Journal
EUROPEAN RESPIRATORY JOURNAL
Volume 58, Issue 4, Pages -Publisher
EUROPEAN RESPIRATORY SOC JOURNALS LTD
DOI: 10.1183/13993003.03312-2020
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Funding
- AstraZeneca
- Swedish Foundation for Strategic Research (SSF)
- MedImmune
- Medical Research Council
- National Institute for Health Research Leicester Biomedical Research Centre (UK)
- AirPROM [FP7270194]
- National Institute for Health Research (NIHR) Manchester Biomedical Research Centre (BRC), North West Lung Centre Charity, Manchester, UK
- AstraZeneca, Gaithersburg, MD, USA
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The study identified a subset of COPD patients with IL-6TS pathway activation, characterized by persistent neutrophilic inflammation, impaired respiratory function, and increased nitrite levels in lung tissue, suggesting that chronic colonization with Haemophilus may be a driving force for these patients.
Background: Interleukin (IL)-6 trans-signalling (IL-6TS) is emerging as a pathogenic mechanism in chronic respiratory diseases; however, the drivers of IL-6TS in the airways and the phenotypic characteristic of patients with increased IL-6TS pathway activation remain poorly understood. Objective: Our aim was to identify and characterise COPD patients with increased airway IL-6TS and to elucidate the biological drivers of IL-6TS pathway activation. Methods: We used an IL-6TS-specific sputum biomarker profile (soluble IL-6 receptor (sIL-6R), IL-6, IL1 beta, IL-8, macrophage inflammatory protein-1 beta) to stratify sputum data from patients with COPD (n=74; Biomarkers to Target Antibiotic and Systemic Corticosteroid Therapy in COPD Exacerbation (BEAT-COPD)) by hierarchical clustering. The IL-6TS signature was related to clinical characteristics and sputum microbiome profiles. The induction of neutrophil extracellular trap formation (NETosis) and IL-6TS by Haemophilus influenzae were studied in human neutrophils. Results: Hierarchical clustering revealed an IL-6TS-high subset (n=24) of COPD patients, who shared phenotypic traits with an IL-6TS-high subset previously identified in asthma. The subset was characterised by increased sputum cell counts (p=0.0001), persistent sputum neutrophilia (p=0.0004), reduced quality of life (Chronic Respiratory Questionnaire total score; p=0.008), and increased levels of pro-inflammatory mediators and matrix metalloproteinases in sputum. IL-6TS-high COPD patients showed an increase in Proteobacteria, with Haemophilus as the dominating genus. NETosis induced by H. influenzae was identified as a potential mechanism for increased sIL-6R levels. This was supported by a significant positive correlation between sIL-6R and NETosis markers in bronchoalveolar lavage fluid from COPD patients. Conclusion: IL-6TS pathway activation due to chronic colonisation with Haemophilus may be an important disease driver in a subset of COPD patients.
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