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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:589702 |
| Date | January 2014 |
| Creators | Greenwood, Hannah Louise |
| Publisher | University of Birmingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://etheses.bham.ac.uk//id/eprint/4793/ |
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