Specialized pro-resolving mediators’ biosynthesis by cystic fibrosis airway epithelial cells and their impact on mucociliary clearance

Abstract

In cystic fibrosis (CF), reduced airway surface liquid (ASL) layer and impaired mucociliary clearance (MCC) lead to chronic infection and inflammation. Acute inflammation is normally followed by an active resolution phase involving specialized pro-resolving mediators (SPM) such as lipoxins (LX) and resolvins (Rv). However, abnormal LXA4 levels have been reported in CF patients’ bronchus and LXA4 and RvD1 restore the ASL height, <i>in vitro</i> (Briottet et al, 2020). Here we tested the role of CF airway epithelium in SPM’s biosynthesis.&nbsp;And&nbsp;we investigated whether these lipids had an impact on ciliary beating, mucin production and ASL. Human nasal epithelial cells (hNECs) from CF and non-CF donors were grown at air-liquid interface. SPMs were studied by mass spectrometry. Ciliary beat frequency (CBF) and synchronisation were analysed from high-speed video-microscopy&nbsp;with the multi-DDM algorithm (Chioccoli, M. et al, 2019). ASL height was measured using confocal microscopy. CF hNECs had a reduced ability to produce LXA4, LXB4, RvD5, RvE1, RvE3, and showed a decreased&nbsp;CBF and higher ciliary coordination. Secreted mucins transcription did not differ between CF and not-CF samples but, the membrane-tethered mucins MUC4 and MUC16 were significantly reduced in CF hNEC. RvD1, LXB4 and RvE1 (nM) restored CBF and reduced cilia coordination. And similarly to LXA4 and RvD1, RvE1 increased the ASL height in CF samples. Our results provided evidence for a role of CF airway epithelium in an altered biosynthesis of LXA4, LXB4, RvD5, RvE1 and RvE3 and that LXB4, RvD1 and RvE1 restored main epithelial functions involved in the defective MCC of CF airway.