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3. Clinical Efficacy of Serum Antiglycopeptidolipid Core IgA Antibody Test for Screening Nontuberculous Mycobacterial Pulmonary Disease in Bronchiectasis: A European Multicenter Cohort Study

Author

Choi, Hayoung, Hughes, Chloe, Eke, Zsofia, Shuttleworth, Morven, Shteinberg, Michal, Polverino, Eva, Goeminne, Pieter C., Welte, Tobias, Blasi, Francesco, Shoemark, Amelia, Long, Merete B., Aliberti, Stefano, Haworth, Charles S., Ringshausen, Felix C., Loebinger, Michael R., Lorent, Natalie, and Chalmers, James D.

Published
2024
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4. The role of neutrophil-derived microvesicles in lung inflammation

Author

Long, Merete, Ridger, Victoria, and Condliffe, Alison

Subjects
616.2
Abstract

During the pathogenesis of chronic obstructive pulmonary disease (COPD) and in subsequent exacerbations, neutrophilic inflammation predominates and contributes to disease progression. Levels of neutrophil-derived microvesicles (NMVs; small extracellular vesicles formed from membrane blebbing in resting and activated cells) have previously been shown to be elevated in COPD patient sputum and in the circulation during inflammation. Evidence of the pro-inflammatory activity of NMVs in several cell types, along with an ability to increase epithelial monolayer permeability, led to the hypothesis that NMVs are released upon neutrophil activation in the circulation and the inflamed airway environment and are subsequently internalised by lung epithelial cells, inducing their pro-inflammatory activation and dysfunction. The overall aim of my PhD was to investigate the role of NMVs in lung inflammation. This was firstly done by characterising circulating MVs in COPD patients as both potential disease biomarkers and as mediators of inflammation using stored plasma samples from two COPD patient cohorts. Subsequently, it was crucial to isolate human neutrophils from the peripheral blood of healthy volunteers so as to generate, isolate and characterise a pure population of NMVs from these cells and to investigate the functional effects of these vesicles using the bronchial epithelial cell line BEAS2B. Finally, to further understand the biological relevance of NMV effects in the lung, C57BL/6 mice were utilised in a series of experiments to explore lung inflammation and NMV fate. Key findings: 1. Plasma MV matrix metalloproteinase-9 (MMP-9) content is significantly increased in COPD patients compared with age-matched controls, however, numbers of circulating leukocytederived MVs are not differential between these groups. 2. NMVs from fMLP-stimulated healthy participant neutrophils contain active MMP-9 and can degrade extracellular matrix proteins, but activated and quiescent neutrophils do not produce differential NMV numbers. 3. NMVs are rapidly taken up by bronchial epithelial cells, likely via an endocytic mechanism, with functional effects of NMVs on epithelial activation, barrier integrity and proliferation. 4. In vivo in mice, airway administration of NMVs does not induce or augment lung inflammation, instead, mass uptake and clearance of these NMVs by alveolar macrophages occurs. In this thesis I have shown that MV-associated protein content is altered in COPD, and investigation of these differences will be important going forward in defining the role of NMVs in chronic lung diseases. Degradation of extracellular matrix shown here and epithelial cell activation and permeability induced by NMVs when applied directly to these cells define key pathological events in COPD and indicate a role of these vesicles in epithelial dysfunction. In contrast, NMV uptake by alveolar macrophages was identified as a mechanism of NMV clearance in healthy lung tissue. Together, these findings provide novel insight into neutrophil interactions and activity in the lungs. This work contributed to our understanding of the processes occurring in inflammation and identified several valuable avenues for future investigation to understand more about complex conditions like COPD.

