32 results found
Ogger PP, Byrne AJ, 2020, Lung fibrosis enters the iron age., J Pathol
Iron is an essential nutrient for numerous cellular processes. However, excess iron in the lung (for example inhaled in pollution/cigarette smoke) can be harmful, acting as a catalyst in the formation of free radicals. Pulmonary iron content is therefore tightly regulated and alterations in iron metabolism have been associated with chronic lung disease. In particular, patients with idiopathic pulmonary fibrosis have been reported to have numerous aspects of dysfunctional iron metabolism in the lung including increased iron levels, presence of iron-laden macrophages, and iron-induced oxidative stress. In the May issue of The Journal of Pathology, Ali et al show a mechanistic link between iron accumulation and pulmonary fibrosis pathology. Using mouse models of iron overload, the authors show that increased iron levels result in reduced lung function and worse pulmonary fibrosis upon lung injury by bleomycin. Treatment with inhaled iron chelator deferoxamine ameliorated pulmonary fibrosis and prevented lung function decline in vivo. This study highlights the importance of iron homeostasis in the lung and provides evidence of pulmonary iron-overload contributing to the development and progression of pulmonary fibrosis. This article is protected by copyright. All rights reserved.
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.
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, 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, 2018, Inception of early life allergen induced airway hyperresponsiveness is reliant on IL-13+CD4+ T cells, Science Immunology, Vol: 3, 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
Denney L, Byrne A, Shea T, et al., 2015, Pulmonary epithelial cell-derived cytokine TGF-β1 Is a critical cofactor for enhanced innate lymphoid cell function, Immunity, Vol: 43, Pages: 945-958, ISSN: 1097-4180
Epithelial cells orchestrate pulmonary homeostasis and pathogen defense and play a crucial role in the initiation of allergic immune responses. Maintaining the balance between homeostasis and inappropriate immune activation and associated pathology is particularly complex at mucosal sites that are exposed to billions of potentially antigenic particles daily. We demonstrated that epithelial cell-derived cytokine TGF-β had a central role in the generation of the pulmonary immune response. Mice that specifically lacked epithelial cell-derived TGF-β1 displayed a reduction in type 2 innate lymphoid cells (ILCs), resulting in suppression of interleukin-13 and hallmark features of the allergic response including airway hyperreactivity. ILCs in the airway lumen were primed to respond to TGF-β by expressing the receptor TGF-βRII and ILC chemoactivity was enhanced by TGF-β. These data demonstrate that resident epithelial cells instruct immune cells, highlighting the central role of the local environmental niche in defining the nature and magnitude of immune reactions.
Weiss M, Byrne AJ, Blazek K, et al., 2015, IRF5 controls both acute and chronic inflammation, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 112, Pages: 11001-11006, ISSN: 0027-8424
Blazek K, Eames HL, Weiss M, et al., 2015, IFN-lambda resolves inflammation via suppression of neutrophil infiltration and IL-1 beta production, Journal of Experimental Medicine, Vol: 212, Pages: 845-853, ISSN: 0022-1007
