Neutrophil migration and inflammation in chronic obstructive pulmonary disease

Stockley, James (2015). Neutrophil migration and inflammation in chronic obstructive pulmonary disease. University of Birmingham. Ph.D.

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Abstract

COPD is a leading cause of morbidity and mortality worldwide and it is believed that the neutrophil is key to the pathology. Evidence to date suggests that neutrophils migrate less accurately in patients with COPD, although the precise mechanisms by which this occurs have not been defined.
We have shown that COPD neutrophils migrate faster (chemokinesis) but less accurately (chemotaxis) in various chemokine gradients. It appears to be an intrinsic cell defect, as incubation of healthy neutrophils in COPD plasma did not alter migratory dynamics. This phenomenon does not occur in other respiratory diseases and is unrelated to age, disease severity, smoking status or the presence of emphysema. Furthermore, there were no differences in markers of neutrophil activation or maturity, although degranulation markers were higher in COPD.
Expression of certain chemokine receptors was lower on quiescent COPD neutrophils, but these differences were abolished after stimulation. Receptors localised to the leading edge effectively in COPD neutrophils and there were no differences in receptor shedding. PI3K phosphorylation was increased in COPD and inhibition of γ and δ isoforms improved chemotaxis. Neither Akt phosphorylation nor intracellular calcium signalling was altered. Simvastatin also improved chemotaxis of COPD neutrophils but CXCR1/2 inhibitors did not.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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