Published
2020

5. Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial

Author

Chalmers, James, Abo-Leyah, Hani, New, Benjamin JM, Almaden-Boyle, Christine, Connell, David, Taylor, Jennifer, Strachan, Jodie, Loftus, Heather, Young, Lesley, Strachan, Angela, Band, Margaret, McLaren-Neil, Fiona, Pilvinyte, Kristina, Adamson, Simon, Lahnsteiner, Eva, Rauchhaus, Petra, Hogarth, Fiona, George, Jacob, Burns, Tricia, Coote, Elizabeth, Keiller, Marney, Patel, Manish, Smith, Andrew, Sage, Elizabeth, Cooper, Jamie, Miller, David, Dosanjh, Davinder, Sutton, Benjamin, Underwood, Jonathan, Frayling, Sharon, Haynes, Matthew, Broad, Lauren, Jones, Laura, Rahilly, Karen, Oliver, Catherine, Evans, Terriann, Balan, Andrea, Davies, Rhys, Forde, Donal, Nye, Clemency, Haboubi, Dr, Hilton, Zoe, Williams, Jennie, McQueen, Alison, Spears, Mark, Edmond, Ian, Salutous, Dario, McGenily, Laura, Scott, Rhona, Henderson, Eilidh, Collins, Andrea, Dhasmana, Devesh, Liu, Patrick, Morrow, Ana, Couser, Mandy, Davey, Fleur, Hicks, Alexander, Wiffen, Laura, Fox, Lauren, Abdelrahim, Mohamed, Darbyshire, Alexander, Cowen, Elena, Rowley, Megan, Giles, Benjamin, Yang, Yingjia, Brown, Tom, Rupani, Hitasha, Hawes, Elizabeth, Barnes, Debi, Brogan, Fiona, Bungue-Tuble, Roneleeh, Howe, Serena, Turner, Charlotte, Baryschpolec, Sonia, Longhurst, Bev, Moon, Maria, Watkins, Lynn, Baker-Moffat, Michelle, Murray, Lisa, Harrington-Davies, Yasmin, Burrows, Kate, Minnis, Chrissie, Wands, Mary, Bamgboye, Adefunke, Wong, Charlotte, Brightling, Christopher, Diver, Sarah, Russell, Richard, McAuley, Hamish, Elneima, Omer, Yousuf, Ahmed, McCourt, Paula, Hargadon, Beverley, Parker, Sarah, Bourne, Michelle, Suntharalingam, Jay, Hartley, Tom, Masan, Vidan, Sturney, Sharon, MacKenzie, Rob, Marchand, Clare, Mason, Rebecca, White, Katie, Kirby, Alison, Meda, Manjula, Diwakar, Lavanya, Russell, Peter, Finn, Joanne, Harris, Sophie, Muir, Carol, Cook, Gemma, Staines, Nikki, Cook, Chris, Thompson, AA Roger, Condliffe, Alison, Hull, Rebecca, Dowey, Rebecca, Turton, Helena, Collini, Paul, Gabriel, Zoé, Hardman, Simon, Newell, Helen, Middle, Janet, Simpson, Phillip, Colton, Hayley, Barker, Joann, Birchall, Katie, Harrington, Kate, Housley, Kay, Lenagh, Rebecca, Wilson, Jayne, Wesonga, Joan, Whitham, Rachel, Bird, Sarah, Jackson, Yvonne, Mbuyisa, Angeline, Anderson, Samantha, Wilson, Anna, Kibutu, Faith, Walker, Sara, Cawthron, Kay, Macharia, Irene, Smart, Lynne, Emery, Anna, Howell, Alice, Hurditch, Elizabeth, Ford, Amber, Turner, Kim, Watson, Lisa, Bowler, Helen, Jackson, Tracy, Jaques, Carol, Dyer, Nichole, Ducker, Shelley, Goodall, Vicky, Udale, Emily, Keir, Holly R, Long, Merete B, Giam, Yan Hui, Vadiveloo, Thenmalar, Pembridge, Thomas, Hull, Rebecca C, Delgado, Lilia, Gilmour, Amy, Hughes, Chloe, Richardson, Hollian, Cassidy, Diane, Dosanjh, Davinder PS, Sage, Beth, Condliffe, Alison M, Shoemark, Amelia, MacLennan, Graeme, and Chalmers, James D

Published
2022
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6. Endotypes of Exacerbation in Bronchiectasis: An Observational Cohort Study

Author

Gao, Yonghua, primary, Richardson, Hollian, additional, Dicker, Alison J., additional, Barton, Alun, additional, Kuzmanova, Elena, additional, Shteinberg, Michal, additional, Perea, Lidia, additional, Goeminne, Pieter C., additional, Cant, Erin, additional, Hennayake, Chandani, additional, Pollock, Jennifer, additional, Abo Leyah, Hani, additional, Choi, Hayoung, additional, Polverino, Eva, additional, Blasi, Francesco, additional, Welte, Tobias, additional, Aliberti, Stefano, additional, Long, Merete, additional, Shoemark, Amelia, additional, Sibila, Oriol, additional, Huang, Jeffrey T. J., additional, and Chalmers, James D., additional

Published
2024
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7. SFX-01 in hospitalised patients with community-acquired pneumonia during the COVID-19 pandemic: a double-blind, randomised, placebo-controlled trial

Author

Long, Merete B., primary, Abo-Leyah, Hani, additional, Giam, Yan Hui, additional, Vadiveloo, Thenmalar, additional, Hull, Rebecca C., additional, Keir, Holly R., additional, Pembridge, Thomas, additional, Alferes De Lima, Daniela, additional, Delgado, Lilia, additional, Inglis, Sarah K., additional, Hughes, Chloe, additional, Gilmour, Amy, additional, Gierlinski, Marek, additional, New, Benjamin J.M., additional, MacLennan, Graeme, additional, Dinkova-Kostova, Albena T., additional, and Chalmers, James D., additional

Published
2024
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8. A serum calprotectin lateral flow test as an inflammatory and prognostic marker in acute lung infection: a prospective observational study

Author

Gilmour, Amy, primary, Hughes, Chloe, additional, Giam, Yan Hui, additional, Hull, Rebecca C, additional, Pembridge, Thomas, additional, Abo-Leyah, Hani, additional, Thompson, AA Roger, additional, Condliffe, Alison M, additional, Shoemark, Amelia, additional, Chalmers, James D, additional, and Long, Merete B, additional

Published
2024
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9. Sputum metagenomics of people with bronchiectasis

Author

Rosenboom, Ilona, primary, Thavarasa, Ajith, additional, Richardson, Hollian, additional, Long, Merete B., additional, Wiehlmann, Lutz, additional, Davenport, Colin F., additional, Shoemark, Amelia, additional, Chalmers, James D., additional, and Tümmler, Burkhard, additional

Published
2024
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10. A Bispecific Monoclonal Antibody Targeting Psl and PcrV Enhances Neutrophil-Mediated Killing of Pseudomonas aeruginosa in Patients with Bronchiectasis.

