CoV2 RNA in the air of hospital waiting areas and wards and of London Underground train carriage. More research is needed to determine the transmission potential of SARS-CoV2 detected in the air.

Published
2023
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3. Decision support system to evaluate ventilation in the acute respiratory distress syndrome (DeVENT study)—trial protocol

Author

Brijesh Patel, Sharon Mumby, Nicholas Johnson, Emanuela Falaschetti, Jorgen Hansen, Ian Adcock, Danny McAuley, Masao Takata, Dan S. Karbing, Matthieu Jabaudon, Peter Schellengowski, Stephen E. Rees, and on behalf of the DeVENT study group

Subjects
Mechanical ventilation, Acute respiratory distress syndrome, COVID-19, Decision support, Critical care, Pandemic, Medicine (General), R5-920
Abstract

Abstract Background 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. Methods 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. Discussion 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. 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 strategy according to the current physiology. Furthermore, the potential for the application of the Beacon Caresystem to facilitate local and remote management of large numbers of ventilated patients (as seen during this COVID-19 pandemic) could change the outcome of mechanically ventilated patients during the course of this and future pandemics. Trial registration ClinicalTrials.gov identifier NCT04115709. Registered on 4 October 2019, version 4.0

Published
2022
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5. Epigenetic impacts of maternal tobacco and e-vapour exposure on the offspring lung

Author

Razia Zakarya, Ian Adcock, and Brian G. Oliver

Subjects
Epigenetics, Airway, Lung development, Asthma, COPD, E-cigarette, Medicine, Genetics, QH426-470
Abstract

Abstract In utero exposure to tobacco products, whether maternal or environmental, have harmful effects on first neonatal and later adult respiratory outcomes. These effects have been shown to persist across subsequent generations, regardless of the offsprings’ smoking habits. Established epigenetic modifications induced by in utero exposure are postulated as the mechanism underlying the inherited poor respiratory outcomes. As e-cigarette use is on the rise, their potential to induce similar functional respiratory deficits underpinned by an alteration in the foetal epigenome needs to be explored. This review will focus on the functional and epigenetic impact of in utero exposure to maternal cigarette smoke, maternal environmental tobacco smoke, environmental tobacco smoke and e-cigarette vapour on foetal respiratory outcomes.

Published
2019
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6. FN3K expression in COPD: a potential comorbidity factor for cardiovascular disease

Author

Irfan Rahman, Emma H Baker, Gaetano Caramori, Alberto Papi, Amr Alderawi, Andrew William Hitchings, Christos Rossios, Ian Adcock, Victor E Ortega, Jeffrey L Curtis, Simon Dunmore, Paul Kirkham, and Paolo Casolari

Subjects
Medicine, Diseases of the respiratory system, RC705-779
Abstract

Introduction Cigarette smoking and oxidative stress are common risk factors for the multi-morbidities associated with chronic obstructive pulmonary disease (COPD). Elevated levels of advanced glycation endproducts (AGE) increase the risk of cardiovascular disease (CVD) comorbidity and mortality. The enzyme fructosamine-3-kinase (FN3K) reduces this risk by lowering AGE levels.Methods The distribution and expression of FN3K protein in lung tissues from stable COPD and control subjects, as well as an animal model of COPD, was assessed by immunohistochemistry. Serum FN3K protein and AGE levels were assessed by ELISA in patients with COPD exacerbations receiving metformin. Genetic variants within the FN3K and FN3K-RP genes were evaluated for associations with cardiorespiratory function in the Subpopulations and Intermediate Outcome Measures in COPD Study cohort.Results This pilot study demonstrates that FN3K expression in the blood and human lung epithelium is distributed at either high or low levels irrespective of disease status. The percentage of lung epithelial cells expressing FN3K was higher in control smokers with normal lung function, but this induction was not observed in COPD patients nor in a smoking model of COPD. The top five nominal FN3K polymorphisms with possible association to decreased cardiorespiratory function (p

Published
2020
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7. How can we minimise the use of regular oral corticosteroids in asthma?

Author

Arnaud Bourdin, Ian Adcock, Patrick Berger, Philippe Bonniaud, Philippe Chanson, Cécile Chenivesse, Jacques de Blic, Antoine Deschildre, Philippe Devillier, Gilles Devouassoux, Alain Didier, Gilles Garcia, Antoine Magnan, Yan Martinat, Thierry Perez, Nicolas Roche, Camille Taillé, Pierre Val, and Pascal Chanez

Subjects
Diseases of the respiratory system, RC705-779
Abstract

Options to achieve oral corticosteroid (OCS)-sparing have been triggering increasing interest since the 1970s because of the side-effects of OCSs, and this has now become achievable with biologics. The Société de Pneumologie de Langue Française workshop on OCSs aimed to conduct a comprehensive review of the basics for OCS use in asthma and issue key research questions. Pharmacology and definition of regular use were reviewed by the first working group (WG1). WG2 examined whether regular OCS use is associated with T2 endotype. WG3 reported on the specificities of the paediatric area. Key “research statement proposals” were suggested by WG4. It was found that the benefits of regular OCS use in asthma outside episodes of exacerbations are poorly supported by the existing evidence. However, complete OCS elimination couldn’t be achieved in any available studies for all patients and the panel felt that it was too early to conclude that regular OCS use could be declared criminal. Repeated or prolonged need for OCS beyond 1 g·year−1 should indicate the need for referral to secondary/tertiary care. A strategic sequential plan aiming at reducing overall exposure to OCS in severe asthma was then held as a conclusion of the workshop.

Published
2020
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8. The anti-proliferative and anti-inflammatory response of COPD airway smooth muscle cells to hydrogen sulfide

Author

Mark M. Perry, Bernadett Tildy, Alberto Papi, Paolo Casolari, Gaetano Caramori, Karen Limbert Rempel, Andrew J. Halayko, Ian Adcock, and Kian Fan Chung

Subjects
COPD, Hydrogen sulfide, Proliferation, IL-6, CXCL8, Airway smooth muscle, Diseases of the respiratory system, RC705-779
Abstract

Abstract Backbround COPD is a common, highly debilitating disease of the airways, primarily caused by smoking. Chronic inflammation and structural remodelling are key pathological features of this disease caused, in part, by the aberrant function of airway smooth muscle (ASM). We have previously demonstrated that hydrogen sulfide (H2S) can inhibit ASM cell proliferation and CXCL8 release, from cells isolated from non-smokers. Methods We examined the effect of H2S upon ASM cells from COPD patients. ASM cells were isolated from non-smokers, smokers and patients with COPD (n = 9). Proliferation and cytokine release (IL-6 and CXCL8) of ASM was induced by FCS, and measured by bromodeoxyuridine incorporation and ELISA, respectively. Results Exposure of ASM to H2S donors inhibited FCS-induced proliferation and cytokine release, but was less effective upon COPD ASM cells compared to the non-smokers and smokers. The mRNA and protein expression of the enzymes responsible for endogenous H2S production (cystathionine-β-synthase [CBS] and 3-mercaptopyruvate sulphur transferase [MPST]) were inhibited by H2S donors. Finally, we report that exogenous H2S inhibited FCS-stimulated phosphorylation of ERK–1/2 and p38 mitogen activated protein kinases (MAPKs), in the non-smoker and smoker ASM cells, with little effect in COPD cells. Conclusions H2S production provides a novel mechanism for the repression of ASM proliferation and cytokine release. The ability of COPD ASM cells to respond to H2S is attenuated in COPD ASM cells despite the presence of the enzymes responsible for H2S production.

