27 results found
McErlean P, Bell CG, Hewitt RJ, et al., 2021, DNA Methylome Alterations are Associated with Airway Macrophage Differentiation and Phenotype During Lung Fibrosis., Am J Respir Crit Care Med
RATIONALE: Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, knowledge of epigenetics of AMs in IPF are limited. METHODS: We undertook DNA methylation profiling using Illumina EPIC (850k) arrays in sorted AMs from Healthy (n=14) and IPF (n=30) donors. Cell-type deconvolution was performed using reference myeloid-cell DNA methylomes. MEASUREMENTS AND MAIN RESULTS: Our analysis revealed epigenetic heterogeneity was a key characteristic of IPF-AMs. DNAm 'clock' analysis indicated epigenetic alterations in IPF-AMs was not associated with accelerated ageing. In differential DNAm analysis, we identified numerous differentially methylated positions (DMPs, n=11) and regions (DMRs, n=49) between healthy and IPF AMs respectively. DMPs and DMRs encompassed genes involved in lipid (LPCAT1) and glucose (PFKFB3) metabolism and importantly, DNAm status was associated with disease severity in IPF. CONCLUSIONS: Collectively, our data identify that changes in the epigenome are associated with development and function of AMs in the IPF lung.
Invernizzi R, Wu BG, Barnett J, et al., 2021, The respiratory microbiome in chronic hypersensitivity pneumonitis is distinct from that of idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 203, Pages: 339-347, ISSN: 1073-449X
RATIONALE: Chronic hypersensitivity pneumonitis (CHP) is a condition that arises following repeated exposure and sensitisation to inhaled antigens. The lung microbiome is increasingly implicated in respiratory disease but to date, no study has investigated the composition of microbial communities in the lower airways in CHP. OBJECTIVE: To characterise and compare the airway microbiome in subjects with CHP, idiopathic pulmonary fibrosis (IPF) and controls. METHODS: We prospectively recruited individuals diagnosed with CHP (n=110), IPF (n=45) and controls (n=28). Subjects underwent bronchoalveolar lavage and bacterial DNA was isolated, quantified by qPCR and the 16S rRNA gene was sequenced to characterise the bacterial communities in the lower airways. MAIN MEASUREMENTS AND RESULTS: Distinct differences in the microbial profiles were evident in the lower airways of subjects with CHP and IPF. At the phylum level, the prevailing microbiota of both IPF and CHP subjects included Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria. However, in IPF, Firmicutes dominated while the percentage of reads assigned to Proteobacteria in the same group was significantly lower compared to CHP subjects. At the genus level, Staphylococcus was increased in CHP and Actinomyces and Veillonella in IPF. The lower airway bacterial burden in CHP subjects was higher than controls but lower than those with IPF. In contrast to IPF, there was no association between bacterial burden and survival in CHP. CONCLUSIONS: The microbial profile of the lower airways in subjects with CHP is distinct from that of IPF and, notably, bacterial burden in individuals with CHP fails to predict survival.
Hewitt RJ, Lloyd CM, 2021, Regulation of immune responses by the airway epithelial cell landscape, NATURE REVIEWS IMMUNOLOGY, Vol: 21, Pages: 347-362, ISSN: 1474-1733
Ogger PP, Albers GJ, Hewitt RJ, et al., 2020, Itaconate controls the severity of pulmonary fibrosis, Science Immunology, Vol: 5, Pages: 1-13, ISSN: 2470-9468
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression (ACOD1) is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, Acod1-/- mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in Acod1-/- tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.