Author

Long, Merete B., Gilmour, Amy, Kehl, Margaret, Tabor, David E., Keller, Ashley E., Warrener, Paul, Gopalakrishnan, Vancheswaran, Rosengren, Sanna, Crichton, Megan L., McIntosh, Eve, Giam, Yan Hui, Keir, Holly R., Brailsford, Wayne, Hughes, Rod, Belvisi, Maria G., Sellman, Bret R., DiGiandomenico, Antonio, and Chalmers, James D.

Subjects
BISPECIFIC antibodies, BRONCHIECTASIS, PSEUDOMONAS aeruginosa, WHOLE genome sequencing, ANTIBODY titer
Abstract

Rationale:Pseudomonas aeruginosa infection is associated with worse outcomes in bronchiectasis. Impaired neutrophil antimicrobial responses contribute to bacterial persistence. Gremubamab is a bivalent, bispecific monoclonal antibody targeting Psl exopolysaccharide and the type 3 secretion system component PcrV. Objectives: This study evaluated the efficacy of gremubamab to enhance killing of P. aeruginosa by neutrophils from patients with bronchiectasis and to prevent P. aeruginosa–associated cytotoxicity. Methods:P. aeruginosa isolates from a global bronchiectasis cohort (n = 100) underwent whole-genome sequencing to determine target prevalence. Functional activity of gremubamab against selected isolates was tested in vitro and in vivo. Patients with bronchiectasis (n = 11) and control subjects (n = 10) were enrolled, and the effect of gremubamab in peripheral blood neutrophil opsonophagocytic killing (OPK) assays against P. aeruginosa was evaluated. Serum antibody titers to Psl and PcrV were determined (n = 30; 19 chronic P. aeruginosa infection, 11 no known P. aeruginosa infection), as was the effect of gremubamab treatment in OPK and anti–cytotoxic activity assays. Measurements and Main Results: Psl and PcrV were conserved in isolates from chronically infected patients with bronchiectasis. Seventy-three of 100 isolates had a full psl locus, and 99 of 100 contained the pcrV gene, with 20 distinct full-length PcrV protein subtypes identified. PcrV subtypes were successfully bound by gremubamab and the monoclonal antibody–mediated potent protective activity against tested isolates. Gremubamab increased bronchiectasis patient neutrophil-mediated OPK (+34.6 ± 8.1%) and phagocytosis (+70.0 ± 48.8%), similar to effects observed in neutrophils from control subjects (OPK, +30.1 ± 7.6%). No evidence of competition between gremubamab and endogenous antibodies was found, with protection against P. aeruginosa–induced cytotoxicity and enhanced OPK demonstrated with and without addition of patient serum. Conclusions: Gremubamab enhanced bronchiectasis patient neutrophil phagocytosis and killing of P. aeruginosa and reduced virulence. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Biomarkers in bronchiectasis.

Author

Johnson, Emma, Long, Merete B., and Chalmers, James D.

Subjects
BIOMARKERS, BRONCHIECTASIS, MUCOCILIARY system, INDIVIDUALIZED medicine, BIOLOGY, PROGNOSIS
Abstract

Bronchiectasis is a heterogeneous disease with multiple aetiologies and diverse clinical features. There is a general consensus that optimal treatment requires precision medicine approaches focused on specific treatable disease characteristics, known as treatable traits. Identifying subtypes of conditions with distinct underlying biology (endotypes) depends on the identification of biomarkers that are associated with disease features, prognosis or treatment response and which can be applied in clinical practice. Bronchiectasis is a disease characterised by inflammation, infection, structural lung damage and impaired mucociliary clearance. Increasingly there are available methods to measure each of these components of the disease, revealing heterogeneous inflammatory profiles, microbiota, radiology and mucus and epithelial biology in patients with bronchiectasis. Using emerging biomarkers and omics technologies to guide treatment in bronchiectasis is a promising field of research. Here we review the most recent data on biomarkers in bronchiectasis. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Proteinase 3 as a marker of clinical severity in bronchiectasis: Data from the EMBARC-BRIDGE study

