Publications
301 results found
Pavord ID, Beasley R, Agusti A, et al., 2017, After asthma: redefining airways diseases., Lancet, Vol: 391, Pages: 350-400, ISSN: 0140-6736
Dean CH, Lloyd CM, 2017, Lung Alveolar Repair: Not All Cells Are Equal, TRENDS IN MOLECULAR MEDICINE, Vol: 23, Pages: 871-873, ISSN: 1471-4914
The lungs are capable of repair but the extent to which this occurs varies widely. Recent data indicate that, following injury, different progenitor cell populations can arise, depending on the molecular environment. In turn, these result in either normal or aberrant alveolar repair. Thus, a key question in lung regenerative medicine is how to maintain a ‘Goldilocks zone’ of repair.
Snelgrove RJ, Lloyd CM, 2017, An NLRP3, IL-1 beta, Neutrophil Axis in the Respiratory Tract Leaves You Breathless, American Journal of Respiratory and Critical Care Medicine, Vol: 196, Pages: 253-254, ISSN: 1073-449X
Lloyd CM, Saglani S, 2017, Development of allergic immunity in early life, IMMUNOLOGICAL REVIEWS, Vol: 278, Pages: 101-115, ISSN: 0105-2896
The growth and maturity of the peripheral immune system and subsequent development of pulmonary immunity in early life is dictated by host, environmental and microbial factors. Dysregulation during the critical window of immune development in the postnatal years results in disease which impacts on lifelong lung health. Asthma is a common disease in childhood and is often preceded by wheezing illnesses during the preschool years. However, the mechanisms underlying development of wheeze and how and why only some children progress to asthma is unknown. Human studies to date have generally focused on peripheral immune development, with little assessment of local tissue pathology in young children. Moreover, mechanisms underlying the interactions between inflammation and tissue repair at mucosal surfaces in early life remain unknown. Disappointingly, mechanistic studies in mice have predominantly used adult models. This review will consider the aspects of the neonatal immune system which might contribute to the development of early life wheezing disorders and asthma, and discuss the external environmental factors which may influence this process.
Andersson CK, Adams A, Nagakumar P, et al., 2017, Intra-epithelial neutrophils in paediatric severe asthma are associated with better lung function, Journal of Allergy and Clinical Immunology, Vol: 139, Pages: 1819-1829.e11, ISSN: 1097-6825
BACKGROUND: Neutrophils and IL-17A have been linked mechanistically in models of allergic airways disease and have been associated with asthma severity. However, their role in paediatric asthma is unknown. OBJECTIVES: To investigate the role of neutrophils and the IL-17A pathway in mediating paediatric severe therapy resistant asthma (STRA). METHODS: Children with STRA (n=51, age 12.6 (6 -16.3) years) and non-asthmatic controls (n=15, age 4.75 (1.6-16) years) underwent clinically indicated fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), endobronchial brushings and biopsy. Neutrophils, IL-17A and IL-17RA expressing cells and levels of IL-17A and IL-22 were quantified in BAL and biopsies and related to clinical features. Primary bronchial epithelial cells (PBECs) were stimulated with IL-17A and/or IL-22, with and without Budesonide. RESULTS: Children with STRA had increased intra-epithelial neutrophils, which positively correlated with FEV1 %predicted (r=0.43, p=0.008). Neutrophil-high patients also had better symptom control, despite lower dose maintenance inhaled steroids. Submucosal neutrophils were not increased in STRA. Submucosal and epithelial IL-17A positive cells and BAL IL-17A and IL-22 levels were similar in STRA and controls. However, there were significantly more IL-17RA positive cells in the submucosa and epithelium in children with STRA compared to controls (p=0.001). Stimulation of PBECs with IL-17A enhanced mRNA expression of IL-17RA and increased release of IL-8, even in the presence of Budesonide. CONCLUSIONS: A proportion of children with STRA exhibit increased intra-epithelial airway neutrophilia that correlated with better lung function. STRA was additionally characterised by increased airway IL-17RA expression. These data suggest a potential beneficial rather than adverse role for neutrophils in paediatric severe asthma pathophysiology.