Ogger P, Ghai P, Hewitt RJ, et al., 2020, Itaconate drives the resolution of pulmonary fibrosis, ERS Lung Science Conference 2020 abstracts, Publisher: European Respiratory Society
Byrne A, powell J, O'Sullivan B, et al., 2020, Dynamics of human monocytes and airway macrophages during healthy aging and post-transplant, Journal of Experimental Medicine, Vol: 217, Pages: 1-9, ISSN: 0022-1007
The ontogeny of airway macrophages (AMs) in human lung and their contribution to disease are poorly mapped out. In mice, aging is associated with an increasing proportion of peripherally, as opposed to perinatally derived AMs. We sought to understand AM ontogeny in human lung during healthy aging and after transplant. We characterized monocyte/macrophage populations from the peripheral blood and airways of healthy volunteers across infancy/childhood (2–12 yr), maturity (20–50 yr), and older adulthood (>50 yr). Single-cell RNA sequencing (scRNA-seq) was performed on airway inflammatory cells isolated from sex-mismatched lung transplant recipients. During healthy aging, the proportions of blood and bronchoalveolar lavage (BAL) classical monocytes peak in adulthood and decline in older adults. scRNA-seq of BAL cells from lung transplant recipients indicates that after transplant, the majority of AMs are recipient derived. These data show that during aging, the peripheral monocyte phenotype is consistent with that found in the airways and, furthermore, that the majority of human AMs after transplant are derived from circulating monocytes.
Hewitt RJ, Graham C, Perez-Lloret J, et al., 2020, A Transcriptomic Profile of the Proximal Airway Epithelial-Immune Niche in Idiopathic Pulmonary Fibrosis, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Ogger PP, Ghai P, Hewitt RJ, et al., 2019, ITACONATE DRIVES THE RESOLUTION OF PULMONARY FIBROSIS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A2-A2, ISSN: 0040-6376
Allden SJ, Ogger PP, Ghai P, et al., 2019, The transferrin receptor CD71 delineates functionally distinct airway macrophage subsets during idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 200, ISSN: 1073-449X
RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating progressive disease with limited therapeutic options. Airway macrophages (AMs) are key components of the defence of the airways and are implicated in the pathogenesis of IPF. Alterations in iron metabolism have been described during fibrotic lung disease and in murine models of lung fibrosis. However, the role of transferrin receptor-1 (CD71)-expressing AMs in IPF is not known. OBJECTIVES: To assess the role of CD71 expressing AMs in the IPF-lung. METHODS: We utilized multi-parameter flow cytometry, gene expression analysis and phagocytosis/transferrin uptake assays to delineate the role of AMs expressing, or lacking, CD71 in the BAL of patients with IPF or healthy controls. MEASUREMENTS AND MAIN RESULTS: There was a distinct increase in proportions of AMs lacking CD71 in IPF patients in comparison to healthy controls. Levels of BAL transferrin were enhanced in IPF-BAL and furthermore, CD71- AMs had an impaired ability to sequester transferrin. CD71+ and CD71- AMs were phenotypically, functionally and transcriptionally distinct, with CD71- AMs characterised by reduced expression of markers of macrophage maturity, impaired phagocytosis and enhanced expression of pro-fibrotic genes. Importantly, proportions of AMs lacking CD71 were independently associated with worse survival, underlining the importance of this population in IPF and as a potential therapeutic target. CONCLUSIONS: Taken together these data highlight how CD71 delineates AM subsets which play distinct roles in IPF and furthermore, CD71- AMs may be an important pathogenic component of fibrotic lung disease.
Hewitt RJ, Maher TM, 2019, Idiopathic Pulmonary Fibrosis: New and Emerging Treatment Options., Drugs Aging
Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating, scarring lung disease with a worse prognosis than some cancers. The incidence of IPF is increasing and while current antifibrotic therapies slow disease progression, they do not offer a cure. The pathobiology of IPF is complex and is driven by aging-associated cellular dysfunction, epithelial injury, and an aberrant wound-healing response characterised by fibroblast activation and extracellular matrix accumulation (ECM) in the interstitium. As understanding of the underlying mechanisms has evolved, new targets for pharmacotherapy have emerged. Novel drugs currently in development for pulmonary fibrosis have diverse molecular properties and mechanisms of action, as well as different routes of administration. A shared primary goal of these agents is reduction of the profibrotic activity of fibroblasts and limitation of ECM deposition, which hinders gas exchange and ultimately leads to respiratory failure. This article provides an overview of some promising new therapeutic options for IPF and considers the challenges for future drug development.
