Date of Award
PhD (Doctor of Philosophy)
Dr Emer Reeves
Professor Noel G. McElvaney
This project was funded by SFI 11/RFP/BMT/3094
Cystic Fibrosis, Alpha 1-Antitrypsin Deficiency, Neutrophil Elastase
Cystic fibrosis (CF) is an inherited disorder characterised by chronic neutrophil recruitment and dysregulated neutrophil dominated inflammation. Lipid rafts are specialised dynamic signaling domains found within the plasma membrane of neutrophils. Cholesterol, a major structural component of lipid rafts, maintains optimum membrane fluidity, lipid raft structure and cell function. In addition, lipid rafts play an important role in neutrophil migration and cell adhesion. In order to understand the mechanism leading to excessive mobilisation of neutrophils into the lungs of patients with CF, the aim of this study was 3-fold. Firstly, to investigate alterations of neutrophil lipid raft structure in relation to cholesterol content in CF neutrophils. Secondly, to examine the effect of chronic inflammation on endoplasmic reticulum (ER) stress related structural changes of circulating neutrophils in adults with CF. Thirdly, to explore whether the ion channel potentiator ivacaftor functions to reduce circulating inflammatory mediators thereby correcting impaired neutrophil function.
Alpha-1 antitrypsin (AAT) deficiency (AATD) is an inherited disorder characterised by sustained neutrophil migration into the airways. As a result of an imbalance between AAT and neutrophil elastase (NE), an abundance of NE is present within the lungs, resulting in airways disease. Dysregulated neutrophil activity has also been reported in AATD. Therefore we assessed whether altered neutrophil function in AATD is a result of reduced plasma membrane cholesterol. Furthermore, we confirmed that AAT augmentation therapy results in normalising neutrophil membrane structure and function in patients with AATD.
In summary, this study establishes a role for plasma membrane cholesterol in maintaining neutrophil structure, which facilitates in neutrophil adhesion, using two distinct airway diseases and two separate treatments. Ultimately, this study has expanded our knowledge on dysregulated neutrophil function in both CF and AATD
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White MW. Altered membrane lipid raft structure: A potential factor leading to dysregulated neutrophil activity in airways disease [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2015.
Available for download on Friday, June 01, 2018