Published
2018
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11. Glucocorticoid Receptor Nuclear Translocation in CD4 T Cells from Severe and Moderate Asthmatic Patients Treated with Fluticasone/Vilanterol

Author

Zahra Alizadeh, Marzieh Mazinani, Esmaeil Mortaz, Mohammad Reza Fazlollahi, Ian Adcock, and Mostafa Moein

Subjects
Corticosteroid, Glucocorticoid receptor, Long-acting b2 agonist, Severe asthma, Medicine
Abstract

Different phenotypes of asthma from mild to severe are categorized based on diverse clinical features. A guideline for the recognition and treatment of asthma has been provided by Global Initiative for Asthma (GINA). To control symptoms and prevent asthma exacerbation in most patients combinational therapy with inhaled corticosteroids (ICS) and a long acting B2-adrenreceptor agonist (LABA) are recommended. Understanding asthma phenotypes would be helpful to improve asthma diagnosis and treatment. The aim of this study was to verify glucocorticoid receptor glcococorticoid receptor (GR) nuclear translocation in CD4 T cells treated with fluticasone furoate (FF), vilanterol (V) and FF/V combination in severe asthmatic patients compare to patients with moderate asthma and healthy controls using Immunocytochemistry (ICC). After taking blood and separating PBMCs from each subject, CD4 T cells were isolated from PBMCs using CD4+ T cell isolation kit. Isolated CD4 T cells were cultured in presence of FF, V and FF/V combination for 1 hour and after cytocentrifugation, cells were incubated with anti GR-antibody and subsequently stained with FITC bound secondary antibody and GR nuclear translocation was observed under microscope. The results showed significant increasing in GR nuclear translocation in treated CD4 T cells from patients with moderate asthma and controls compare to those severe asthmatic patients, along with treating cells with FF/V combination no significant GR nuclear translocation was observed compare to that of using mono treatment of cells with FF and V. Based on our findings, it can be concluded different mechanisms are responsible for severe asthma and moderate asthma.

Published
2018

12. Inferring cell-scale signalling networks via compressive sensing.

Author

Lei Nie, Xian Yang, Ian Adcock, Zhiwei Xu, and Yike Guo

Subjects
Medicine, Science
Abstract

Signalling network inference is a central problem in system biology. Previous studies investigate this problem by independently inferring local signalling networks and then linking them together via crosstalk. Since a cellular signalling system is in fact indivisible, this reductionistic approach may have an impact on the accuracy of the inference results. Preferably, a cell-scale signalling network should be inferred as a whole. However, the holistic approach suffers from three practical issues: scalability, measurement and overfitting. Here we make this approach feasible based on two key observations: 1) variations of concentrations are sparse due to separations of timescales; 2) several species can be measured together using cross-reactivity. We propose a method, CCELL, for cell-scale signalling network inference from time series generated by immunoprecipitation using Bayesian compressive sensing. A set of benchmark networks with varying numbers of time-variant species is used to demonstrate the effectiveness of our method. Instead of exhaustively measuring all individual species, high accuracy is achieved from relatively few measurements.

Published
2014
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13. Effects of N-acetylcysteine in ozone-induced chronic obstructive pulmonary disease model.

Author

Feng Li, Cornelis Wiegman, Joanna M Seiffert, Jie Zhu, Colin Clarke, Yan Chang, Pank Bhavsar, Ian Adcock, Junfeng Zhang, Xin Zhou, and Kian Fan Chung

Subjects
Medicine, Science
Abstract

Chronic exposure to high levels of ozone induces emphysema and chronic inflammation in mice. We determined the recovery from ozone-induced injury and whether an antioxidant, N-acetylcysteine (NAC), could prevent or reverse the lung damage.Mice were exposed to ozone (2.5 ppm, 3 hours/12 exposures, over 6 weeks) and studied 24 hours (24h) or 6 weeks (6W) later. Nac (100 mg/kg, intraperitoneally) was administered either before each exposure (preventive) or after completion of exposure (therapeutic) for 6 weeks.After ozone exposure, there was an increase in functional residual capacity, total lung volume, and lung compliance, and a reduction in the ratio of forced expiratory volume at 25 and 50 milliseconds to forced vital capacity (FEV25/FVC, FEV50/FVC). Mean linear intercept (Lm) and airway hyperresponsiveness (AHR) to acetylcholine increased, and remained unchanged at 6W after cessation of exposure. Preventive NAC reduced the number of BAL macrophages and airway smooth muscle (ASM) mass. Therapeutic NAC reversed AHR, and reduced ASM mass and apoptotic cells.Emphysema and lung function changes were irreversible up to 6W after cessation of ozone exposure, and were not reversed by NAC. The beneficial effects of therapeutic NAC may be restricted to the ASM.

Published
2013
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14. SARS-CoV2 in public spaces in West London UK during COVID-19 pandemic

Author

Hisham Abubakar-Waziri, Gopinath Kalaiarasan, Rebecca Wawman, Faye Hobbs, Ian Adcock, Claire Dilliway, Fangxin Fang, Christopher Pain, Alexandra Porter, Pankaj K Bhavsar, Emma Ransome, Vincent Savolainen, Prashant Kumar, and Kian Fan Chung

Subjects
Pulmonary and Respiratory Medicine
Abstract

BackgroundSpread of SARS-CoV2 by aerosol is considered an important mode of transmission over distances >2 m, particularly indoors.ObjectivesWe determined whether SARS-CoV2 could be detected in the air of enclosed/semi-enclosed public spaces.Methods and analysisBetween March 2021 and December 2021 during the easing of COVID-19 pandemic restrictions after a period of lockdown, we used total suspended and size-segregated particulate matter (PM) samplers for the detection of SARS-CoV2 in hospitals wards and waiting areas, on public transport, in a university campus and in a primary school in West London.ResultsWe collected 207 samples, of which 20 (9.7%) were positive for SARS-CoV2 using quantitative PCR. Positive samples were collected from hospital patient waiting areas, from hospital wards treating patients with COVID-19 using stationary samplers and from train carriages in London underground using personal samplers. Mean virus concentrations varied between 429 500 copies/m3in the hospital emergency waiting area and the more frequent 164 000 copies/m3found in other areas. There were more frequent positive samples from PM samplers in the PM2.5 fractions compared with PM10 and PM1. Culture on Vero cells of all collected samples gave negative results.ConclusionDuring a period of partial opening during the COVID-19 pandemic in London, we detected SARS-CoV2 RNA in the air of hospital waiting areas and wards and of London Underground train carriage. More research is needed to determine the transmission potential of SARS-CoV2 detected in the air.

Published
2023

15. Abstracts

Author

Norman Morris, Michelle Schwager, Ian Adcock, and Khoa Tran

Subjects
Pulmonary and Respiratory Medicine
Published
2022
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17. Effects of Toll Like Receptor Agonists and SARS-Cov-2 Antigens on Interferon (IFN) Expression by Peripheral Blood CD3+ T Cells in COVID-19 Patients

Author

Samaneh A Abdolmohammadi-Vahid, Behzad Baradaran, Armin Sadeghi, Gilina Bezemer, Fatemeh K Kiaee, Ian Adcock, Gert Folkerts, Johan Garssen, and Esmaeil Mortaz