Tregoning JS, Mallia P, Webber J, et al., 2018, Role of airway glucose in bacterial infections in chronic obstructive pulmonary disease, Journal of Allergy and Clinical Immunology, Vol: 142, Pages: 815-823.e6, ISSN: 0091-6749
BackgroundPatients with chronic obstructive pulmonary disease (COPD) have increased susceptibility to respiratory tract infection, which contributes to disease progression and mortality, but mechanisms of increased susceptibility to infection remain unclear.ObjectivesThe aim of this study was to determine whether glucose concentrations were increased in airway samples (nasal lavage fluid, sputum, and bronchoalveolar lavage fluid) from patients with stable COPD and to determine the effects of viral infection on sputum glucose concentrations and how airway glucose concentrations relate to bacterial infection.MethodsWe measured glucose concentrations in airway samples collected from patients with stable COPD and smokers and nonsmokers with normal lung function. Glucose concentrations were measured in patients with experimentally induced COPD exacerbations, and these results were validated in patients with naturally acquired COPD exacerbations. Relationships between sputum glucose concentrations, inflammatory markers, and bacterial load were examined.ResultsSputum glucose concentrations were significantly higher in patients with stable COPD compared with those in control subjects without COPD. In both experimental virus-induced and naturally acquired COPD exacerbations, sputum and nasal lavage fluid glucose concentrations were increased over baseline values. There were significant correlations between sputum glucose concentrations and sputum inflammatory markers, viral load, and bacterial load. Airway samples with higher glucose concentrations supported more Pseudomonas aeruginosa growth in vitro.ConclusionsAirway glucose concentrations are increased in patients with stable COPD and further increased during COPD exacerbations. Increased airway glucose concentrations might contribute to bacterial infections in both patients with stable and those with exacerbated COPD. This has important implications for the development of nonantibiotic therapeutic strategies for the prev
Wickremasinghe M, Hewitt R, Wells A, 2017, General Principles of Diagnosis and Management, Clinical Handbook of Interstitial Lung Disease, Publisher: CRC Press, ISBN: 9781498768252
This handbook provides clinical guidance to the practicing physician on the diagnosis and treatment of Interstitial Lung Diseases (ILD).
Hewitt RJ, Molyneaux PL, 2017, The respiratory microbiome in idiopathic pulmonary fibrosis., Ann Transl Med, Vol: 5, ISSN: 2305-5839
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease of unknown cause. Current evidence suggests that it arises in genetically susceptible individuals as a consequence of an aberrant wound-healing response following repetitive alveolar injury. Overt respiratory infection and immunosuppression carry a high mortality, while polymorphisms in genes related to epithelial integrity and host defence predispose to IPF. Recent advances in sequencing technologies have allowed the use of molecular microbial technologies to characterise the respiratory microbiota in patients with IPF. Studies have suggested that changes in the overall bacterial burden are related to disease progression and highlighted significant differences between the microbiota in IPF subjects and healthy controls. Indeed differences in the microbiota between IPF patients may differentiate those with stable compared to progressive disease. As our understanding of the IPF microbiome evolves, along with refinement and advances in sampling and sequencing methodologies we may be able to use microbial signatures as a biomarker to guide prognostication and even treatment stratification in this devastating disease.
