Neutrophil phenotypes and accelerated ageing as a cause of disease pathogenesis, progression and multi-morbidity in chronic obstructive pulmonary disease

Hughes, Michael James ORCID: 0000-0002-5793-415X (2021). Neutrophil phenotypes and accelerated ageing as a cause of disease pathogenesis, progression and multi-morbidity in chronic obstructive pulmonary disease. University of Birmingham. Ph.D.

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Abstract

Chronic Obstructive Pulmonary Disease (COPD) remains one of the leading causes of mortality globally and places a high burden on patient quality of life. Neutrophils have been linked to multiple facets of disease pathology and are abundant in lung secretions of patients with COPD. However, recurrent infection and the lack of inflammatory resolution in COPD suggest neutrophil dysfunction. In addition, these patients also commonly present with other chronic diseases, termed multimorbidity, such as diabetes and cardiovascular disease and changes in circulating neutrophils may provide a link between these diseases.
This thesis aimed to investigate changes in peripheral neutrophil phenotype in healthy ageing and COPD, with a focus on how multimorbidity may influence these changes. Systemic neutrophil activation, senescence and maturity status appeared unaltered in stable COPD compared to healthy controls and did not suggest an accelerated ageing phenotype. However, expression of a key chemokine receptor, CXCR2, was shown to be reduced and impacted by the presence of multimorbidity in these patients and further reduced during exacerbations. Multiple changes in both surface and gene expression were also seen during an exacerbation, suggesting the neutrophil phenotype can be altered by both chronic and acute inflammation.
In addition, an activated phenotype was observed when neutrophils from healthy individuals were incubated with plasma from patients with COPD, suggesting systemic inflammation in patients with COPD was present and was able to activate neutrophils, further highlighting changes in the neutrophil phenotype due to chronic disease.
Differences in the neutrophil phenotype described here demonstrate the heterogeneity of neutrophils, as well as the different impact caused by multimorbidity. Altered phenotypes suggest a change in function, providing further understanding to the role of neutrophils in COPD.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):