Subjects
biology_other
Abstract

Background: Signaling by toll like receptors (TLRs) initiates important immune responses against viral infection. The role of TLRs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is not well elucidated. Thus, we investigated the interaction of TLRs agonists and SARS-COV-2 antigens with immune cells in vitro. Material & methods: 30 coronavirus disease 2019 (COVID-19) patients (15 severe and 15 moderate) and 10 age and sex matched control (HC) were enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated and activated with TLR3, 7, 8 and 9 agonists, the spike protein (SP) of SARS-CoV-2 and the Receptor Binding Domain (RBD) unit of SP. Frequencies of CD3+IFN-β+ T cells, and CD3+IFN-g+ T cells was evaluated by flow cytometry. Interferon (IFN)-b gene expression was assessed by qRT-PCR. Results: The frequency of CD3+IFN-β+ T cells was higher in moderate and severe patients at baseline in comparison with HCs. Stimulation of PBMCs from moderate patients with SP and TLR8 agonist significantly upregulated the frequency of CD3+IFN-β+ T cells (P=0.0005 and 0.0024, respectively) when compared to non-stimulated (NS) samples. The greatest increase in CD3+IFN-b+ T cell frequency in PBMCs from severe patients was seen with TLR8 and TLR7 agonists when compared to NS (P= 0.003 and 0.0167, respectively). TLR stimulation did not significantly enhance the frequency of CD3+IFN-g+ T cells generated from PBMCs from moderate and severe patients compared with unstimulated controls. However, the frequency of CD3+IFN-ɣ+ T cells in PBMCs from moderate patients was upregulated by agonists of TLR3, 8 and 9, SP and RBD when compared with NS samples from HCs. The expression of the IFN-β gene after stimulation of CD3+T cells with the TLR8 agonist was also up-regulated in moderate than severe patients (moderate vs. severe: p=0.0006). In addition, stimulation of CD3+ T cells with SP, up-regulated the expression of IFN-β gene expression in cells from patients with moderate disease (moderate vs. severe: p=0.01). Conclusion: Stimulation of PBMCs from COVID-19 patients with a TLR8 agonist and with SP enhanced IFN-b protein and gene levels. This may potentiate immune responses against SARS-CoV-2 infection and prevent viral replication and spread.

Published
2022

18. H influenzae & M catarrhalis in sputum of severe asthma with inflammasome and neutrophil activation

Author

Kian Fan Chung, Ali Versi, Fransiskus Xaverius Ivan, Mahmoud Ibrahim, Stewart Bates, John Riley, Frederic Baribaud, Nazanin Zounemat Kermani, Paolo Montuschi, Sven-Erik Dahlén, Ratko Djukanovic, Peter Sterk, Anke-Hilse Maitland-van der Zee, Sanjay Haresh Chotirmall, Peter Howarth, and Ian Adcock

Abstract

Background. Because of altered airway microbiome in asthma, we analysed the bacterial species in sputum of patients with severe asthma. Methods. Whole genome sequencing was performed on induced sputum from non-smoking (SAn) and current or ex-smoker (SAs/ex) severe asthma patients, mild/moderate asthma (MMA) and healthy controls (HC). Data was analysed by asthma severity, inflammatory status and transcriptome-associated clusters (TACs). Results. α-diversity at the species level was lower in SAn and SAs/ex, with an increase in Haemophilus influenzae and Moraxella catarrhalis, and Haemophilus influenzae and Tropheryma whipplei, respectively, compared to HC. In neutrophilic asthma, there was greater abundance of Haemophilus influenzae and Moraxella catarrhalis and in eosinophilic asthma, Tropheryma whipplei was increased. There was a reduction in α-diversity in TAC1 and TAC2 that expressed high levels of Haemophilus influenzae and Tropheryma whipplei, and Haemophilus influenzae and Moraxella catarrhalis, respectively, compared to HC. Sputum neutrophils correlated positively with Moraxella catarrhalis and negatively with Prevotella, Neisseria and Veillonella species and Haemophilus parainfluenzae. Sputum eosinophils correlated positively with Tropheryma whipplei which correlated with pack-years of smoking. α- and β-diversities were stable at one year. Conclusions.Haemophilus influenzae and Moraxella catarrhalis were more abundant in severe neutrophilic asthma and TAC2 linked to inflammasome and neutrophil activation, while Haemophilus influenzae and Tropheryma whipplei were highest in SAs/ex and in TAC1 associated with highest expression of IL-13 Type 2 and ILC2 signatures with the abundance of Tropheryma whipplei correlating positively with sputum eosinophils. Whether these bacterial species drive the inflammatory response in asthma needs evaluation.

Published
2022
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19. Th2 high and mast cell gene signatures are associated with corticosteroid sensitivity in COPD

Author

Alen Faiz, Stelios Pavlidis, Chih-Hsi Kuo, Anthony Rowe, Pieter S Hiemstra, Wim Timens, Marijn Berg, Marissa Wisman, Yi-Ke Guo, Ratko Djukanović, Peter Sterk, Kerstin B Meyer, Martijn C Nawijn, Ian Adcock, Kian Fan Chung, Maarten van den Berge, Groningen Research Institute for Asthma and COPD (GRIAC), Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Pulmonology

Subjects
Pulmonary and Respiratory Medicine, COPD pathology, oxidative stress, airway epithelium
Abstract

RationaleSevere asthma and chronic obstructive pulmonary disease (COPD) share common pathophysiological traits such as relative corticosteroid insensitivity. We recently published three transcriptome-associated clusters (TACs) using hierarchical analysis of the sputum transcriptome in asthmatics from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort comprising one Th2-high inflammatory signature (TAC1) and two Th2-low signatures (TAC2 and TAC3).ObjectiveWe examined whether gene expression signatures obtained in asthma can be used to identify the subgroup of patients with COPD with steroid sensitivity.MethodsUsing gene set variation analysis, we examined the distribution and enrichment scores (ES) of the 3 TACs in the transcriptome of bronchial biopsies from 46 patients who participated in the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease COPD study that received 30 months of treatment with inhaled corticosteroids (ICS) with and without an added long-acting β-agonist (LABA). The identified signatures were then associated with longitudinal clinical variables after treatment. Differential gene expression and cellular convolution were used to define key regulated genes and cell types.Measurements and main resultsBronchial biopsies in patients with COPD at baseline showed a wide range of expression of the 3 TAC signatures. After ICS±LABA treatment, the ES of TAC1 was significantly reduced at 30 months, but those of TAC2 and TAC3 were unaffected. A corticosteroid-sensitive TAC1 signature was developed from the TAC1 ICS-responsive genes. This signature consisted of mast cell-specific genes identified by single-cell RNA-sequencing and positively correlated with bronchial biopsy mast cell numbers following ICS±LABA. Baseline levels of gene transcription correlated with the change in RV/TLC %predicted following 30-month ICS±LABA.ConclusionSputum-derived transcriptomic signatures from an asthma cohort can be recapitulated in bronchial biopsies of patients with COPD and identified a signature of airway mast cells as a predictor of corticosteroid responsiveness.

Published
2022

20. Long-standing COVID-19 disease in immunedeficient patients; case reports and literature review

Author

Esmaeil Mortaz, Neda Dalil Roofchayee, Hamidreza Jamaati, Zahra Abtahian, Babak afshar, Shahrzad Ahmadi, Mahsa Rekabi, Ian Adcock, and Payam Tabarsi

Abstract

Introduction: Patients with primary or secondary immunodeficiency are at higher risk of severe disease and death following SARS-CoV-2 infection compared with the general population. We describe here the effect of rituximab therapy in 5 patients with humoral and cellular immune deficiencies (1 patient with thymoma or Good`syndrome, 1 HIV/AIDS positive patient, 2 patients with Multiple Sclerosis (MS) and 1 patient with chronic lymphocytic leukemia (CLL). T cell responses were evaluated using the QuantiFERON SARS-CoV-2 assay following incubation with the SARS-CoV-2 Ag1, Ag2 and Ag3 viral antigens. Immunephenotyping of T cells (TCD4+, TCD8+) and B cells (CD19+ and CD20+) was determined by flow cytometry. Results: All studied immunocompromised patients showed reduced cellular immune responses (release of interferon (IFN)-g) to SARS-CoV-2 antigens than healthy controls [patients; Ag1, Ag2 and Ag3 and Nil (Median 5-95% percentile) (12 (1-95), 12 (1.5-78), 13.5 (12-95) and 3 (1-98) U/ml)], ]controls; Ag1,Ag2 and Ag3 and Nil (Median 5-95% percentile) 24.5 (7-89), 65 (31-173), 53.5 (13-71.5) and 3 (1-14) U/ml)]. The frequency of peripheral blood B cells was also reduced in these patients compared to healthy control subjects (p=0.0282). Conclusion: T-cell dependent antibody responses require the activation of B cells by helper T cells. Reduced B cell numbers in immunocompromised patients infected with SARS-CoV-2 indicates the need for these patients to take additional precautions to prevent COVID-19 infection

