45 results found
Molyneaux PL, Fahy WA, Byrne AJ, et al., 2022, CYFRA 21-1 predicts progression in IPF: a prospective longitudinal analysis of the PROFILE cohort, American Journal of Respiratory and Critical Care Medicine, Vol: 205, Pages: 1440-1448, ISSN: 1073-449X
OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a progressive and inevitably fatal condition for which there are a lack of effective biomarkers to guide therapeutic decision making. RATIONALE: To determine the relationship between serum levels of the cytokeratin fragment CYFRA 21-1 and disease progression and mortality in individuals with IPF enrolled in the PROFILE study. METHODS: CYFRA 21-1 was identified by immunohistochemistry in samples of human lung. Concentrations of CYFRA 21-1 were measured using an Elisa-based assay in serum, collected at baseline, 1- and 3-months, from 491 individuals with an incident diagnosis of IPF enrolled in the PROFILE study and from 100 control subjects. Study subjects were followed for a minimum of 3 years. MEASUREMENTS AND MAIN RESULTS: CYFRA 21-1 localises to hyperplastic epithelium in IPF lung. CYFRA 21-1 levels were significantly higher in IPF subjects compared to healthy controls in both discovery (n=132) (control 0.96±0.81 ng/mL versus IPF; 2.34±2.15 ng/mL, p < 0.0001) and validation (n=359) (control; 2.21±1.54 ng/mL and IPF; 4.13±2.77 ng/mL, p<0.0001) cohorts. Baseline levels of CYFRA 21-1 distinguished individuals at risk of 12-month disease progression (C-statistic 0.70 (95% CI 0.61-0.79), p < 0.0001) and were predictive of overall-mortality (HR 1.12 (1.06-1.19) per 1 ng/mL increase in CYFRA 21-1, p=0.0001). Furthermore, 3-month change in levels of CYFRA 21-1 separately predicted 12-month and overall survival in both the discovery and validation cohorts. CONCLUSIONS: CYFRA 21-1, a marker of epithelial damage and turnover, has the potential to be an important prognostic and therapeutic biomarker in individuals with IPF.
Byrne AJ, Saglani S, Snelgrove RJ, 2022, An Alarmin Role for P2Y(13) Receptor during Viral-driven Asthma Exacerbations, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 205, Pages: 263-265, ISSN: 1073-449X
McErlean P, Bell CG, Hewitt RJ, et al., 2021, DNA methylome alterations are associated with airway macrophage differentiation and phenotype during lung fibrosis., American Journal of Respiratory and Critical Care Medicine, Vol: 204, Pages: 954-966, ISSN: 1073-449X
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 about the epigenetics of AMs in IPF is limited. Objectives: To assess the role of epigenetic regulation of AMs during lung fibrosis. Methods: We undertook DNA methylation (DNAm) profiling by using Illumina EPIC (850k) arrays in sorted AMs from healthy donors (n = 14) and donors with IPF (n = 30). Cell-type deconvolution was performed by using reference myeloid-cell DNA methylomes. Measurements and Main Results: Our analysis revealed that epigenetic heterogeneity was a key characteristic of IPF AMs. DNAm "clock" analysis indicated that epigenetic alterations in IPF AMs were not associated with accelerated aging. In differential DNAm analysis, we identified numerous differentially methylated positions (n = 11) and differentially methylated regions (n = 49) between healthy and IPF AMs, respectively. Differentially methylated positions and differentially methylated regions encompassed genes involved in lipid (LPCAT1 [lysophosphatidylcholine acyltransferase 1]) and glucose (PFKFB3 [6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3]) metabolism, and importantly, the DNAm status was associated with disease severity in IPF. Conclusions: Collectively, our data identify that changes in the epigenome are associated with the development and function of AMs in the IPF lung.
Invernizzi R, Giallourou N, Swann JR, et al., 2021, THE RESPIRATORY MICROBIOME AND METABOLOME IN IDIOPATHIC PULMONARY FIBROSIS, Publisher: BMJ PUBLISHING GROUP, Pages: A2-A3, ISSN: 0040-6376
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.