Author

Johnson, Emma, primary, Crichton, Megan L, additional, Keir, Holly R, additional, Long, Merete, additional, Shuttleworth, Morven, additional, Cant, Erin, additional, De Soyza, Anthony, additional, Dimakou, Katerina, additional, Shteinberg, Michal, additional, Spinou, Arietta, additional, Ringshausen, Felix, additional, Lorent, Natalie, additional, Goeminne, Pieter, additional, Loebinger, Michael, additional, Chotirmall, Sanjay, additional, Dhar, Raja, additional, Haworth, Charles, additional, Altenburg, Josje, additional, Blasi, Francesco, additional, Welte, Tobias, additional, Siblia, Oriol, additional, Aliberti, Stefano, additional, Shoemark, Amelia, additional, and Chalmers, James D, additional

Published
2023
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16. Neutrophil metabolomics in bronchiectasis: data from the EMBARC BRIDGE study

Author

Shoemark, Amelia, primary, Giam, Yan Hui, additional, Gilmour, Amy, additional, Long, Merete B, additional, Keir, Holly R, additional, Pembridge, Thomas, additional, Hughes, Chloe, additional, Hull, Rebecca C, additional, Mcintosh, Eve, additional, Lind, Holly, additional, Crichton, Megan L, additional, Polverino, Eva, additional, Aliberti, Stefano, additional, Blasi, Francesco, additional, Goeminne, Pieter C, additional, Welte, Tobias, additional, Altenburg, Josje, additional, Shteinberg, Michal, additional, and Chalmers, James D, additional

Published
2023
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18. Neutrophil microvesicles drive atherosclerosis by delivering miR-155 to atheroprone endothelium

Author

Gomez, Ingrid, Ward, Ben, Souilhol, Celine, Recarti, Chiara, Ariaans, Mark, Johnston, Jessica, Burnett, Amanda, Mahmoud, Marwa, Luong, Le Anh, West, Laura, Long, Merete, Parry, Sion, Woods, Rachel, Hulston, Carl, Benedikter, Birke, Niespolo, Chiara, Bazaz, Rohit, Francis, Sheila, Kiss-Toth, Endre, van Zandvoort, Marc, Schober, Andreas, Hellewell, Paul, Evans, Paul C., and Ridger, Victoria

Published
2020
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20. Highlights of the ERS Lung Science Conference 2022

Author

Hanstock, Helen G., primary, Kapellos, Theodore S., additional, Keir, Holly R., additional, Khedoe, P. Padmini S.J., additional, Long, Merete B., additional, Evren, Elza, additional, Ubags, Niki D., additional, and Cruz, Joana, additional

Published
2022
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21. Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial

