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.

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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.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: School of Immunity and Infection
Funders: None/not applicable
Subjects: R Medicine > R Medicine (General)


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