Published
2022
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25. Adult Severe Asthma

Author

Piers Dixey, Hisham Abubakar-Waziri, Katie Raby, Ramzi Lakhdar, Nazanin Kermani, Sharon Mumby, Elizabeth Owen, Ian Adcock, Pankaj Bhavsar, and Kian Fan Chung

Published
2022
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26. The carnitine pathway is dysregulated in asthma in an oral corticosteroid-independent mechanism

Author

Stacey Reinke, Shama Naz, Nazanin Kermani, Romanas Chaleckis, Johan Kolmert, Marika Ström, Åsa Wheelock, Ratko Djukanovic, Fan Chung, Ian Adcock, Sven-Erik Dahlen, Craig Wheelock, Ubiopred Study Group, Engineering & Physical Science Research Council (EPSRC), and Commission of the European Communities

Subjects
Severe asthma, Science & Technology, business.industry, Mechanism (biology), medicine.drug_class, Respiratory System, Pharmacology, medicine.disease, Asthma - mechanism, Medicine, Corticosteroid, Personalised medicine, Carnitine, business, Life Sciences & Biomedicine, 11 Medical and Health Sciences, Asthma, medicine.drug
Abstract

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

Published
2021

27. Association of HLA-DR Alleles With Pulmonary Cystic Fibrosis

Author

alireza asef, Hossein Ali Ghaffaripour, hamidreza Jamaati, Mohammad Varahram, Ian Adcock, and Esmaeil Mortaz

Subjects
genetic structures
Abstract

Background: Cystic fibrosis (CF) is the most common lethal autosomal recessive disease in white Caucasians. It affects many organs including the lung, pancreas, and liver. Whilst CF is a monogenic disease, several studies revealed a complex relationship between genotype and clinical phenotype of diseases. Objective of study: We examined the expression of HLA class II alleles among Iranian CF patients in relation to disease-related bacterial infection. Materials and methods: This study was conducted on 50 CF patients (27 males, 23 females aged 15.5±6.5 years) hospitalized in the Masih Daneshvari hospital in Tehran, Iran and 50 healthy age- and gender-matched control subjects. 5ml whole blood was harvested and after isolation of genomic DNA, HLA-DRB1 subtypes were determined by Single Specific Primer Polymerase Chain Reaction (SSP-PCR) methods. Results: HLA-DRB1*10 was less frequent than HLA-DRB1*04 and HLA-DRB1*11 but none reached significance. 16 CF patients with high serum IgE levels (430.25 ± 219.7 IU/ml) and 27 CF patients positive for Pseudomonas aeruginosa colonization were most closely associated with the HLA-DRB1*04 allele. 31 CF patients had candida Albicans colonization which was most closely associated with HLA-DRB1*11. 3 CF patients had allergic bronchopulmonary aspergillosis (ABPA) and two were diabetic. Discussion: The DR4 and DR11 serotypes that recognize the HLA-DRB1*04 and HLA-DRB1*11 gene products respectively, are not significantly enriched in the Iranian CF population. Further research should be conducted on DR4 and DR11 in CF patients to understand their possible role in infection and IgE expression.Trial registration: The study was approved by Ethical committee of Masih Daneshvari Hospital IR.SBMU.NRITLD.1395.234

Published
2021
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28. Nrf2-interacting nutrients and COVID-19: time for research to develop adaptation strategies