Nagakumar P, Artusio L, Fainardi V, et al., 2017, Role of airway Ilc2 And Ilc3 compared to Th2 And Th17 cells in paediatric severe therapy resistant asthma (stra), International Conference of the American-Thoracic-Society (ATS), Publisher: American Thoracic Society, ISSN: 1073-449X
Edwards MR, Saglani S, Schwarze J, et al., 2017, Addressing unmet needs in understanding asthma mechanisms: From the European Asthma Research and Innovation Partnership (EARIP) Work Package (WP)2 collaborators, European Respiratory Journal, Vol: 49, ISSN: 1399-3003
Asthma is a heterogeneous, complex disease with clinical phenotypes that incorporate persistent symptoms and acute exacerbations. It affects many millions of Europeans throughout their education and working lives and puts a heavy cost on European productivity. There is a wide spectrum of disease severity and control. Therapeutic advances have been slow despite greater understanding of basic mechanisms and the lack of satisfactory preventative and disease modifying management for asthma constitutes a significant unmet clinical need. Preventing, treating and ultimately curing asthma requires co-ordinated research and innovation across Europe. The European Asthma Research and Innovation Partnership (EARIP) is an FP7-funded programme which has taken a co-ordinated and integrated approach to analysing the future of asthma research and development. This report aims to identify the mechanistic areas in which investment is required to bring about significant improvements in asthma outcomes.
Lloyd CM, Marsland BJ, 2017, Lung homeostasis: influence of age, microbes, and the immune system, Immunity, Vol: 46, Pages: 549-561, ISSN: 1074-7613
Pulmonary immune homeostasis is maintained by a network of tissue-resident cells that continually monitor the external environment, and in health, instruct tolerance to innocuous inhaled particles while ensuring that efficient and rapid immune responses can be mounted against invading pathogens. Here we review the multiple pathways that underlie effective lung immunity in health, and discuss how these may be affected by external environmental factors and contribute to chronic inflammation during disease. In this context, we examine the current understanding of the impact of the microbiota in immune development and function and in the setting of the threshold for immune responses that maintains the balance between tolerance and chronic inflammation in the lung. We propose that host interactions with microbes are critical for establishing the immune landscape of the lungs.
Low CM, Akthar S, Patel D, et al., 2017, The development of novel LTA4H modulators to selectively target LTB4 generation, Scientific Reports, Vol: 7, ISSN: 2045-2322
The pro-inflammatory mediator leukotriene B4 (LTB4) is implicated in the pathologies of an array of diseases and thus represents an attractive therapeutic target. The enzyme leukotriene A4 hydrolase (LTA4H) catalyses the distal step in LTB4 synthesis and hence inhibitors of this enzyme have been actively pursued. Despite potent LTA4H inhibitors entering clinical trials all have failed to show efficacy. We recently identified a secondary anti-inflammatory role for LTA4H in degrading the neutrophil chemoattractant Pro-Gly-Pro (PGP) and rationalized that the failure of conventional LTA4H inhibitors may be that they inadvertently prevented PGP degradation. We demonstrate that these inhibitors do indeed fail to discriminate between the dual activities of LTA4H, and enable PGP accumulation in mice. Accordingly, we have developed novel compounds that potently inhibit LTB4 generation whilst leaving PGP degradation unperturbed. These novel compounds could represent a safer and superior class of LTA4H inhibitors for translation into the clinic.