Author

Keir, Holly R, primary, Long, Merete B, additional, Abo-Leyah, Hani, additional, Giam, Yan Hui, additional, Vadiveloo, Thenmalar, additional, Pembridge, Thomas, additional, Hull, Rebecca C, additional, Delgado, Lilia, additional, Band, Margaret, additional, McLaren-Neil, Fiona, additional, Adamson, Simon, additional, Lahnsteiner, Eva, additional, Gilmour, Amy, additional, Hughes, Chloe, additional, New, Benjamin JM, additional, Connell, David, additional, Dowey, Rebecca, additional, Turton, Helena, additional, Richardson, Hollian, additional, Cassidy, Diane, additional, Cooper, Jamie, additional, Suntharalingam, Jay, additional, Diwakar, Lavanya, additional, Russell, Peter, additional, Underwood, Jonathan, additional, Hicks, Alexander, additional, Dosanjh, Davinder PS, additional, Sage, Beth, additional, Dhasmana, Devesh, additional, Spears, Mark, additional, Thompson, AA Roger, additional, Brightling, Christopher, additional, Smith, Andrew, additional, Patel, Manish, additional, George, Jacob, additional, Condliffe, Alison M, additional, Shoemark, Amelia, additional, MacLennan, Graeme, additional, Chalmers, James D, additional, Chalmers, James, additional, Almaden-Boyle, Christine, additional, Taylor, Jennifer, additional, Strachan, Jodie, additional, Loftus, Heather, additional, Young, Lesley, additional, Strachan, Angela, additional, Pilvinyte, Kristina, additional, Rauchhaus, Petra, additional, Hogarth, Fiona, additional, Burns, Tricia, additional, Coote, Elizabeth, additional, Keiller, Marney, additional, Sage, Elizabeth, additional, Miller, David, additional, Dosanjh, Davinder, additional, Sutton, Benjamin, additional, Frayling, Sharon, additional, Haynes, Matthew, additional, Broad, Lauren, additional, Jones, Laura, additional, Rahilly, Karen, additional, Oliver, Catherine, additional, Evans, Terriann, additional, Balan, Andrea, additional, Davies, Rhys, additional, Forde, Donal, additional, Nye, Clemency, additional, Haboubi, Dr, additional, Hilton, Zoe, additional, Williams, Jennie, additional, McQueen, Alison, additional, Edmond, Ian, additional, Salutous, Dario, additional, McGenily, Laura, additional, Scott, Rhona, additional, Henderson, Eilidh, additional, Collins, Andrea, additional, Liu, Patrick, additional, Morrow, Ana, additional, Couser, Mandy, additional, Davey, Fleur, additional, Wiffen, Laura, additional, Fox, Lauren, additional, Abdelrahim, Mohamed, additional, Darbyshire, Alexander, additional, Cowen, Elena, additional, Rowley, Megan, additional, Giles, Benjamin, additional, Yang, Yingjia, additional, Brown, Tom, additional, Rupani, Hitasha, additional, Hawes, Elizabeth, additional, Barnes, Debi, additional, Brogan, Fiona, additional, Bungue-Tuble, Roneleeh, additional, Howe, Serena, additional, Turner, Charlotte, additional, Baryschpolec, Sonia, additional, Longhurst, Bev, additional, Moon, Maria, additional, Watkins, Lynn, additional, Baker-Moffat, Michelle, additional, Murray, Lisa, additional, Harrington-Davies, Yasmin, additional, Burrows, Kate, additional, Minnis, Chrissie, additional, Wands, Mary, additional, Bamgboye, Adefunke, additional, Wong, Charlotte, additional, Diver, Sarah, additional, Russell, Richard, additional, McAuley, Hamish, additional, Elneima, Omer, additional, Yousuf, Ahmed, additional, McCourt, Paula, additional, Hargadon, Beverley, additional, Parker, Sarah, additional, Bourne, Michelle, additional, Hartley, Tom, additional, Masan, Vidan, additional, Sturney, Sharon, additional, MacKenzie, Rob, additional, Marchand, Clare, additional, Mason, Rebecca, additional, White, Katie, additional, Kirby, Alison, additional, Meda, Manjula, additional, Finn, Joanne, additional, Harris, Sophie, additional, Muir, Carol, additional, Cook, Gemma, additional, Staines, Nikki, additional, Cook, Chris, additional, Condliffe, Alison, additional, Hull, Rebecca, additional, Collini, Paul, additional, Gabriel, Zoé, additional, Hardman, Simon, additional, Newell, Helen, additional, Middle, Janet, additional, Simpson, Phillip, additional, Colton, Hayley, additional, Barker, Joann, additional, Birchall, Katie, additional, Harrington, Kate, additional, Housley, Kay, additional, Lenagh, Rebecca, additional, Wilson, Jayne, additional, Wesonga, Joan, additional, Whitham, Rachel, additional, Bird, Sarah, additional, Jackson, Yvonne, additional, Mbuyisa, Angeline, additional, Anderson, Samantha, additional, Wilson, Anna, additional, Kibutu, Faith, additional, Walker, Sara, additional, Cawthron, Kay, additional, Macharia, Irene, additional, Smart, Lynne, additional, Emery, Anna, additional, Howell, Alice, additional, Hurditch, Elizabeth, additional, Ford, Amber, additional, Turner, Kim, additional, Watson, Lisa, additional, Bowler, Helen, additional, Jackson, Tracy, additional, Jaques, Carol, additional, Dyer, Nichole, additional, Ducker, Shelley, additional, Goodall, Vicky, additional, and Udale, Emily, additional

Published
2022
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22. Dipeptidyl Peptidase-1 Inhibition in Patients Hospitalized with COVID-19: a Multicentre Randomized Double-Blind Placebo Controlled Trial

Author

Keir, Holly R., primary, Long, Merete B., additional, Abo-Leyah, Hani, additional, Giam, Yan H., additional, Vadiveloo, Thenmalar, additional, Pembridge, Thomas, additional, Hull, Rebecca C., additional, Delgado, Lilia, additional, Band, Margaret, additional, Mclaren-Neil, Fiona, additional, Adamson, Simon, additional, Lahnsteiner, Eva, additional, Gilmour, Amy, additional, Hughes, Chloe, additional, New, Benjamin Jm., additional, Connell, David, additional, Dowey, Rebecca, additional, Turton, Helena, additional, Richardson, Hollian, additional, Cassidy, Diane, additional, Cooper, Jamie, additional, Suntharalingam, Jay, additional, Diwakar, Lavanya, additional, Russell, Peter, additional, Underwood, Jonathan, additional, Hicks, Alexander, additional, Dosanjh, Davinder Ps, additional, Sage, Beth, additional, Dhasmana, Devesh, additional, Spears, Mark, additional, Thompson, Aa Roger, additional, Brightling, Christopher, additional, Smith, Andrew, additional, Patel, Manish, additional, George, Jacob, additional, Condliffe, Alison M, additional, Shoemark, Amelia, additional, Maclennan, Graeme, additional, and Chalmers, James D, additional

Published
2022
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23. Neutrophil proteomics identifies temporal changes and hallmarks of delayed recovery in COVID19

