Neutrophil migration in the healthy elderly: causes and consequences for the resolution of inflammation

Greenwood, Hannah Louise (2014). Neutrophil migration in the healthy elderly: causes and consequences for the resolution of inflammation. University of Birmingham. Ph.D.

Preview

Greenwood13PhD.pdf
PDF - Accepted Version
Download (5MB)

Abstract

Neutrophils constitute the main immune defense against microbial invasion. When activated, they migrate towards the site of infection where they eliminate any foreign material in an effort to prevent wide-spread tissue damage and ultimately resolve infection. Previous work on neutrophil function in the elderly has highlighted a number of neutrophil effector functions, including phagocytosis, superoxide production and migration that exhibit decreased efficiency suggesting the potential for reduced pathogen clearance in older adults.
This thesis reveals a migratory phenotype distinctive of neutrophils isolated from healthy elderly donors (> 60 years) and characterized by a maintained speed of migration (chemokinesis) but with significantly reduced directional migration (chemotaxis) and overall migratory accuracy in response to a range of chemoattractants. This migratory phenotype was shown to be associated with a constitutive basal activation of PI3Kinase in neutrophils isolated from older donors and appears to be a causative factor as treatment of neutrophils with inhibitors selective for PI3Kinase-γ and –δ, was able to restore migratory dynamics. The ‘old-migratory’ phenotype was amenable to correction by pre-incubation with 1nM Simvastatin in vitro and a two-week prescription of 80mg/day Simvastatin in vivo in healthy older adults.
The ability of simvastatin to modulate migratory dynamics potentially provides a safe, cost effective intervention to reduce morbidity and mortality from infections in the elderly population.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):