Poobalasingam T, Yates LL, Walker SA, et al., 2017, Heterozygous Vangl2 looptail mice reveal novel roles for the planar cell polarity pathway in adult lung homeostasis and repair, Disease Models & Mechanisms, Vol: 10, Pages: 409-423, ISSN: 1754-8403
Lung diseases impose a huge economic and health burden worldwide. A key aspect of several adult lung diseases, such as Idiopathic pulmonary fibrosis (IPF) and Chronic Obstructive pulmonary Disease (COPD), including emphysema, is aberrant tissue repair, which leads to an accumulation of damage and impaired respiratory function. Currently, there are few effective treatments available for these diseases and their incidence is rising.The Planar Cell Polarity (PCP) pathway is critical for the embryonic development of many organs, including kidney and lung. We have previously shown that perturbation of the PCP pathway impairs tissue morphogenesis, which disrupts the number and shape of epithelial tubes formed within these organs during embryogenesis. However, very little is known about the role of the PCP pathway beyond birth, partly due to the perinatal lethality of many PCP mouse mutant lines.Here we have investigated heterozygous Looptail (Lp) mice, in which a single copy of the core PCP gene, Vangl2, is disrupted. We show that these mice are viable but display severe airspace enlargement and impaired adult lung function. Underlying these defects, we find that Vangl2Lp/+ lungs exhibit altered distribution of actin microfilaments and abnormal regulation of the actin modifying protein cofilin. In addition, we show that Vangl2Lp/+ lungs exhibit many of the hallmarks of tissue damage including an altered macrophage population, abnormal elastin deposition and elevated levels of the elastin-modifying enzyme, Mmp12, all of which are observed in the lung disease, emphysema.In vitro, VANGL2 disruption impairs directed cell migration and reduces the rate of repair following scratch wounding of human alveolar epithelial cells. Moreover, using population data from a birth cohort of young adults, all aged 31, we found evidence of an interactive effect between VANGL2 and smoking (a tissue damaging insult) on lung function. Finally, we show that that PCP genes VANGL2 and SCRIBBLE (SC
Weiss G, Lai C, Fife ME, et al., 2016, Reversal of TREM-1 ectodomain shedding and improved bacterial clearance by intranasal metalloproteinase inhibitors, MUCOSAL IMMUNOLOGY, Vol: 10, Pages: 1021-1030, ISSN: 1933-0219
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.
Löser S, Gregory LG, Zhang Y, et al., 2016, Pulmonary ORMDL3 is critical for induction of Alternaria induced allergic airways disease, Journal of Allergy and Clinical Immunology, Vol: 139, Pages: 1496-1507.e3, ISSN: 1097-6825
BACKGROUND: Genome-wide association studies have identified the ORMDL3 (ORM (yeast)-like protein isoform 3) gene locus on human chromosome 17q to be a highly significant risk factor for childhood-onset asthma. OBJECTIVE: We sought to investigate in vivo the functional role of ORMDL3 in disease inception. METHODS: An Ormdl3 deficient mouse was generated and the role of ORMDL3 in the generation of allergic airways disease to the fungal aeroallergen Alternaria alternata determined. An adeno-associated viral vector was also utilized to reconstitute ORMDL3 expression in airway epithelial cells of Ormdl3 KO mice. RESULTS: Ormdl3 knock-out mice were found to be protected from developing allergic airways disease and showed a marked decrease in pathophysiology, including lung function and airway eosinophilia induced by Alternaria. Alternaria is a potent inducer of cellular stress and the unfolded protein response and ORMDL3 was found to play a critical role in driving the ATF6 mediated arm of this response through Xbp1 and downstream activation of the endoplasmic reticulum-associated degradation pathway. Additionally ORMDL3 mediated uric acid release, another marker of cellular stress. In the knockout mice, reconstitution of Ormdl3 transcript levels specifically in the bronchial epithelium resulted in reinstatement of susceptibility to fungal allergen-induced allergic airways disease. CONCLUSIONS: This study demonstrates that ORMDL3, an asthma susceptibility gene identified by genome-wide association studies, contributes to key pathways that promote changes in airway physiology during allergic immune responses.
Zhang Y, Dean C, Loeser S, et al., 2016, Systematic dissection of ORMDL3 function in vitro and in vivo, ERS International Congress 2016, Publisher: European Respiratory Society, ISSN: 0903-1936
ORMDL3 on human chromosome 17q21 is a major genetic influence for childhood asthma, severe asthma and asthma exacerbations. To understand further the functional roles of ORMDL3, we established both human airway epithelial models and a recombineering-generated murine Ormdl3 knockout model. The influences of ORMDL3 on inflammatory responses in vitro and in vivo were investigated.We performed gene silencing using siRNA for two days in airway epithelium cells (A549, Beas2B and NHBE cells) after which cells were stimulated with IL1B. ORMDL3 knockdown-epithelial cells released much less IL6 and IL8 at 10 hours after stimulation (P < 0.01 respectively). Over-expression of ORMDL3 in epithelial cells resulted in a significant increase in release of IL6 and IL8 shortly after stimulation. Serine-palmitoyl transferase (SPT) is the key enzyme of sphingolipid metabolism. Treatment of epithelial cells with the SPT inhibitor myriocin resulted in an increase in release of IL6 and IL8 after stimulation, mirroring the results seen with the overexpression model. A systemic metabolic screening of the ORMDL3 knockdown epithelial cells revealed ORMDL3 to be involved not only in regulating sphingolipid metabolism but also lysophospholipids metabolism and the regulation of glycolysis. Parallel global gene expression profiling of the same cells identified key transcripts involved in regulating the inflammatory response. The lung function of Ormdl3 knockout mice also exhibited a reduced response after Alternaria alternata challenge.Our findings indicate ORMDL3 is a key molecule involved in the regulation of the inflammation response through multiple pathways and is a potential therapeutic target for asthma.