Author

Bousquet, Jean, Cristol, Jean-Paul, Czarlewski, Wienczyslawa, Anto, Josep M, Martineau, Adrian, Haahtela, Tari, Fonseca, Susana C, Iaccarino, Guido, Blain, Hubert, Fiocchi, Alessandro, Canonica, G Walter, Fonseca, Joao A, Vidal, Alain, Choi, Hak-Jong, Kim, Hyun Ju, Le Moing, Vincent, Reynes, Jacques, Sheikh, Aziz, Akdis, Cezmi A, Zuberbier, Torsten, Amir Hamzah Abdul Latiff, Baharudin, Abdullah, Werner, Aberer, Nancy, Abusada, Ian, Adcock, Alejandro, Afani, Ioana, Agache, Xenofon, Aggelidis, Jenifer, Agustin, Cezmi, A Akdis, Mübeccel, Akdis, Mona, Al-Ahmad, Abou Al-Zahab Bassam, Hussam, Alburdan, Oscar, Aldrey-Palacios, Emilio Alvarez Cuesta, Hiba Alwan Salman, Ashraf, Alzaabi, Salma, Amade, Gene, Ambrocio, Rosana, Angles, Isabella, Annesi-Maesano, Ignacio, J Ansotegui, Josep, M Anto, Paula Ara Bardajo, Stefania, Arasi, Margarete, Arrais, Hasan, Arshad, Maria-Cristina, Artesani, Estrella, Asayag, Francesca, Avolio, Khuzama, Azhari, Claus, Bachert, Diego, Bagnasco, Ilaria, Baiardini, Nissera, Bajrović, Petros, Bakakos, Sergio Bakeyala Mongono, Christine, Balotro-Torres, Sergio, Barba, Cristina, Barbara, Elsa, Barbosa, Bruno, Barreto, Joan, Bartra, Xavier, Basagana, Eric, D Bateman, Lkhagvaa, Battur, Anna, Bedbrook, Martín Bedolla Barajas, Bianca, Beghé, Antra, Bekere, Elizabeth, Bel, Ali Ben Kheder, Mikael, Benson, Elena-Camelia, Berghea, Karl-Christian, Bergmann, Roberto, Bernardini, David, Bernstein, Mike, Bewick, Slawomir, Bialek, Artur, Białoszewski, Thomas, Bieber, Nils, E Billo, Maria-Beatrice, Bilo, Carsten, Bindslev-Jensen, Leif, Bjermer, Hubert, Blain, Irina, Bobolea, Malgorzata Bochenska Marciniak, Christine, Bond, Attilio, Boner, Matteo, Bonini, Sergio, Bonini, Sinthia, Bosnic-Anticevich, Isabelle, Bosse, Sofia, Botskariova, Jacques, Bouchard, Louis-Philippe, Boulet, Rodolphe, Bourret, Philippe, Bousquet, Fulvio, Braido, Andrew, Briggs, Christopher, E Brightling, Jan, Brozek, Luisa, Brussino, Roland, Buhl, Roxana, Bumbacea, Rosalva, Buquicchio, 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E.-C., Bergmann K.-C., Bernardini R., Bernstein D., Bewick M., Bialek S., Bialoszewski A., Bieber T., Billo N.E., Bilo M.-B., Bindslev-Jensen C., Bjermer L., Bobolea I., Bochenska Marciniak M., Bond C., Boner A., Bonini M., Bonini S., Bosnic-Anticevich S., Bosse I., Botskariova S., Bouchard J., Boulet L.-P., Bourret R., Bousquet P., Braido F., Briggs A., Brightling C.E., Brozek J., Brussino L., Buhl R., Bumbacea R., Buquicchio R., Burguete Cabanas M.-T., Bush A., Busse W.W., Buters J., Caballero-Fonseca F., Calderon M.A., Calvo M., Camargos P., Camuzat T., Canevari F., Cano A., Canonican G.W., Capriles-Hulett A., Caraballo L., Cardona V., Carlsen K.-H., Carmona Pirez J., Caro J., Carr W., Carreiro-Martins P., Carreon-Asuncion F., Carriazo A.-M., CarrionyRibas C., Casale T., Castor M.-A., Castro E., Caviglia A.G., Cecchi L., Cepeda Sarabia A., Chalubinski M., Chandrasekharan R., Chang Y.-S., Chato-Andeza V., Chatzi L., Chatzidaki C., Chavannes N.H., Chaves Loureiro C., Chavez Garcia A.-A., Chelninska M., Chen Y., Cheng L., Chinthrajah S., Chivato T., Chkhartishvili E., Christoff G., Chrystyn H., Chu D.K., Chua A., Chuchalin A., Chung K.F., Ciceran A., Cingi C., Ciprandi G., Cirule I., Coelho A.-C., Compalati E., Constantinidis J., Correia de Sousa J., Costa E.M., Costa D., del Carmen Costa Dominguez M., Coste A., Cottini M., Cox L., Crisci C., Crivellaro M.A., Cruz A.A., Cullen J., Custovic A., Cvetkovski B., D'Amato G., da Silva J., Dahl R., Dahlen S.-E., Daniilidis V., Darjazini Nahhas L., Darsow U., Davies J., de Blay F., De Feo G., De Guia E., De la Torre Navarrete J.-R., De los Santos C., De Manuel Keenoy E., De Vries G., Deleanu D., Demoly P., Denburg J., Devillier P., Didier A., Dimic Janjic S., Dimou M., Dinh-Xuan A.T., Djukanovic R., Do Ceu Texeira M., Dokic D., Dominguez Silva M.G., Douagui H., Douladiris N., Doulaptsi M., Dray G., Dubakiene R., Dupas E., Durham S., Duse M., Dykewicz M., Ebo D., Edelbaher N., Eiwegger T., Eklund P., El-Gamal Y., El-Sayed Z.A., El-Sayed S.S., El-Seify M., Emuzyte R., Enecilla L., Erhola M., Espinoza H., Espinoza Contreras J.G., Farrell J., Fernandez L., Fimbres Jimenez P., Fink Wagner A., Fokkens W.J., Folletti L., Fontaine J.-F., Forastiere F., Fuentes Perez J.M., Gaerlan-Resureccion E., Gaga M., Galvez Romero J.L., Gamkrelidze A., Garcia A., Garcia Cobas C.Y., de la Luz Hortensia Garcia Cruz M., Ortiz V.G., Gayraud J., Gelardi M., Gemicioglu B., Gennimata D., Genova S., Gereda J., Gerth van Wijk R., Giuliano A., Gomez R.-M., Gonzalez Ballester M.-A., Gonzalez Diaz S., Gotua M., Grigoreas C., Grisle I., Guidacci M., Guldemond N., Gutter Z., Guzman A., Halloum R., Halpin D., Hamelmann E., Hammadi S., Harvey R., Heffler E., Heinrich J., Hejjaoui A., Hellquist-Dahl B., Hernandez Velazquez L., Hew M., Hossny E., Howarth P., Hrubisko M., Huerta Villalobos Y.R., Humbert M., Husain S., Hyland M., Ibrahim M., Ilina N., Illario M., Incorvaia C., Infantino A., Irani C., Ispayeva Z., Ivancevich J.C., Jares E.E., Jarvis D., Jassem E., Jenko K., Jimeneracruz Uscanga R.D., Johnston S.L., Joos G., Jost M., Julge K., Jung K.-S., Just J., Jutel M., Kaidashev I., Kalayci O., Kalyoncu F., Kapsali J., Kardas P., Karjalainen J., Kasala C.A., Katotomichelakis M., Kavaliukaite L., Bennoor K.S., Keil T., Keith P., Khaitov M., Khaltaev N., Kim Y.-Y., Kirenga B., Kleine-Tebbe J., Klimek L., Ko F.W., Koffi N'Goran B., Kompoti E., Kopac P., Koppelman G., Koren Jeverica A., Koskinen S., Kosnik M., Kostka T., Kostov K.V., Kowalski M.L., Kralimarkova T., Kramer Vrscaj K., Kraxner H., Kreft S., Kritikos V., Kudlay D., Kuitunen M., Kull I., Kuna P., Kupczyk M., Kvedariene V., Kyriakakou M., Lalek N., Landi M., Lane S., Larenas-Linnemann D.E., Lau S., Laune D., Lavrut J., Le L., Lenzenhuber M., Leo G., Lessa M., Levin M., Li J., Lieberman P., Liotta G., Lipworth B., Liu X., Lobo R., Lodrup Carlsen K.C., Lombardi C., Louis R., Loukidis S., Lourenco O., Luna Pech J.A., Madjar B., Maggi E., Magnan A., Mahboub B., Mair A., Maitland van der Zee A.-H., Makela M., Makris M., Malling H.-J., Mandajieva M., Manning P., Manousakis M., Maragoudakis P., Marseglia G., Marshall G., Masjedi M.R., Maspero J.F., Matta Campos J.J., Maurer M., Mavale-Manuel S., Meco C., Melen E., Melioli G., Melo-Gomes E., Meltzer E.O., Menditto E., Menzies-Gow A., Merk H., Michel J.-P., Micheli Y., Miculinic N., Midao L., Mihaltan F., Mikos N., Milanese M., Milenkovic B., Mitsias D., Moalla B., Moda G., Mogica Martinez M.D., Mohammad Y., Moharra F.-M., Moin M., Molimard M., Momas I., Mommers M., Monaco A., Montefort S., Montenegro L.-E., Monti R., Mora D., Morais-Almeida M., Mosges R., Mostafa B.E., Mullol J., Munter L., Muraro A., Murray R., Musarra A., Mustakov T., Naclerio R., Nadeau K.C., Nadif R., Nakonechna A., Namazova-Baranova L., Navarro-Locsin G., Neffen H., Nekam K., Neou A., Nettis E., Neuberger D., Nicod L., Nicola S., Niederberger-Leppin V., Niedoszytko M., Nieto A., Novellino E., Nunes E., Nyembue D., O'Hehir R.E., Odjakova C., Ohta K., Okamoto Y., Okubo K., Oliver B., Onorato G.L., Orru M.P., Ouedraogo S., Ouoba K., Padilla F.-J., Paggiaro P.L., Pagkalos A., Pajno G., Pala G., Palaniappan S., Pali-Scholl I., Palkonen S., Palmer S., Panaitescu Bunu C., Panzner P., Papadopoulos N.G., Papanikolaou V., Papi A., Paralchev B., Paraskevopoulos G., Park H.-S., Passalacqua G., Patella V., Pavord I., Pawankar R., Pedersen S., Peleve S., Pellegino S., Pereira A., Pereira M., Perez T., Perna A., Peroni D., Pfaar O., Pham-Thi N., Pigearias B., Pin I., Piskou K., Pitsios C., Plavec D., Poethig D., Pohl W., Poplas Susic A., Popov T.A., Portejoie F., Potter P., Poulsen L., Prados-Torres A., Prarros F., Price D., Prokopakis E., Puggioni F., Puig-Domenech E., Puy R., Rabe K., Rabotti S., Raciborski F., Ramos J., Recalcati C., Recto M.T., Reda S.M., Regateiro F.S., Reider N., Reitsma S., Repka-Ramirez S., Ridolo E., Rimmer J., Rivero Yeverino D., Rizzo J.A., Robalo-Cordeiro C., Roberts G., Robles K., Roche N., Rodriguez Gonzalez M., Rodriguez Zagal E., Rolla G., Rolland C., Roller-Wirnsberger R., Roman Rodriguez M., Romano A., Romantowski J., Rombaux P., Romualdez J., Rosado-Pinto J., Rosario N., Rosenwasser L., Rossi O., Rottem M., Rouadi P.W., Rovina N., Rozman Sinur I., Ruiz M., Ruiz Segura L.T., Ryan D., Sagara H., Sakai D., Sakurai D., Saleh W., Salimaki J., Samitas K., Samolinski B., Sanchez Coronel M.G., Sanchez-Borges M., Sanchez-Lopez J., Sansonna M., Sarafoleanu C., Sarquis Serpa F., Sastre J., Savi E., Savonyte A., Sawaf B., Scadding G.K., Scheire S., Schmid-Grendelmeier P., Schuhl J.F., Schunemann H., Schvalbova M., Schwarze J., Scichilone N., Senna G., Sepulveda C., Serrano E., Shamai S., Shields M., Shishkov V., Siafakas N., Simeonov A., Simons E.F., Sisul J.C., Sitkauskiene B., Skrindo I., Soklic Kosak T., Sole D., Sondermann M., Sooronbaev T., Soto-Martinez M., Soto-Quiros M., Pinto B.S., Sova M., Soyka M., Specjalski K., Sperl A., Spranger O., Stamataki S., Stefanaki L., Stellato C., Stelmach R., Strandberg T., Stute P., Subramaniam A., Suppli Ulrik C., Sutherland M., Sylvestre S., Syrigou A., Taborda Barata L., Takovska N., Tan R., Tan F., Tan V., Tang I.P., Taniguchi M., Tannert L., Tantilipikorn P., Tattersall J., Tesi F., Thieme U., Thijs C., Thomas M., To T., Todo-Bom A.M., Togias A., Tomazic P.-V., Tomic-Spiric V., Toppila-Salmi S., Torres Jaen M.-J., Toskala E., Triggiani M., Triller N., Triller K., Tsiligianni I., Uberti M., Ulmeanu R., Urbancic J., Urrutia Pereira M., Vachova M., Valdes F., Valenta R., Valentin Rostan M., Valero A., Valiulis A., Vallianatou M., Valovirta E., Van Eerd M., Van Ganse E., van Hage M., Vandenplas O., Vasankari T., Vassileva D., Velasco Munoz C., Ventura M.T., Vera-Munoz C., Viart F., Vicheva D., Vichyanond P., Vidgren P., Viegi G., Vogelmeier C., Von Hertzen L., Vontetsianos T., Vourdas D., Tran Thien Quan V., Wagenmann M., Walker S., Wallace D., De Wang Y., Waserman S., Wehner K., Wickman M., Williams S., Williams D., Wilson N., Wong G., Woo K., Wozniak L., Wright J., Wroczynski P., Xepapadaki P., Yakovliev P., Yamaguchi M., Yan K., Yap Y.Y., Yassin M., Yawn B., Yiallouros P., Yorgancioglu A., Yoshihara S., Young I., Yusuf O.B., Zaidi A., Zaitoun F., Zalud P., Zar H., Zedda M.T., Zernotti M.E., Zhang L., Zhong N., and Zidarn M.