Russell AM, Sonecha S, Datta A, et al., 2016, DEVELOPMENT OF PATIENT REPORTED EXPERIENCE MEASURE (PREM) FOR IDIOPATHIC PULMONARY FIBROSIS (IPF), Publisher: BMJ PUBLISHING GROUP, Pages: A238-A238, ISSN: 0040-6376
Hewitt R, Farne H, Ritchie A, et al., 2016, The role of viral infections in exacerbations of chronic obstructive pulmonary disease and asthma, Therapeutic Advances in Respiratory Disease, Vol: 10, Pages: 158-174, ISSN: 1753-4666
Asthma and chronic obstructive pulmonary disease (COPD) are major causes of global morbidity and mortality worldwide. The clinical course of both asthma and COPD are punctuated by the occurrence of exacerbations, acute events characterized by increased symptoms and airflow obstruction. Exacerbations contribute most of the morbidity, mortality and excess healthcare costs associated with both asthma and COPD. COPD and asthma exacerbations are frequently associated with respiratory virus infections and this has led to an intense research focus into the mechanisms of virus-induced exacerbations over the past decade. Current therapies are effective in reducing chronic symptoms but are less effective in preventing exacerbations, particularly in COPD. Understanding the mechanisms of virus-induced exacerbation will lead to the development of new targeted therapies that can reduce the burden of virus-induced exacerbations. In this review we discuss current knowledge of virus-induced exacerbations of asthma and COPD with a particular focus on mechanisms, human studies, virus–bacteria interactions and therapeutic advances.
Hewitt R, Webber J, Farne H, et al., 2016, Airway Glucose In Virus-Induced COPD Exacerbations, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Hewitt RJ, Dimopoulos K, Alexander D, et al., 2015, PERIOPERATIVE OUTCOMES IN PATIENTS WITH PULMONARY HYPERTENSION UNDERGOING NON-CARDIAC NON-OBSTETRIC SURGERY IN A DESIGNATED UK PULMONARY HYPERTENSION CENTRE, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A214-A214, ISSN: 0040-6376
Reynolds M, Larsson E, Hewitt R, et al., 2015, Development and evaluation of a pocket card to support prescribing by junior doctors in an English hospital., International Journal of Clinical Pharmacy, Vol: 37, Pages: 762-766, ISSN: 2210-7711
Background Junior doctors do most inpatient prescribing, with a relatively high error rate, and locally had reported finding prescribing very stressful. Objective To develop an intervention to improve Foundation Year 1 (FY1) doctors' experience of prescribing, and evaluate their satisfaction with the intervention and perceptions of its impact. Methods Based on findings of a focus group and questionnaire, we developed a pocket Dose Reference Card ("Dr-Card") for use at the point of prescribing. This summarised common drugs and dosing schedules and was distributed to all new FY1 doctors in a London teaching trust. A post-intervention questionnaire explored satisfaction and perceived impact. Results Focus group participants (n = 12) described feeling anxious and time pressured when prescribing; a quick reference resource for commonly prescribed drug doses was suggested. Responses to the exploratory questionnaire reinforced these findings. Following Dr-Card distribution, the post-intervention questionnaire revealed that 29/38 (76 %) doctors were still using it 2 months after distribution and 38/38 (100 %) would recommend ongoing production. Conclusions FY1 doctors reported feeling stressed and time pressured when prescribing; this was perceived to contribute to error. A pocket card presenting common drugs and doses was well-received, perceived to be useful, and recommended for on-going use.
