Ineffective correction correction of PPAR-γ signaling in cystic fibrosis airway epithelial cells undergoing repair

Peroxisome proliferator-activated receptor gamma (PPAR gamma) represents a potential target to treat airway mucus hypersecretion in cystic fibrosis (CF). We aimed to determine if PPAR gamma is altered in CF human airway epithelial cells (HAECs), if PPAR gamma contributes to mucin expression and HAEC differentiation, and if PPAR gamma ligand therapy corrects the CF phenotype. To this end, well-differentiated CF and NCF HAEC primary cultures were wounded to monitor the expression of key genes involved in PPAR gamma activation and mucus homeostasis, and to evaluate the effect of a PPAR gamma agonist, at different times of repair. Hydroxyprostaglandin dehydrogenase (HPGD) converts prostaglandin E2 to 15-keto PGE2 (15kPGE2), an endogenous PPAR gamma ligand. Interestingly, PPAR gamma and HPGD expression dramatically decreased in CF HAECs. These changes were accompanied by an increase in the expression of MUC5B. The correlation between PPAR gamma and MUC5B was confirmed in an airway epithelial cell line after CFTR knock-down. Exposure of HAECs to 15kPGE2 did not correct the CF phenotype but revealed a defect in the process of basal cell (BC) differentiation. The HPGD/PPAR gamma axis is deregulated in primary HAEC cultures from CF patients, which may impact the maturation of BCs to differentiated luminal cells. Importantly, PPAR-gamma therapy was inefficient in correcting the CF defect. (C) 2016 Elsevier Ltd. All rights reserved.