Albers GJ, Iwasaki J, McErlean P, et al., 2021, IRF5 regulates airway macrophage metabolic responses, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 204, Pages: 134-143, ISSN: 0009-9104
Pallett LJ, Dimeloe S, Sinclair LV, et al., 2021, A glutamine 'tug-of-war': targets to manipulate glutamine metabolism for cancer immunotherapy., Immunother Adv, Vol: 1
Within the tumour microenvironment (TME), there is a cellular 'tug-of-war' for glutamine, the most abundant amino acid in the body. This competition is most evident when considering the balance between a successful anti-tumour immune response and the uncontrolled growth of tumour cells that are addicted to glutamine. The differential effects of manipulating glutamine abundance in individual cell types is an area of intense research and debate. Here, we discuss some of the current strategies in development altering local glutamine availability focusing on inhibition of enzymes involved in the utilisation of glutamine and its uptake by cells in the TME. Further studies are urgently needed to complete our understanding of glutamine metabolism, to provide critical insights into the pathways that represent promising targets and for the development of novel therapeutic strategies for the treatment of advanced or drug resistant cancers.
Ogger PP, Byrne AJ, 2020, Macrophage metabolic reprogramming during chronic lung disease, MUCOSAL IMMUNOLOGY, Vol: 14, Pages: 282-295, ISSN: 1933-0219
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.
Trachalaki A, Tsitoura E, Invernizzi R, et al., 2020, Inflammasome activation in airway macrophages and the lung microbiome in IPF, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Albers GJ, Iwasaki J, Mcerlean P, et al., 2020, IRF5 regulates airway macrophage metabolic responses to viral challenge, European-Academy-of-Allergology-and-Clinical-Immunology Digital Congress (EAACI), Publisher: WILEY, Pages: 42-43, ISSN: 0105-4538
Ogger PP, Byrne AJ, 2020, Lung fibrosis enters the iron age, JOURNAL OF PATHOLOGY, Vol: 252, Pages: 1-3, ISSN: 0022-3417
Invernizzi R, Barnett J, Rawal B, et al., 2020, Bacterial burden in the lower airways predicts disease progression in idiopathic pulmonary fibrosis and is independent of radiological disease extent, European Respiratory Journal, Vol: 55, Pages: 1-9, ISSN: 0903-1936
Increasing bacterial burden in the lower airways of patients with idiopathic pulmonary fibrosis confers an increased risk of disease progression and mortality. However, it remains unclear whether this increased bacterial burden directly influences progression of fibrosis or simply reflects the magnitude of the underlying disease extent or severity.We prospectively recruited 193 patients who underwent bronchoscopy and received a multidisciplinary diagnosis of idiopathic pulmonary fibrosis. Quantification of the total bacterial burden in bronchoalveolar lavage fluid was performed by 16S rRNA gene qPCR. Imaging was independently evaluated by two readers assigning quantitative scores for extent, severity and topography of radiographic changes and relationship of these features with bacterial burden was assessed.Increased bacterial burden significantly associated with disease progression (hazard ratio 2.1; 95% confidence interval 1.287–3.474; p=0.0028). Multivariate stepwise regression demonstrated no relationship between bacterial burden and radiological features or extent of disease. When specifically considering patients with definite or probable usual interstitial pneumonia there was no difference in bacterial burden between these two groups. Despite a postulated association between pleuroparenchymal fibroelastosis and clinical infection, there was no relationship between either the presence or extent of pleuroparenchymal fibroelastosis and bacterial burden.We demonstrate that bacterial burden in the lower airways is not simply secondary to the extent of the underlying architectural destruction of the lung parenchyma seen in idiopathic pulmonary fibrosis. The independent nature of this association supports a relationship with the underlying pathogenic mechanisms and highlights the urgent need for functional studies.
