The role of lipoxin A4 in regulating ion transport and airway surface liquid dynamics in cystic fibrosis bronchial epithelium Mazen Al-Alawi 10.25419/rcsi.10804478.v1 https://repository.rcsi.com/articles/thesis/The_role_of_lipoxin_A4_in_regulating_ion_transport_and_airway_surface_liquid_dynamics_in_cystic_fibrosis_bronchial_epithelium/10804478 <p>The thesis reports novel findings on the role of LXA<sub>4</sub> 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 A<sub>4</sub> (LXA<sub>4</sub>) is produced at inflammatory sites, and exerts antiinflammatoiy effects and has been reported to be reduced in cystic fibrosis (CF) airways. The altered Cl<sup>-</sup> secretion and Na<sup>+</sup> hyperabsorption in CF affects the ASL height and leads to a defective mucociliary clearance, chronic infection, inflammation and progressive lung destruction. The role of LXA<sub>4</sub> 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. LXA<sub>4</sub> 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. LXA<sub>4</sub> (1 nM) treatment for 15 minutes, increased ASL height in Nuli-1 and CuFi-1 epithelia. The stimulatory effect of LXA<sub>4</sub> on ASL height was inhibited by the LXA<sub>4</sub> receptor FPR2/ALX inhibitor, boc-2; in addition to bumetanide, reactive blue and extracellular hexolinase, while amiloride was showed an additive effect to LXA<sub>4</sub>. LXA<sub>4</sub> was activated Cl<sup>-</sup> secretion and inhibited Na<sup>+</sup> absorption in the CF epithelia. In addition, LXA<sub>4</sub> stimulated an apical Boc-2 sensitive release of ATP in CF epithelia. This thesis provides evidence for a novel effect of LXA<sub>4</sub> involving the FPR2/ALX receptor, apical ATP release and purinoreceptor activation, inhibition of Na<sup>+</sup> absorption and stimulation of Cl<sup>+</sup> 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.</p> 2019-11-22 17:45:24 Cystic Fibrosis Therapy