Subjects
MAPK/ERK pathway, ARIA group, Allergy, [SDV]Life Sciences [q-bio], NF-KAPPA-B, debelost, Review, Pharmacology, Resveratrol, PROTECTS, chemistry.chemical_compound, 0302 clinical medicine, RESPIRATORY SYNDROME CORONAVIRUS, ENDOPLASMIC-RETICULUM STRESS, Medicine and Health Sciences, Immunology and Allergy, Medicine, OXIDATIVE STRESS, COVID-19, Foods, Insulin resistance, Nrf2, Nutrients, Obesity, TRPA1, 2. Zero hunger, 0303 health sciences, RESPIRATORY, INSULIN-RESISTANCE, Muscle cell proliferation, SULFORAPHANE, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, SIGNALING PATHWAY, Signal transduction, Life Sciences & Biomedicine, Pulmonary and Respiratory Medicine, NRF2 ACTIVATORS, MUSCLE-CELL PROLIFERATION, Immunology, 610 Medicine & health, Lung injury, Settore MED/10 - Malattie Dell'Apparato Respiratorio, ACUTE LUNG INJURY, 03 medical and health sciences, COVID-19, Foods, Insulin resistance, Nrf2, Nutrients, Obesity, TRPA1, udc:616.9, odpornost proti inzulinu, SULFORAPHANE PROTECTS, Transcription factor, PI3K/AKT/mTOR pathway, 030304 developmental biology, Science & Technology, business.industry, SARS-CoV-2, food, medicine.disease, chemistry, hranila, SYNDROME CORONAVIRUS, business, hrana, GREEN TEA
Abstract

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPARγ:Peroxisome proliferator-activated receptor, NFκB: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2α:Elongation initiation factor 2α). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT1R axis (AT1R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity.

Published
2020
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29. Correction to: Is diet partly responsible for differences in COVID-19 death rates between and within countries?

Author

Dmitry Kudlay, Igor Kaidashev, Line Tannert, Gabrielle Laura Onorato, Abirami Subramaniam, Rudolf Valenta, Jaime Correia de Sousa, Holger Schünemann, Lorenzo Cecchi, Anke Maitland-van der Zee, Ana Margarida Pereira, George Christoff, Nombeko Monica Mashiya, Klaus F. Rabe, Luís Midão, Linda Cox, Jeroen Buters, Frederico Regateiro, Jean Bousquet, Mona Al-Ahmad, Sergio Bonini, Peter Howarth, Filip Raciborski, Gerard Dray, Luo Zhang, Didier EBO, Adnan Custovic, Elham Hossny, Ratko Djukanovic, Violeta Kvedarienė, Heather Zar, Alessandro Fiocchi, Chris Brightling, Cem Meco, Sietze Reitsma, Derek Chu, Ian Adcock, Olga Lourenço, University of Zurich, Bousquet, Jean, Bousquet, J, Anto, Jm, Iaccarino, G, Czarlewski, W, Haahtela, T, Anto, A, Akdis, Ca, Blain, H, Walter Canonica, G, Cardona, V, Cruz, Aa, Illario, M, Ivancevich, Jc, Jutel, M, Klimek, L, Kuna, P, Laune, D, Larenas-Linnemann, D, Mullol, J, Papadopoulos, Ng, Pfaar, O, Samolinski, B, Valiulis, A, Yorgancioglu, A, Zuberbier, T, UCL - SSS/IREC/PNEU - Pôle de Pneumologie, ORL et Dermatologie, and UCL - (MGD) Service de pneumologie

Subjects
Pulmonary and Respiratory Medicine, 2019-20 coronavirus outbreak, 2403 Immunology, ARIA group, Coronavirus disease 2019 (COVID-19), business.industry, Mortality rate, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, MEDLINE, Correction, 610 Medicine & health, RC581-607, Virology, 10183 Swiss Institute of Allergy and Asthma Research, 2740 Pulmonary and Respiratory Medicine, 2723 Immunology and Allergy, Immunology and Allergy, Medicine, Immunologic diseases. Allergy, business
Abstract

Reported COVID-19 deaths in Germany are relatively low as compared to many European countries. Among the several explanations proposed, an early and large testing of the population was put forward. Most current debates on COVID-19 focus on the differences among countries, but little attention has been given to regional differences and diet. The low-death rate European countries (e.g. Austria, Baltic States, Czech Republic, Finland, Norway, Poland, Slovakia) have used different quarantine and/or confinement times and methods and none have performed as many early tests as Germany. Among other factors that may be significant are the dietary habits. It seems that some foods largely used in these countries may reduce angiotensin-converting enzyme activity or are anti-oxidants. Among the many possible areas of research, it might be important to understand diet and angiotensin-converting enzyme-2 (ACE2) levels in populations with different COVID-19 death rates since dietary interventions may be of great benefit.