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, Virtual 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
Santermans E, Ford P, Kreuter M, et al., 2019, Modelling forced vital capacity in idiopathic pulmonary fibrosis: optimising trial design., Advances in Therapy, Vol: 36, Pages: 3059-3070, ISSN: 0741-238X
INTRODUCTION: Forced vital capacity is the only registrational endpoint in idiopathic pulmonary fibrosis clinical trials. As most new treatments will be administered on top of standard of care, estimating treatment response will become more challenging. We developed a simulation model to quantify variability associated with forced vital capacity decline. METHODS: The model is based on publicly available clinical trial summary and home spirometry data. A single, illustrative trial setting is reported. Model assumptions are 400 subjects randomised 1:1 to investigational drug or placebo over 52 weeks, 50% of each group receiving standard of care (all-comer population), and a 90-mL treatment difference in annual forced vital capacity decline. Longitudinal profiles were simulated and the impact of varying clinical scenarios evaluated. RESULTS: Power to detect a significant treatment difference was 87-97%, depending on the analysis method. Repeated measures analysis generally outperformed analysis of covariance and mixed linear models, particularly with missing data (as simulated data were non-linear). A 15% yearly random dropout rate led to 0.6-5% power loss. Forced vital capacity decline-related dropout introduced greater power loss (up to 12%), as did subjects starting/stopping standard of care or investigational drug. Power was substantially lower for a 26-week trial due to the smaller assumed treatment effect at week 26 (sample size would need doubling to reach a power similar to that of a 52-week trial). CONCLUSIONS: Our model quantifies forced vital capacity decline and associated variability, with all the caveats of background therapy, permitting robust power calculations to inform future idiopathic pulmonary fibrosis clinical trial design. FUNDING: Galapagos NV (Mechelen, Belgium).
Ng B, Dong J, D'Agostino G, et al., 2019, Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis, Science Translational Medicine, Vol: 11, Pages: 1-14, ISSN: 1946-6234
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease where invasive pulmonary myofibroblasts secrete collagen and destroy lung integrity. Here, we show that interleukin-11 (IL11) is up-regulated in the lung of patients with IPF, associated with disease severity, and IL-11 is secreted from IPF fibroblasts. In vitro, IL-11 stimulates lung fibroblasts to become invasive actin alpha 2, smooth muscle–positive (ACTA2+), collagen-secreting myofibroblasts in an extracellular signal–regulated kinase (ERK)–dependent, posttranscriptional manner. In mice, fibroblast-specific transgenic expression or administration of murine IL-11 induces lung myofibroblasts and causes lung fibrosis. IL-11 receptor subunit alpha-1 (Il11ra1)–deleted mice, whose lung fibroblasts are unresponsive to profibrotic stimulation, are protected from fibrosis in the bleomycin mouse model of pulmonary fibrosis. We generated an IL-11–neutralizing antibody that blocks lung fibroblast activation downstream of multiple stimuli and reverses myofibroblast activation. In therapeutic studies, anti–IL-11 treatment diminished lung inflammation and reversed lung fibrosis while inhibiting ERK and SMAD activation in mice. These data prioritize IL-11 as a drug target for lung fibrosis and IPF.
Byrne AJ, 2019, Reply to: CD71-Alveolar Macrophages in IPF: a Look Beyond the Borders of the Disease., Am J Respir Crit Care Med
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.
Velez TE, Byrne AJ, Wechsler JB, et al., 2019, Histamine-driven responses are sustained via a bioactive metabolite, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 2287-2290.e1, ISSN: 0091-6749
A histamine metabolite, imidazole acetic acid (IAA), recapitulates key histamine-driven biology, including recruitment of eosinophils, induction of itch, and induction of anaphylaxis. IAA may perpetuate anaphylactic and other allergic responses after the initial release and metabolism of histamine.