The most studied biological role of type III interferons (IFNs) has so far been their antiviral activity, but their role in autoimmune and inflammatory diseases remains largely unexplored. Here, we show that treatment with IFN-λ2/IL-28A completely halts and reverses the development of collagen-induced arthritis (CIA) and discover cellular and molecular mechanisms of IL-28A antiinflammatory function. We demonstrate that treatment with IL-28A dramatically reduces numbers of proinflammatory IL-17–producing Th17 and γδ T cells in the joints and inguinal lymph nodes, without affecting T cell proliferative responses or levels of anticollagen antibodies. IL-28A exerts its antiinflammatory effect by restricting recruitment of IL-1b–expressing neutrophils, which are important for amplification of inflammation. We identify neutrophils as cells expressing high levels of IFN-λ receptor 1 (IFNLR1)–IL-28 receptor α (IL28RA) and targeted by IL-28A. Our data highlight neutrophils as contributors to the pathogenesis of autoimmune arthritis and present IFN-λs or agonists of IFNLR1–IL28RA as putative new therapeutics for neutrophil-driven inflammation.IFN-λ1, -λ2, and -λ3 (or IL-29, IL-28A, and IL-28B, respectively) are members of the class II cytokine family evolutionarily related to both IL-10 and type I IFNs (IFN-α/β), and are collectively referred to as type III IFNs. IFN-λ1 (IL-29) is the main cytokine of this family produced in human cells, but it is not expressed in mice, where IL-28A/B play the major role. Despite the use of a distinct receptor complex, IFNLR1–IL28RA activates similar signaling pathways to that of the type I IFN receptor (Kotenko et al., 2003; Sheppard et al., 2003), and the most studied biological role of IFN-λs has so far been their antiviral activity. However, there is evidence to suggest that they may also have pleiotropic immune functions. IF
Lee DC, Walker SA, Byrne AJ, et al., 2015, Perinatal paracetamol exposure in mice does not affect the development of allergic airways disease in early life., Thorax, ISSN: 1468-3296
Current data concerning maternal paracetamol intake during pregnancy, or intake during infancy and risk of wheezing or asthma in childhood is inconclusive based on epidemiological studies. We have investigated whether there is a causal link between maternal paracetamol intake during pregnancy and lactation and the development of house dust mite (HDM) induced allergic airways disease (AAD) in offspring using a neonatal mouse model.
Denney L, Gregory LG, Shea TJ, et al., 2014, Pulmonary epithelial-derived TGF-beta 1 is critical for the inception of innate lymphoid cell mediated allergic airways disease, Publisher: WILEY-BLACKWELL, Pages: 41-41, ISSN: 0019-2805
Saliba DG, Heger A, Eames HL, et al., 2014, IRF5:RelA Interaction Targets Inflammatory Genes in Macrophages, CELL REPORTS, Vol: 8, Pages: 1308-1317, ISSN: 2211-1247
Denney L, Byrne AJ, Saglani S, et al., 2013, GATA3 expressing innate lymphoid cells are an important early source of Th2 cytokines driving allergen induced inflammation and AHR, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL, Pages: 90-90, ISSN: 0019-2805
Wechsler JB, Schroeder HA, Byrne AJ, et al., 2013, Anaphylactic responses to histamine in mice utilize both histamine receptors 1 and 2, ALLERGY, Vol: 68, Pages: 1338-1340, ISSN: 0105-4538
Byrne A, Lloyd C, Walker S, et al., 2013, Overexpression of IRF5 ameliorates house dust mite-mediated airway hyper-responsiveness via macrophage polarisation towards a classically activated phenotype, EUROPEAN RESPIRATORY JOURNAL, Vol: 42, ISSN: 0903-1936
Byrne AJ, Jones CP, Gowers K, et al., 2013, Lung Macrophages Contribute to House Dust Mite Driven Airway Remodeling via HIF-1 alpha, PLOS ONE, Vol: 8, ISSN: 1932-6203
Weiss M, Blazek K, Byrne AJ, et al., 2013, IRF5 Is a Specific Marker of Inflammatory Macrophages In Vivo, MEDIATORS OF INFLAMMATION, Vol: 2013, ISSN: 0962-9351
Swartzendruber JA, Byrne AJ, Bryce PJ, 2012, Cutting Edge: Histamine Is Required for IL-4-Driven Eosinophilic Allergic Responses, JOURNAL OF IMMUNOLOGY, Vol: 188, Pages: 536-540, ISSN: 0022-1767
Smarr CB, Hsu C-L, Byrne AJ, et al., 2011, Antigen-Fixed Leukocytes Tolerize Th2 Responses in Mouse Models of Allergy, JOURNAL OF IMMUNOLOGY, Vol: 187, Pages: 5090-5098, ISSN: 0022-1767
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