Date of Award

Summer 8-7-2015

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Professor Brian Harvey

Second Supervisor

Dr Valerie Urbach

Third Supervisor

Professor Paul McNally

Funder/Sponsor

National Children's Research Centre, Health Research Board of Ireland

Keywords

Pro-resolution Mediators, Cystic Fibrosis, Lung Disease

Abstract

CF is caused by a mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) and results in airway surface liquid (ASL) dehydration, impaired muco-ciliary clearance, chronic pulmonary infection and inflammation leading to progressive lung destruction. Specialized Pro-Resolution Mediators (SPM’s) such as Lipoxins and Resolvins are SPM’s involved in the active resolution of inflammation. Previous work showed that Lipoxin A4 restores airway surface liquid height in CF bronchial epithelium. Our aim was to investigate the role of SPMs, including Lipoxin A4 and Resolvin D1 in CF airway disease. We studied the physiological effects of RvD1 in CF using primary CF alveolar macrophages and polarized, differentiated Primary CF and NuLi-1, and CuFi-1 cell lines as a bronchial epithelial model. We collected bronchoalveolar lavage (BAL) samples from young children with CF and controls at clinical baseline (SHIELD CF) and sputum from school aged children during CF Pulmonary Exacerbation (CFPE) (PRINCE Study). We report that Resolvin D1 restored ASL height in Primary CF bronchial epithelia and CuFi-1 cells. Resolvin D1 attenuated TNFα induced IL8 secretion in CuFi-1 cells. Furthermore Resolvin D1 improved phagocytic capacity and bacterial killing of Pseudomonas aeruginosa in primary CF alveolar macrophages. We demonstrate an imbalance in Lipoxin A4 (LXA4) versus Leukotriene B4 (LTB4) production in CF airways, despite the absence of infection, related to a deficiency of the LXA4 synthetic enzyme 15 Lipoxygenase-2 in CF macrophages. We have demonstrated that the levels of Resolvin D2 and 15-d-Prostaglandin J2 correlate strongly with the extent of recovery of premorbid FEV1 during CF pulmonary exacerbation. We have elucidated important beneficial physiological effects of SPMs in CF airway cells, shown defective class switching in children with CF compared to controls, and demonstrated a link between sputum SPM levels and lung function recovery during acute infection in CF. Our findings shed some light on the failure 23 to resolve inflammation in CF airways and suggest strong therapeutic potential for SPMs in CF.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

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Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2015.

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