Hewitt RJ, Singanayagam A, Sridhar S, et al., 2015, Screening for latent tuberculosis before tumour necrosis factor antagonist therapy, EUROPEAN RESPIRATORY JOURNAL, Vol: 45, Pages: 1510-1512, ISSN: 0903-1936
Hewitt RJ, Francis M, Singanayagam A, et al., 2015, RATIONAL TESTING Screening tests for tuberculosis before starting biological therapy, BMJ-BRITISH MEDICAL JOURNAL, Vol: 350, ISSN: 1756-1833
Hewitt RJ, Wright C, Adeboyeku D, et al., 2013, Primary nodal anthracosis identified by EBUS-TBNA as a cause of FDG PET/CT positive mediastinal lymphadenopathy., Respiratory Medicine Case Reports, Vol: 10, Pages: 48-52, ISSN: 2213-0071
Isolated mediastinal lymphadenopathy can result from a number of potentially serious aetiologies. Traditionally those presenting with mediastinal lymphadenopathy would undergo mediastinoscopy to elucidate a final diagnosis or receive empirical treatment. There is now increased utilization of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), in this setting. Five cases of mediastinal lymphadenopathy are presented here in which lymph node anthracosis was identified as the primary diagnosis using EBUS-TBNA. They were female, non-smokers presenting with non-specific symptoms, who retrospectively reported cooking over wood fires. Four were from South Asia. Three were investigated by F-18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scanning and increased signal was identified in the anthracotic nodes sampled. With expansion of PET/CT and EBUS-TBNA services it is likely that primary nodal anthracosis will be encountered more frequently and should be considered in the differential diagnosis of those with PET/CT positive lymphadenopathy. It may mimic pathologies including tuberculosis and malignancy, thus accurate sampling and follow-up are essential.
Pegna V, Hewitt R, Iorga R, et al., 2012, The Development of Major Trauma Centres in the UK: Issues and Data from the first year of operation of a new Neurotrauma Centre in London., Pages: 569-569
Zakeri N, Creagh-Brown B, Hector LR, et al., 2010, POLYMORPHISMS IN GENES ENCODING RAGE OR RAGE LIGANDS PREDISPOSE PATIENTS TO ADVERSE OUTCOMES FOLLOWING SURGERY NECESSITATING CARDIOPULMONARY BYPASS, British-Thoracic-Society-Winter-Meeting 2010, Publisher: B M J PUBLISHING GROUP, Pages: A49-A49, ISSN: 0040-6376
Lagan AL, Hewitt RJ, Melley DD, et al., 2010, Adverse Outcomes From Cardiac Surgery Requiring Cardiopulmonary Bypass: Influence Of Polymorphism In Genes Encoding A Panel Of Cytokines, Am J Respir Crit Care Med, American Thoracic Society International Congress, Pages: A1161-A1161
Hewitt RJ, Melley DD, Hector LR, et al., 2009, POLYMORPHISMS IN INFLAMMATORY PATHWAY GENES PREDISPOSE PATIENTS TO ADVERSE OUTCOMES AFTER CARDIOPULMONARY BYPASS SURGERY, Winter Meeting of the British-Thoracic-Society, Publisher: B M J PUBLISHING GROUP, Pages: A26-A27, ISSN: 0040-6376
Boustani K, Ghai P, Invernizzi R, et al., Airway-specific autoantibodies identify a subset of patients with fibrotic interstitial lung disease
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Fibrotic interstitial lung disease (fILD) has previously been associated with the presence of autoantibody. While studies have focused on systemic autoimmunity, the role of local autoantibodies in the airway remains unknown. We therefore extensively characterised the airway and peripheral autoantibody profiles in patients with fILD and assessed association with disease severity and outcome.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Bronchoalveolar lavage (BAL) was collected from a cohort of fILD patients and total airway antibody concentrations were quantified. An autoantigen microarray was used to measure IgG and IgA autoantibodies against 124 autoantigens in BAL from 40 idiopathic pulmonary fibrosis (IPF), 20 chronic hypersensitivity pneumonitis (CHP), 20 connective tissue disease-associated ILD (CTD-ILD) patients and 20 controls.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>A subset of patients with fILD but not healthy controls had a local autoimmune signature in their airways that was not present systemically, regardless of disease. The proportion of patients with IPF with a local autoantibody signature was comparable to that of CTD-ILD, which has a known autoimmune pathology, identifying a potentially novel subset of patients. The presence of an airway autoimmune signature was not associated with reduced survival probability or changes in lung function in the cohort as a whole. Patients with IPF had increased airway total IgA and IgG1 while subjects with CHP had increased airway IgA, IgG1 and IgG4. In patients with CHP, increased airway total IgA was associated with reduced survival probability.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>The presence of ai
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