Date of Award
PhD (Doctor of Philosophy)
Professor Brian Harvey
Professor Richard Costello
Cystic Fibrosis, Therapy
The thesis reports novel findings on the role of LXA4 in inodulating the airway surface liquid (ASL) layer height and in particular expanding the deficient ASL observed in CF as a novel means to augmenting existing therapy. Lipoxin A4 (LXA4) is produced at inflammatory sites, and exerts antiinflammatoiy effects and has been reported to be reduced in cystic fibrosis (CF) airways. The altered Cl- secretion and Na+ hyperabsorption in CF affects the ASL height and leads to a defective mucociliary clearance, chronic infection, inflammation and progressive lung destruction. The role of LXA4 in modulating ion transport and ASL height in CF and non-CF airway epithelia was investigated. CF (CuFi-1) and non-CF (NuLi-1) bronchial epithelial cell lines were grown into well-differentiated epithelia. LXA4 effects were explored using laser confocal inicroscopy to measure ASL height, short-circuit current to investigate ion transporters activity, and ATP assay to measure ATP release at the apical side of CF epithelia. LXA4 (1 nM) treatment for 15 minutes, increased ASL height in Nuli-1 and CuFi-1 epithelia. The stimulatory effect of LXA4 on ASL height was inhibited by the LXA4 receptor FPR2/ALX inhibitor, boc-2; in addition to bumetanide, reactive blue and extracellular hexolinase, while amiloride was showed an additive effect to LXA4. LXA4 was activated Cl- secretion and inhibited Na+ absorption in the CF epithelia. In addition, LXA4 stimulated an apical Boc-2 sensitive release of ATP in CF epithelia. This thesis provides evidence for a novel effect of LXA4 involving the FPR2/ALX receptor, apical ATP release and purinoreceptor activation, inhibition of Na+ absorption and stimulation of Cl+ secretion in CF and non-CF epithelia to finally increase ASL height. These effects open up a new therapeutic avenue in the treatment of CF.
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Al-Alawi M. The role of lipoxin A4 in regulating ion transport and airway surface liquid dynamics in cystic fibrosis bronchial epithelium [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2010