Palau H, Meng C, Bhargava A, et al., 2019, Lentivirus Gene Therapy for Autoimmune Pulmonary Alveolar Proteinosis, 22nd Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), Publisher: CELL PRESS, Pages: 43-44, ISSN: 1525-0016
Ng B, Dong J, Viswanathan S, et al., 2019, IL-11 Is a Therapeutic Target in Idiopathic Pulmonary Fibrosis, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Saglani S, Gregory LG, Manghera AK, et al., 2018, Inception of early life allergen induced airway hyperresponsiveness is reliant on IL-13+CD4+ T cells, Science Immunology, Vol: 3, Pages: 1-12, ISSN: 2470-9468
Airway hyperresponsiveness (AHR) is a critical feature of wheezing and asthma in children, but the initiating immune mechanisms remain unconfirmed. We demonstrate that both recombinant interleukin-33 (rIL-33) and allergen [house dust mite (HDM) or Alternaria alternata] exposure from day 3 of life resulted in significantly increased pulmonary IL-13+CD4+ T cells, which were indispensable for the development of AHR. In contrast, adult mice had a predominance of pulmonary LinnegCD45+CD90+IL-13+ type 2 innate lymphoid cells (ILC2s) after administration of rIL-33. HDM exposure of neonatal IL-33 knockout (KO) mice still resulted in AHR. However, neonatal CD4creIL-13 KO mice (lacking IL-13+CD4+ T cells) exposed to allergen from day 3 of life were protected from AHR despite persistent pulmonary eosinophilia, elevated IL-33 levels, and IL-13+ ILCs. Moreover, neonatal mice were protected from AHR when inhaled Acinetobacter lwoffii (an environmental bacterial isolate found in cattle farms, which is known to protect from childhood asthma) was administered concurrent with HDM. A. lwoffii blocked the expansion of pulmonary IL-13+CD4+ T cells, whereas IL-13+ ILCs and IL-33 remained elevated. Administration of A. lwoffii mirrored the findings from the CD4creIL-13 KO mice, providing a translational approach for disease protection in early life. These data demonstrate that IL-13+CD4+ T cells, rather than IL-13+ ILCs or IL-33, are critical for inception of allergic AHR in early life.
Cook J, Martin-Alonso A, Sanghani N, et al., 2018, Children with Pre-School Wheeze Have Neutrophilic Airway Inflammation Associated with Bacteria and Viruses During Periods of Clinical Stability, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Byrne AJ, Weiss M, Mathie SA, et al., 2016, A critical role for IRF5 in regulating allergic airway inflammation, Mucosal Immunology, Vol: 10, Pages: 716-726, ISSN: 1935-3456
Interferon regulatory factor 5 (IRF5) is a key transcription factor involved in the control of theexpression of pro-inflammatory cytokine and responses to infection, however its role in regulatingpulmonary immune responses to allergen is unknown. We used genetic ablation, adenoviralvector-driven overexpression and adoptive transfer approaches to interrogate the role of IRF5 inpulmonary immunity and during challenge with the aero-allergen, house dust mite. Global IRF5deficiency resulted in impaired lung function and extracellular matrix (ECM) deposition. IRF5was also essential for effective responses to inhaled allergen, controlling airway hyper-responsiveness, mucus secretion and eosinophilic inflammation. Adoptive transfer of IRF5-deficient alveolar macrophages into the WT pulmonary milieu was sufficient to drive airwayhyper-reactivity, at baseline or following antigen challenge. These data identify IRF5-expressingmacrophages as a key component of the immune defence of the airways. Manipulation of IRF5activity in the lung could therefore be a viable strategy for the redirection of pulmonary immuneresponses and thus, the treatment of lung disorders.
Byrne AJ, Maher TM, Lloyd CM, 2016, Pulmonary macrophages: a new therapeutic pathway in fibrosing lung disease?, Trends in Molecular Medicine, Vol: 22, Pages: 303-316, ISSN: 1471-4914
Pulmonary fibrosis (PF) is a growing clinical problem which can result in breathlessness or respiratory failure and has an average life expectancy of 3 years from diagnosis. Therapeutic options for PF are limited and there is therefore a significant unmet clinical need. The recent resurgent interest in macrophage biology has led to a new understanding of lung macrophage origins, biology, and phenotypes. In this review we discuss fibrotic mechanisms and focus on the role of macrophages during fibrotic lung disease. Data from both human and murine studies are reviewed, highlighting novel macrophage-orientated biomarkers for disease diagnosis and potential targets for future anti-fibrotic therapies.
Toshner RJ, Allden SJ, Byrne AJ, et al., 2016, The Il-33/st2 Axis Is Upregulated In Fibrotic Lung Disease, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Allden SJ, Toshner RJ, Byrne AJ, et al., 2016, Expression Of Cd71 On Alveolar Macrophages Reveals Distinct Cell Populations In Human Bronchoalveolar Lavage From Patients With Interstitial Lung Disease, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Byrne AJ, Mathie SA, Gregory LG, et al., 2015, Pulmonary macrophages: key players in the innate defence of the airways, THORAX, Vol: 70, Pages: 1189-1196, ISSN: 0040-6376
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