Abstract
Neutrophil extracellular traps (NETs) are a relatively recently described form of host defence against infection in which neutrophils release webs of DNA studded with antimicrobial proteins to trap and immobilise pathogens. NETs have been implicated in multiple inflammatory diseases, including chronic airway diseases. Neutrophil inflammation is a hallmark of Chronic Obstructive Pulmonary Disease (COPD) and bronchiectasis, and there is an urgent need to develop therapies that can modulate neutrophilic inflammation without increasing the risk of infection.The primary role of neutrophils is to control infection with pathogens including bacteria. It is now well recognised that the lungs harbour diverse microbial communities that play an active role in maintaining lung health, termed the lung microbiome. COPD and bronchiectasis are associated with changes to the microbiome and increases in pathogenic bacteria. How neutrophils and NETs relate to this microbial dysbiosis has not been fully characterised.
This thesis describes a series of investigations into the role of NETs in bronchiectasis and COPD, and their relationship with the lung microbiome. We investigate the mechanisms of inflammation in patients with bronchiectasis using sputum proteomics and through several UK and international cohorts investigate the relationship between NETs disease severity, outcomes, the microbiome and response to treatments such as antibiotics. We demonstrate that NET formation is associated with disease severity, reduced lung function and mortality in bronchiectasis. Further to this, NET levels can be reduced, and patient outcomes improved, through antibiotic and macrolide therapy.
In COPD we investigate a potential therapy to modulate NET formation through a pilot randomized controlled trial of a novel CXCR2 antagonist, danirixin, using novel measures of NET formation in sputum, blood and other matrices while also investigating whether modulating neutrophilic inflammation also results in changes in the microbiome. We found that CXCR2 antagonism did not reduce NET formation or markers of neutrophilic inflammation in patients with COPD. Additionally, we identified a subset of patients for whom NET formation is independent of CXCL-8.
Finally, we investigate whether the most widely used anti-inflammatory treatment in COPD patients, inhaled corticosteroids, modulates neutrophilic inflammation and the microbiome in a multicentre UK randomized controlled trial. We investigate changes in the microbiome over time, their relationship with airway inflammation and changes at exacerbation. We found that while ICS withdrawal had no effect on upper or lower airway bacterial load, withdrawal was associated with significant changes to the microbiome including increases in Streptococcus and Rothia. By utilising rapid PCR and multiplex ELISA panels we were able to identify novel endotypes of exacerbation in COPD with distinct inflammatory profiles.
Together, this thesis represents an extensive translational research investigation into the important of neutrophil extracellular traps in chronic lung disease and the potential to modulate them with new and existing therapies.
| Date of Award | 2022 |
|---|---|
| Original language | English |
| Supervisor | James Chalmers (Supervisor) & Amelia Shoemark (Supervisor) |