Lloyd C, 2016, Regulation of lung immunity by epithelial derived cytokines, International Congress of Immunology (ICI), Publisher: WILEY-BLACKWELL, Pages: 499-499, ISSN: 0014-2980
Fainardi V, Nagakumar P, Saglani S, et al., 2016, IL-4 and IL-13 secreting Type 2 innate lymphoid cells are present in human cord blood, Pediatric Pulmonology, Vol: 51, Pages: S84-S84, ISSN: 8755-6863
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.
Lloyd CM, Harker JA, 2016, Location, Location, Location: Localized Memory Cells Take Residence in the Allergic Lung, IMMUNITY, Vol: 44, Pages: 13-15, ISSN: 1074-7613
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Saglani S, Lloyd CM, 2016, Prostacyclin as a potential novel means to manipulate type 2 innate lymphoid cell function, American Journal of Respiratory and Critical Care Medicine, Vol: 193, Pages: 2-4, ISSN: 1535-4970
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
Grime CJ, Saglani S, Lloyd CM, et al., 2016, Children With Obstructive Sleep Apnoea Have Lower T-Regulatory Cells In The Upper Airway And Peripherally Compared To Controls, 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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Saglani S, Lloyd CM, 2015, Novel concepts in airway inflammation and remodelling in asthma, EUROPEAN RESPIRATORY JOURNAL, Vol: 46, Pages: 1796-1804, ISSN: 0903-1936
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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.
Brown SM, Bush A, Davies J, et al., 2015, REGULATORY T CELLS INCREASE IN THE PAEDIATRIC CF AIRWAY IN ASSOCIATION WITH AIRWAY NEUTROPHILIA, PEDIATRIC PULMONOLOGY, Vol: 50, Pages: 237-237, ISSN: 8755-6863
Snelgrove RJ, 2015, Matrikines are key regulators in modulating the amplitude of lung inflammation in acute pulmonary infection, Nature Communications, Vol: 6, Pages: 1-14, ISSN: 2041-1723
Bioactive matrix fragments (matrikines) have been identified in a myriad of disorders, but their impact on the evolution of airway inflammation has not been demonstrated. We recently described a pathway where the matrikine and neutrophil chemoattractant proline–glycine–proline (PGP) could be degraded by the enzyme leukotriene A4 hydrolase (LTA4H). LTA4H classically functions in the generation of pro-inflammatory leukotriene B4, thus LTA4H exhibits opposing pro- and anti-inflammatory activities. The physiological significance of this secondary anti-inflammatory activity remains unknown. Here we show, using readily resolving pulmonary inflammation models, that loss of this secondary activity leads to more pronounced and sustained inflammation and illness owing to PGP accumulation. PGP elicits an exacerbated neutrophilic inflammation and protease imbalance that further degrades the extracellular matrix, generating fragments that perpetuate inflammation. This highlights a critical role for the secondary anti-inflammatory activity of LTA4H and thus has consequences for the generation of global LTA4H inhibitors currently being developed.
Brown SM, Bush A, Davies J, et al., 2015, The ratio IL-8:IL-10 is increased in the paediatric CF airway as compared to other neutrophilic lung diseases, Pediatric Pulmonology, Vol: 50, Pages: 237-238, ISSN: 8755-6863
Grime C, Nagakumar P, Tan H-L, et al., 2015, Innate lymphoid cells are proportionally higher in children with atopy, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Nagakumar P, Denney L, Fleming L, et al., 2015, Type 2 innate lymphoid cells in induced sputum from children with severe asthma, Journal of Allergy and Clinical Immunology, Vol: 137, Pages: 624-626.e6, ISSN: 1097-6825
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