Author

Long, Merete B, primary, Howden, Andrew JM, additional, Keir, Holly R, additional, Rollings, Christina M, additional, Giam, Yan Hui, additional, Pembridge, Thomas, additional, Delgado, Lilia, additional, Abo-Leyah, Hani, additional, Lloyd, Amy F, additional, Sollberger, Gabriel, additional, Hull, Rebecca, additional, Gilmour, Amy, additional, Hughes, Chloe, additional, New, Benjamin JM, additional, Cassidy, Diane, additional, Shoemark, Amelia, additional, Richardson, Hollian, additional, Lamond, Angus I, additional, Cantrell, Doreen A, additional, Chalmers, James D, additional, and Brenes, Alejandro J, additional

Published
2022
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25. Hypoxia increases the potential for neutrophil-mediated endothelial damage in COPD

Author

Lodge, Katharine M, Vassallo, Arlette, Liu, Bin, Long, Merete, Newby, Paul R, Agha-Jaffar, Danya, Paschalaki, Koralia, Green, Clara E, Belchamber, Kylie BR, Ridger, Victoria C, Stockley, Robert A, Sapey, Elizabeth, Summers, Charlotte, Cowburn, Andrew S, Chilvers, Edwin R, Li, Wei, Condliffe, Alison M, Lodge, Katharine M [0000-0002-3203-9941], and Apollo - University of Cambridge Repository

Subjects
Pulmonary Disease, Chronic Obstructive, cardiovascular disease, Neutrophils, Endothelial Cells, Humans, cell degranulation, Vascular System Injuries, Hypoxia, Leukocyte Elastase, neutrophil elastase, vascular endothelium, respiratory tract diseases
Abstract

Rationale: Chronic obstructive pulmonary disease (COPD) patients experience excess cardiovascular morbidity and mortality, and exacerbations further increase the risk of such events. COPD is associated with persistent blood and airway neutrophilia, and systemic and tissue hypoxia. Hypoxia augments neutrophil elastase release, enhancing capacity for tissue injury. Objective: To determine whether hypoxia-driven neutrophil protein secretion contributes to endothelial damage in COPD. Methods: The healthy human neutrophil secretome generated under normoxic or hypoxic conditions was characterised by quantitative mass spectrometry, and the capacity for neutrophil-mediated endothelial damage assessed. Histotoxic protein levels were measured in normoxic versus hypoxic neutrophil supernatants and plasma from exacerbating COPD patients and healthy controls. Main results: Hypoxia promoted PI3Kγ-dependent neutrophil elastase secretion, with greater release seen in neutrophils from COPD patients. Supernatants from neutrophils incubated under hypoxia caused pulmonary endothelial cell damage and identical supernatants from COPD neutrophils increased neutrophil adherence to endothelial cells. Proteomics revealed differential neutrophil protein secretion under hypoxia and normoxia; hypoxia augmented secretion of a subset of histotoxic granule and cytosolic proteins, with significantly greater release seen in COPD neutrophils. The plasma of COPD patients had higher content of hypoxia-upregulated neutrophil-derived proteins and protease activity, and vascular injury markers. Conclusions: Hypoxia drives a destructive ‘hyper-secretory’ neutrophil phenotype conferring enhanced capacity for endothelial injury, with a corresponding signature of 5 neutrophil degranulation and vascular injury identified in COPD patient plasma. Thus, hypoxic enhancement of neutrophil degranulation may contribute to increased cardiovascular risk in COPD. These insights may identify new therapeutic opportunities for endothelial damage in COPD.

Published
2022

26. Highlights of the ERS Lung Science Conference 2022

Author

Hanstock, Helen G., Kapellos, Theodore S., Keir, Holly R., Khedoe, P. Padmini S.J., Long, Merete B., Evren, Elza, Ubags, Niki D., Cruz, Joana, Hanstock, Helen G., Kapellos, Theodore S., Keir, Holly R., Khedoe, P. Padmini S.J., Long, Merete B., Evren, Elza, Ubags, Niki D., and Cruz, Joana

Abstract

Every year, the European Respiratory Society (ERS) organises the Lung Science Conference (LSC), in Estoril, to discuss basic and translational science. The topic of the 20th LSC was “Mucosal immunology of the lung: balancing protective immunity and chronic inflammation”. This was the first time that the LSC was organised as a hybrid congress with both in person and online attendance. In addition to an outstanding scientific programme, the LSC provides excellent opportunities for career development and inclusion of early career members (ECMs). All scientific and poster sessions are chaired by an ECM who is paired with a senior faculty to allow ECMs to become acquainted with session chairing, and there is a session organised by the Early Career Member Committee (ECMC) dedicated to career development. Moreover, travel bursaries are made available to abstract authors, and all bursary recipients and first-time attendees are invited to take part in a mentorship lunch. In this article, we provide the names of the ECM awardees and describe the scientific highlights of the LSC 2022 for those who could not attend.

