Investigating the role of the eosinophil in COPD

Thesis

Now the third leading cause of death worldwide, chronic obstructive pulmonary disease (COPD) is characterised by unpredictable acute worsening of symptoms. A third of these crisis events are associated with an eosinophilic phenotype that has an unknown mechanism of injury. In this thesis, I have shown that RNA-sequencing of eosinophils isolated during exacerbations revealed upregulation of genes related to redox systems. Furthermore, eosinophils isolated during crisis events had increased capacity to produce reactive oxygen species (ROS), had a higher resting state of ROS generation, and released more mitochondrial specific ROS compared to neutrophils. Eosinophils also had comparatively low levels of the antioxidant enzyme glutathione, which appeared to be less oxidised, indicating that eosinophils have a weak ability to scavenge excess ROS. Finally, in a co-culture system, eosinophils were shown to disrupt epithelial barriers and induce hyperpermeability, which was further increased upon eosinophil stimulation. These findings would suggest that when COPD patients experience an eosinophilic exacerbation and consequently, an influx of activated eosinophils into the airways, there is damage caused to the local tissue milieu due to the release of ROS. This mechanism proposes a new therapeutic avenue at the point of an eosinophilic exacerbation. Additionally, analysis of serum and sputum samples highlighted IL-5 as a key eosinophil mediator released during eosinophilic exacerbations. Flow cytometry analysis identified the IL-3 receptor as a potential marker of eosinophil activation status.

Authors: Camp, JR

• DOI: 10.5287/ora-xovojn9kv
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: COPD; Eosinophils; ROS; Oxidative stress
• Subjects: Immunology