Details

Autor(en) / Beteiligte

• Caballero, Ignacio
• Ringot-Destrez, Bélinda
• Si-Tahar, Mustapha
• Barbry, Pascal
• Guillon, Antoine
• Lantier, Isabelle
• Berri, Mustapha
• Chevaleyre, Claire
• Fleurot, Isabelle
• Barc, Céline
• Ramphal, Reuben
• Pons, Nicolas
• Paquet, Agnès
• Lebrigand, Kévin
• Baron, Carole
• Bähr, Andrea
• Klymiuk, Nikolai
• Léonard, Renaud
• Robbe-Masselot, Catherine

Titel

Evidence of early increased sialylation of airway mucins and defective mucociliary clearance in CFTR-deficient piglets

Ist Teil von

• Journal of cystic fibrosis, 2021-01, Vol.20 (1), p.173-182

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2021

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• •CFTR-deficient pigs present increased lung mucin sialylation at birth in the absence of inflammation.•Increased mucin sialylation is linked to increased pseudomonas aeruginosa adhesion to mucins.•CF pigs also present a mucociliary clearance defect, in the absence of inflammation, which may contribute bacterial colonization and development of early lung disease. These defects seems to be linked to the absence of CFTR functionality since they are independent of an inflammatory environment in the lungs. Bacterial colonization in cystic fibrosis (CF) lungs has been directly associated to the loss of CFTR function, and/or secondarily linked to repetitive cycles of chronic inflammation/infection. We hypothesized that altered molecular properties of mucins could contribute to this process. Newborn CFTR+/+ and CFTR−/− were sacrificed before and 6 h after inoculation with luminescent Pseudomonas aeruginosa into the tracheal carina. Tracheal mucosa and the bronchoalveolar lavage (BAL) fluid were collected to determine the level of mucin O-glycosylation, bacteria binding to mucins and the airways transcriptome. Disturbances in mucociliary transport were determined by ex-vivo imaging of luminescent Pseudomonas aeruginosa. We provide evidence of an increased sialylation of CF airway mucins and impaired mucociliary transport that occur before the onset of inflammation. Hypersialylation of mucins was reproduced on tracheal explants from non CF animals treated with GlyH101, an inhibitor of CFTR channel activity, indicating a causal relationship between the absence of CFTR expression and the sialylation of mucins. This increased sialylation was correlated to an increased adherence of P. aeruginosa to mucins. In vivo infection of newborn CF piglets by live luminescent P. aeruginosa demonstrated an impairment of mucociliary transport of this bacterium, with no evidence of pre-existing inflammation. Our results document for the first time in a well-defined CF animal model modifications that affect the O-glycan chains of mucins. These alterations precede infection and inflammation of airway tissues, and provide a favorable context for microbial development in CF lung that hallmarks this disease.