Published
2022
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27. Hypoxia Increases the Potential for Neutrophil-mediated Endothelial Damage in Chronic Obstructive Pulmonary Disease

Author

Lodge, Katharine M., primary, Vassallo, Arlette, additional, Liu, Bin, additional, Long, Merete, additional, Tong, Zhen, additional, Newby, Paul R., additional, Agha-Jaffar, Danya, additional, Paschalaki, Koralia, additional, Green, Clara E., additional, Belchamber, Kylie B. R., additional, Ridger, Victoria C., additional, Stockley, Robert A., additional, Sapey, Elizabeth, additional, Summers, Charlotte, additional, Cowburn, Andrew S., additional, Chilvers, Edwin R., additional, Li, Wei, additional, and Condliffe, Alison M., additional

Published
2022
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29. Profiling systemic inflammation and neutrophil function in hospitalized patients with COVID19: results from PREDICT-COVID19

Author

Long, Merete, primary, Keir, Holly R, additional, Giam, Yan Hui, additional, Howden, Andrew J M, additional, Brenes, Alejandro J, additional, Rollings, Christina, additional, Pembridge, Thomas, additional, Delgado, Lilia, additional, Abo-Leyah, Hani, additional, Hull, Rebecca C, additional, Gilmour, Amy, additional, Hughes, Chloe, additional, Dowey, Rebecca, additional, Turton, Helena, additional, New, Benjamin J M, additional, Connell, David W, additional, Richardson, Hollian, additional, Thompson, Roger, additional, Condliffe, Alison M, additional, Lamond, Angus I, additional, Cassidy, Diane M, additional, Shoemark, Amelia, additional, Cantrell, Doreen A, additional, and Chalmers, James D, additional

Published
2022
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30. ERS International Congress 2021: highlights from the Respiratory Infections Assembly

Author

Meldrum, Oliver W., primary, Belchamber, Kylie B.R., additional, Chichirelo-Konstantynovych, Kiarina D., additional, Horton, Katie L., additional, Konstantynovych, Tetyana V., additional, Long, Merete B., additional, McDonnell, Melissa J., additional, Perea, Lidia, additional, Garcia-Basteiro, Alberto L., additional, Loebinger, Michael R., additional, Duarte, Raquel, additional, and Keir, Holly R., additional

Published
2022
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32. Rapid diagnosis of bacterial co-infection and antimicrobial resistance in patients with SARS-Cov-2 infection

Author

Richardson, Hollian, primary, Maccallum, Jane, additional, Falconer, Kerry, additional, Cassidy, Diane, additional, Long, Merete, additional, Keir, Holly R, additional, Giam, Yan Hui, additional, Delgado, Lilia, additional, Pembridge, Thomas, additional, Parcell, Benjamin, additional, Haynes, Steven, additional, Abo-Leyah, Hani, additional, Connell, David, additional, and Chalmers, James D, additional

Published
2021
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36. Neutrophil microvesicles drive atherosclerosis by deliveringmiR-155to atheroprone endothelium

Author

Gomez, Ingrid, primary, Ward, Ben, additional, Souilhol, Celine, additional, Recarti, Chiara, additional, Ariaans, Mark, additional, Johnston, Jessica, additional, Burnett, Amanda, additional, Mahmoud, Marwa, additional, Luong, Le Anh, additional, West, Laura, additional, Long, Merete, additional, Parry, Sion, additional, Woods, Rachel, additional, Hulston, Carl, additional, Benedikter, Birke, additional, Bazaz, Rohit, additional, Francis, Sheila, additional, Kiss-Toth, Endre, additional, Zandvoort, Marc van, additional, Schober, Andreas, additional, Hellewell, Paul, additional, Evans, Paul C., additional, and Ridger, Victoria, additional

Published
2018
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37. Clinical Efficacy of Serum Anti-glycopeptidolipid-core IgA Antibody Test for Screening Nontuberculous Mycobacterial Pulmonary Disease in Bronchiectasis: A European Multicenter Cohort Study

Author

Choi, Hayoung, Hughes, Chloe, Eke, Zsofia, Shuttleworth, Morven, Shteinberg, Michal, Polverino, Eva, Goeminne, Pieter C., Welte, Tobias, Blasi, Francesco, Shoemark, Amelia, Long, Merete B., Aliberti, Stefano, Haworth, Charles S., Ringshausen, Felix C., Loebinger, Michael R., Lorent, Natalie, and Chalmers, James D.

Abstract

Serum anti-glycopeptidolipid (GPL) core immunoglobuin A (IgA) antibody test has been proposed as a diagnostic tool for Mycobacterium aviumcomplex pulmonary diseases. Cross-reactivity with other non-tuberculous mycobacteria (NTM), including M. abscessus, indicates that it may have a role as a broader screening test for NTM pulmonary disease (NTM-PD). NTM-PD is believed to be underdiagnosed in patients with bronchiectasis.

Published
2024
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38. Broad Immunomodulatory Effects of the Dipeptidyl-peptidase-1 Inhibitor Brensocatib in Bronchiectasis: Data from the Phase 2, Double-Blind, Placebo-controlled WILLOW Trial.