Published
2020
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30. Happy Hypoxia: Higher NO in red blood cells of COVID-19 patients

Author

Esmaeil Moratz, Majid Malekmohammad, Hamidreza Jamaati, Parisa Adimi Naghan, Mohammadreza Hashemian, Payam Tabarsi, Maohammad Varahram, Hamidreza Zaheri, Efsun Gonca Uğur Chousein, Gert Folkerts, and Ian Adcock

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has spread to almost 100 countries, infected over 10M patients and resulted in 505K deaths worldwide as of 30th June 2020. The major clinical feature of severe COVID-19 requiring ventilation is acute Respiratory Distress Syndrome (ARDS) with multi-functional failure as a result of a cytokine storm with increased serum levels of cytokines. The pathogenesis of the respiratory failure in COVID-19 is yet unknown, but diffuse alveolar damage with interstitial thickening leading to compromised gas exchange is a plausible mechanism. Hypoxia has been seen in the COVID-19 patients however, patients present with a distinct phenotype. Intracellular levels of NO playing important role in the vasodilation of small vessels.Objectives: To elucidate the intracellular levels of NO inside of RBCs in COVID-19 patients compared with that of healthy control subjects.Methods: We recruited 14 COVID-19 infected cases who had pulmonary involvement of their disease, 4 non-COVID-19 healthy controls (without pulmonary involvement and were not hypoxic) and 2 hypoxic non-COVID-19 patients subjects who presented at the Masih Daneshvari Hospital of Tehran, Iran between March-May 2020. Whole blood samples were harvested from patients and intracellular levels of NO in 1 million red blood cells (RBC) was measured by DAF staining using flow cytometry (FACS Calibour, BD, CA, USA).Results: The Mean florescent of intensity for NO was significantly enhanced in COVID-19 patients compared with healthy control subjects (P≤0.05). As a further control for whether hypoxia induced this higher intracellular NO, we evaluated the levels of NO inside RBC of hypoxic patients. No significant differences in NO levels were seen between the hypoxic and non-hypoxic control group.Conclusions: This pilot study demonstrates increased levels of intracellular NO in RBCs from COVID-19 patients. Future studies should examine whether intracellular NO would be increased in large number of COVID-19 patients for usage of possible NO therapy in severe patients.

Published
2020
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31. Airway epithelial cell damage in asthma: mechanisms and biomarkers

Author

Yuemei Yang, Man Jia, Xin Yao, Ian Adcock, and Yingwei Ou

Subjects
business.industry, Disease, respiratory system, medicine.disease, Phenotype, Epithelium, respiratory tract diseases, Pathogenesis, medicine.anatomical_structure, Immunology, Respiratory epithelium, Medicine, business, Airway, Pathological, Asthma
Abstract

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.

Published
2020
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33. Abstracts of ICI 2016 International Congress of Immunology, 21-26 August 2016, Melbourne, Australia

Author

Soumita De, Amanda Patchett, Carolina Johnstone, Glenn Arendts, Sine Reker Hadrup, Daniel Fatovich, Juan Sebastian Pappalardo, Sunil Kumar Saini, Ana Pamplona, Prashant Sadanandan, Stephen Macdonald, Amalie Kai Bentzen, Krzysztof Selmaj, Terence O'Neill, Claire Jessup, Rebecca Coll, Paul Dawson, Xi Zen Yap, Zewen Kelvin Tuong, Jonathan Tan, Michael Nissen, Mark Slee, Miriam Lichtner, Ian Adcock, and Magdalini Lourda

Subjects
0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, biology, Immunity, Immunology, biology.protein, Immunology and Allergy, Antibody, Malaria in pregnancy, Complement (complexity)
Published
2016

34. Effects of dexamethasone and anti-inflammatory drugs on inflammatory cytokines from bronchial epithelial cells of COPD patients

Author

Ian Adcock, Hasan Bayram, Ibrahim Koc, Bulent Gogebakan, Recep Bayraktar, Demet Taşdemir, and Ufkun Ozdemir

Subjects
medicine.medical_specialty, COPD, business.industry, medicine.drug_class, Copd patients, Kinase, Interleukin, Granulocyte, medicine.disease, Anti-inflammatory, Proinflammatory cytokine, Endocrinology, medicine.anatomical_structure, Internal medicine, Medicine, business, Dexamethasone, medicine.drug
Abstract

Studies suggest steroid resistance in COPD patients.We cultured primary BECs from non-smokers (NS), smokers (S) and patients with COPD and incubated with dexamethasone (DEX, 0.1-100nM), N-acetylcysteine (NAC, 3.3-10mM), or c-jun N-terminal kinase inhibitor (SP600125; 3.3-33µM) under unstimulated and stimulated condition by 1ng/ml interleukin (IL)-1β.IL-6, IL-8 and granulocyte macrophage-colony stimulating factor (GM-CSF) levels,mRNA expression was assessed.DEX inhibited release of GM-CSF from un-stimulated COPD BECs (median= 1.047ng/ml) at 1nM, 100nM, and from stimulated cells (median=21.6ng/ml), at 1nM (median=15ng/ml; p

Published
2015
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35. Targeting Th2 Cells in Asthmatic Airways

Author

Gaetano Caramori, Kazuhiro Ito, and Ian Adcock

Subjects
Pharmacology, Immunology, Th1 Cells, Asthma, Cyclic Nucleotide Phosphodiesterases, Type 4, Th2 Cells, 3',5'-Cyclic-AMP Phosphodiesterases, Animals, Humans, Immunology and Allergy, Receptors, Chemokine, Anti-Asthmatic Agents, Immunotherapy, Chemokines, T-Lymphocytes, Cytotoxic, Transcription Factors
Abstract

The most effective anti-asthmatic drugs currently available include inhaled beta2-agonists and glucocorticoids and control asthma in about 95% of patients. The current asthma therapies are not cures and symptoms return soon after the treatment is stopped even after long-term therapy. In addition, severe glucocorticoid-dependent and -resistant asthma still represents a great clinical burden accounting for approximately 50% of the health care costs of asthma and reducing the side-effects of glucocorticoids using novel dissociated steroids, soft steroids or with steroid-sparing agents will prove beneficial. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Hopefully, it will soon be possible to identify and manipulate the molecular switches that result in asthmatic inflammation. This may lead to the treatment of susceptible individuals at birth or in the early years and thus prevent the disease from becoming established. Drug development for asthma has been directed at improving currently available drugs and finding new compounds that usually target the Th2-driven airway inflammatory response. Several new drugs have been developed to target specific components of the Th2-driven inflammatory process in asthma (e.g. IgE antibodies, cytokines and/or chemokines, immunomodulators, antagonists of adhesion molecules), although they have not yet been proven to be particularly effective. Some of these new Th2-oriented strategies may in the future not only control symptoms, but also potentially prevent or cure the disease.

Published
2004
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37. Role of Vitamin D Deficiency in Allergic Diseases: Is this Due to an Impaired Patients’ Response to Corticosteroid Therapy?

Author

Yassine Amrani and Ian Adcock

Subjects
Lung, medicine.anatomical_structure, Corticosteroid therapy, business.industry, Immunology, medicine, Vitamin D and neurology, medicine.disease, business, vitamin D deficiency, Hormone
Abstract

Accumulating evidence now shows that low level of vitamin D is associated with the development and/or aggravation of a number of lung diseases in both adults and children [1-3]. Clinically, low levels of vitamin D refers to hormone deficiency which is defined by a serum level

Published
2014
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38. Reply

Author

Peter Barnes, Ian Adcock, and Mohamed Shamji

Subjects
Text mining, Biochemistry, business.industry, Immunology, Amine oxidase (copper-containing), Immunology and Allergy, Medicine, business
Published
2015
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40. Inflammasome signaling in pathogenesis of lung diseases

Author

Esmaeil Mortaz, Mohammad Reza Masjedi, Mohammadreza Masjedi, Ian Adcock, and Abdolamir Allameh

Subjects
Lung Diseases, Inflammasomes, Inflammation, Disease, Pathogenesis, Pulmonary Disease, Chronic Obstructive, Immune system, Drug Discovery, medicine, Animals, Humans, Asthma, Pharmacology, COPD, Lung, business.industry, Toll-Like Receptors, NF-kappa B, Inflammasome, medicine.disease, Chromatin, respiratory tract diseases, medicine.anatomical_structure, Immunology, medicine.symptom, Inflammation Mediators, business, medicine.drug, Signal Transduction
Abstract

Asthma and Chronic Obstructive Pulmonary Disease (COPD) are two important lung and airways diseases which affect the lives of ~500 million people worldwide. Asthma is a heterogeneous disease that is broadly defined as a clinical syndrome characterized by altered lung function, mucus hypersecretion, peribronchial inflammation and hyperresponsiveness In contrast, the effect of inhalation of toxic particles and gases on the innate and adaptive inflammatory immune systems underlie the pathogenesis of COPD. In the last decade, knowledge concerning the pathophysiologic mechanisms underlying asthma and COPD has risen tremendously and current dogma suggests that the pathogenesis of both diseases is driven by the chronic inflammation present in the airways of these patients. Thus, understanding the mechanisms for the persistence of inflammation may lead to new therapeutic approaches. In this review, we provide an overview of the main signal transduction pathways implicated in asthma and COPD pathophysiology focusing on inflammasome signaling in various cells types which result in altered inflammatory mediator expression.