Author

Johnson ED, Long MB, Perea L, Shih VH, Fernandez C, Teper A, Cipolla D, McIntosh E, Galloway R, Eke Z, Shuttleworth M, Hull R, Spinou A, De Soyza A, Ringshausen FC, Goeminne P, Lorent N, Haworth C, Loebinger MR, Blasi F, Shteinberg M, Aliberti S, Polverino E, Sibila O, Shoemark A, Mange K, Huang JTJ, Stobo J, and Chalmers JD

Abstract

Rationale: In the WILLOW trial, the Dipeptidyl peptidase-1 inhibitor brensocatib reduced neutrophil serine protease (NSP) activity and prolonged time to first exacerbation in patients with bronchiectasis., Objectives: We hypothesized that, by reducing NSPs, brensocatib would affect antimicrobial peptides, mucins, and cytokines throughout the inflammatory cascade., Methods: The WILLOW trial was a phase 2 randomized trial of brensocatib (10mg and 25mg) versus placebo. Sputum was collected at baseline, week 4, week 24 (end of treatment) and week 28 (4 weeks post-treatment). The antimicrobial peptides secretory leukoproteinase inhibitor (SLPI) and α-defensin-3 were measured by ELISA, mucin-5AC (MUC5AC) by liquid chromatography mass spectrometry, myeloperoxidase by immunoassay and 45 inflammatory cytokines by Olink ® Target 48 assay. The relationship between these markers and sputum neutrophil elastase was validated using the EMBARC-BRIDGE bronchiectasis cohort., Measurements and Main Results: Of 82 patients randomized to 10mg brensocatib, 87 to 25mg brensocatib, and 87 to placebo, 71, 71 and 73 with sputum available for at least two time points were included. SLPI and α-defensin-3 increased significantly with brensocatib compared to placebo at both week 4 and week 24. MUC5AC reduced in response to treatment. Sub-analysis showed this was primarily among patients with high baseline neutrophil elastase. Myeloperoxidase did not change. 15 cytokines and chemokines increased significantly compared to placebo at week 4 or 28. CXCL10, CCL8, CCL7, CCL3 and IL-6 increased at both doses at both timepoints. In the EMBARC-BRIDGE cohort neutrophil elastase correlated inversely with SLPI, CCL13, IL7, CCL11, CXCL10, CCL8, CCL7, all markers increased by brensocatib., Conclusions: Brensocatib exerts broad anti-inflammatory effects beyond its known effects on serine proteases. Clinical trial registration available at www., Clinicaltrials: gov, ID: NCT03218917.

Published
2025
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39. Extensive acute and sustained changes to neutrophil proteomes post-SARS-CoV-2 infection.

Author

Long MB, Howden AJM, Keir HR, Rollings CM, Giam YH, Pembridge T, Delgado L, Abo-Leyah H, Lloyd AF, Sollberger G, Hull R, Gilmour A, Hughes C, New BJM, Cassidy D, Shoemark A, Richardson H, Lamond AI, Cantrell DA, Chalmers JD, and Brenes AJ

Subjects
Humans, SARS-CoV-2, Neutrophils, Proteome, Cytokines, COVID-19
Abstract

Background: Neutrophils are important in the pathophysiology of coronavirus disease 2019 (COVID-19), but the molecular changes contributing to altered neutrophil phenotypes following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not fully understood. We used quantitative mass spectrometry-based proteomics to explore neutrophil phenotypes immediately following acute SARS-CoV-2 infection and during recovery., Methods: Prospective observational study of hospitalised patients with PCR-confirmed SARS-CoV-2 infection (May to December 2020). Patients were enrolled within 96 h of admission, with longitudinal sampling up to 29 days. Control groups comprised non-COVID-19 acute lower respiratory tract infection (LRTI) and age-matched noninfected controls. Neutrophils were isolated from peripheral blood and analysed using mass spectrometry. COVID-19 severity and recovery were defined using the World Health Organization ordinal scale., Results: Neutrophil proteomes from 84 COVID-19 patients were compared to those from 91 LRTI and 42 control participants. 5800 neutrophil proteins were identified, with >1700 proteins significantly changed in neutrophils from COVID-19 patients compared to noninfected controls. Neutrophils from COVID-19 patients initially all demonstrated a strong interferon signature, but this signature rapidly declined in patients with severe disease. Severe disease was associated with increased abundance of proteins involved in metabolism, immunosuppression and pattern recognition, while delayed recovery from COVID-19 was associated with decreased granule components and reduced abundance of metabolic proteins, chemokine and leukotriene receptors, integrins and inhibitory receptors., Conclusions: SARS-CoV-2 infection results in the sustained presence of circulating neutrophils with distinct proteomes suggesting altered metabolic and immunosuppressive profiles and altered capacities to respond to migratory signals and cues from other immune cells, pathogens or cytokines., Competing Interests: Conflict of interest: H.R. Keir has received speaker fees from Insmed. A. Shoemark has received grant funding from AstraZeneca. A.J. Brenes has received support for attending meetings from the British Society for Proteome research. J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed and Trudell, and received consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell and Zambon. All other authors declare no conflicts of interest., (Copyright ©The authors 2024.)

Published
2024
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