Published
2011

43. MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying PI3K-mediated suppression of HDAC2 (HYP7P.262)

Author

Philip Hansbro, Richard Kim, James Pinkerton, Malcolm Starkey, Ama-Tawiah Essilfie, Jemma Mayall, Bernadette Jones, Tatt Haw, Simon Keely, Joerg Mattes, Ian Adcock, Paul Foster, and Jay Horvat

Subjects
Immunology, Immunology and Allergy
Abstract

BACKGROUND: Severe, steroid-insensitive (SSI) asthma is a substantial clinical problem. Effective treatments are urgently required, however, their development is hampered by a lack of understanding of the mechanisms that promote disease. SSI asthma is associated with respiratory infections and non-eosinophilic endotypes of disease, including neutrophilic asthma. OBJECTIVES: To develop and use mouse models of SSI neutrophilic asthma to investigate pathogenic mechanisms involving microRNA (miR)-21, phosphoinositide-3-kinase (PI3K) and histone deacetylase (HDAC)2 in order to identify new therapeutic approaches. METHODS: Novel mouse models of respiratory infection and ovalbumin-induced, SSI neutrophilic allergic airway disease (SSIAAD) in BALB/c mice were developed. The roles of infection-induced miR-21 expression and PI3K-dependent signalling in the lung were examined using a specific miR-21 inhibitor (antagomir-21) and the pan-PI3K inhibitor LY294002. RESULTS: Infection induced a miR-21-dependent, PI3K-mediated signalling pathway that decreased nuclear HDAC2 levels and promoted steroid-insensitive neutrophilic inflammation and airway hyper-responsiveness (AHR) in AAD. Inhibition of miR-21 or PI3K suppressed nuclear pAkt levels and restored HDAC2 levels and steroid sensitivity. CONCLUSIONS: We have identified a novel role for a miR-21/PI3K/HDAC2 signalling axis in SSIAAD. Our data highlights miR-21 as a novel target for treating this form of asthma.

Published
2015
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46. CPG potentiates the effects of cigarette smoke on releases of IL-8 in neutrophils (B55)

Author

Esmaeil Mortaz, Ian Adcock, Kazuhiro Ito, and Frans P Nijkamp

Subjects
Immunology, Immunology and Allergy
Abstract

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Smoking is considered the major cause of the disease. All smokers develop airway inflammation through oxidative stress with macrophages, neutrophiles and mediators (such as IL-8) involved. Previous studies have implicated a role of bacterial DNA(CpG, in the initiation of inflammation. In this study we investigated the capacity of cigarette smoke extracts (CSE) and CpG-DNA to trigger and modulate IL-8 responses in human neutrophils. A human isolated neutrophils, were exposed to the CSE, CpG, or in combination. Supernatants were isolated and analyzed for IL-8 by ELISA. The NF-B and AP-1/c-Fos activities were monitored by Western blot by using antibodies. CSE and CpG induced the release of IL-8. When co-administered release of IL-8 synergically increased which was correspondence with degradation of IB- in cytoplasm. CpG and CSE evoked concomitant increases in intracellular NO levels and consequently, nuclear accumulation of c-Fos and NF-B. Pharmacological inhibition of NF-B activity or using of N-acetylcysteine (NAC) attenuated IL-8 release. These results identify reactive oxygen dependent activation of NF-B and c-Fos as an important mechanism to CSE and CpG. In conclusion, this study show that the combination of CSE and CpG provide a substantial release of IL-8 which may accounts to exacerbation of lung in COPD patients when they are exposed to bacterium infections. κκκακακκ

Published
2007
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48. Histone Deacetylase Activity and COPD

Author

Peter Barnes, Angshu Bhowmik, and Ian Adcock

Subjects
COPD, Histone deacetylase 5, business.industry, Histone deacetylase 2, Cancer research, medicine, General Medicine, Histone deacetylase activity, medicine.disease, business
Published
2005
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49. Inhibition of interleukin-8 expression by dexamethasone in human cultured airway epithelial cells

Author

Oj, Kwon, Bt, Au, Pd, Collins, James Nicholas Baraniuk, Ian Adcock, Kf, Chung, and Pj, Barnes

Subjects
Adult, Male, Adolescent, Tumor Necrosis Factor-alpha, Interleukin-8, Respiratory System, Gene Expression, Middle Aged, Blotting, Northern, Dexamethasone, Epithelium, cardiovascular system, Humans, Female, Collagen, RNA, Messenger, Child, Cells, Cultured, Interleukin-1, Research Article
Abstract

Interleukin-8 (IL-8) is a neutrophil chemotactic factor expressed in many cell types, including human airway epithelial cells (HAEC). Inhaled corticosteroids are now used increasingly early in the treatment of airway inflammation such as in asthma, and directly interact with HAEC at relatively high concentrations. We have investigated the effect of dexamethasone on IL-8 expression in primary cultured HAEC obtained from transplantation donors. Northern blot analysis was used to measure IL-8 mRNA levels in HAEC, and radioimmunoassay was used to measure IL-8 protein in culture supernatant fluids. We demonstrated that IL-8 was expressed by primary cultured HAEC and that this was enhanced by IL-1 beta and tumour necrosis factor-alpha stimulation, but not by IL-6 or lipopolysaccharide. Dexamethasone suppressed IL-8 mRNA expression and protein synthesis dose-dependently in both resting and stimulated HAEC. The half-life of IL-8 mRNA determined in the presence of actinomycin D was less than 1 hr, and dexamethasone preincubation had no effect on mRNA stability. These results support the view that HAEC may play an important role in the pathogenesis of airway inflammatory diseases, and that glucocorticosteroids may exert their anti-inflammatory effects by blocking IL-8 gene expression and generation in these cells.

Published
1994

50. Anti-inflammatory actions of steroids: molecular mechanisms

Author

Peter J. Barnes, Ian Adcock, Michael Spedding, and Paul M. Vanhoutte

Subjects
DNA, Complementary, Transcription, Genetic, Molecular Sequence Data, Anti-Inflammatory Agents, Inflammation, Biology, Toxicology, Glucocorticoid receptor, Receptors, Glucocorticoid, Transcription (biology), Gene expression, medicine, Animals, Amino Acid Sequence, Receptor, Psychological repression, Transcription factor, Pharmacology, Base Sequence, Mechanism of action, Immunology, Cytokines, Steroids, Amino Acid Oxidoreductases, medicine.symptom, Nitric Oxide Synthase, Cell Adhesion Molecules, Transcription Factors
Abstract

Glucocorticosteroids are highly effective in controlling inflammation and the molecular mechanisms involved are now becoming clear. Activation of glucocorticoid receptors results in increased or decreased transcription of a number of genes involved in the inflammatory process. Of particular importance is the repression of cytokine gene transcription and the direct interaction between the glucocorticoid receptor and other transcription factors activated in chronic inflammation. In this review, Peter Barnes and Ian Adcock discuss recent studies that have increased our understanding of these mechanisms and that may lead to improved anti-inflammatory therapies in the future.

Published
1993

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